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

Lipid mediators in the prevention and therapy of neuroblastoma

Neuroblastoma is a cancer of the nervous system that mainly affects infants and young children. It is the most common solid extracranial tumor of childhood, and accounts for almost 10% of all childhood cancer deaths. Despite intense multimodal treatment consisting of surgery, chemotherapy, radiotherapy, and stem cell rescue, survival is only 50% in the high-risk group, and the overall survival is around 70%. We therefore need to improve existing treatment protocols and search for new medications. Inflammation drives cancer growth and targeted therapy that dampens inflammatory responses is anti-proliferative. We have previously shown that the inducible COX-2 enzyme that converts the omega-6 fatty acid arachidonic acid (AA) to various inflammatory prostaglandins is upregulated in neuroblastoma tissue. We have also shown that celecoxib, a selective inhibitor of COX-2, may inhibit neuroblastoma growth. This thesis shows that celecoxib both prevents tumor formation and reduces tumor growth in a neuroblastoma xenograft rat model. In addition, celecoxib enhances the effect of the chemotherapeutic drugs irinotecan and doxorubicin. By immunohistochemistry, we detected reduced proliferation and inhibited angiogenesis in tumors from animals treated with celecoxib, either by gavage or by an enriched diet. Omega-3 fatty acids oppose the effects of omega-6 fatty acids such as AA and have been implicated in cancer treatment and prevention. Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are precursors of anti-inflammatory compounds. From EPA, a different series of prostaglandins are produced, and from DHA, resolvins and protectins are produced, which are potent pro-resolving lipid mediators essential for the clearance of inflammatory cells and mediators at an injured site. In this thesis I show that DHA is toxic to neuroblastoma cells both in vivo and in vitro. In vivo, DHA is able to delay time to tumor development and reduce tumor growth in neuroblastoma xenograft models. In vitro, DHA acts by inducing mitochondrial-dependent apoptosis. We also show that neuroblastoma cells convert DHA to hydroperoxy and hydroxy fatty acids through both enzymatic and non-enzymatic mechanisms. However, DHA is not converted to resolvins or protectins in neuroblastoma cells. DHA also potentiates the effect of other cytotoxic drugs such as chemotherapeutics, arsenic trioxide, and non-steroidal anti-inflammatory drugs (NSAIDs). In summary, this thesis shows that inhibiting the omega-6 fatty acid pathway and enhancing the omega-3 fatty acid pathway are both possible new strategies for neuroblastoma treatment, and suggests these compounds to be tested as novel therapy for children with neuroblastoma in clinical trials

Den lille byggherren – The underdog

This paper aims to describe how a small developer can survive in a market dominated by a few large developers. Plan monopoly gives municipalities’ absolute right to control land use. This often results in lowered prioritizing of innovation and new thinking, in favor of larger projects which are characterized by monotonous design. We have investigated how municipalities in the Stockholm area perceive smaller developers by performing interviews with several development managers. We have investigated what factors that plays a role when a developer wants to make his entrance into the market. Is the background just a complicated law to interpret, or is there any area where the municipalities can further assist small unproven developers? We have also interviewed some developers to understand what the reality looks like from their perspective. We will describe the problems they face and how they do when they compete against larger players. We have found that due to the fact that municipalities are bound to certain laws and regulations, they can’t adjust these to fit the small developer. They can however choose to divide the land area into smaller sizes which makes it possible for smaller developer to buy them. Another intriguing conclusion drawn from this study is that small developers tend to organize themselves into groups with other developers with similar size and condition. By joining together they become stronger financially and more competitive against larger developers, and hence get better options of buying land from the municipalities.Denna uppsats har till syfte att redogöra för hur en liten byggherre kan överleva på en marknad som domineras av ett fåtal stora aktörer. Planmonopolet ger kommunerna absolut rätt att bestämma över markanvändningen. Detta resulterar allt för ofta i att innovation och nytänkande bortprioriteras till förmån för stora projekt präglade av monoton utformning. Vi har undersökt hur kommuner kring Stockholms stad ser på de små byggherrarna genom att utföra intervjuer med exploateringskontoren där vi går in på vilka faktorer som spelar roll när en mindre aktör vill göra entré på marknaden. Är bakgrunden bara en krånglig lagstiftning eller finns det utrymme från kommunernas sida att ytterligare underlätta för små obeprövade aktörer. Vi har även intervjuat några byggherrar för att förstå hur verkligheten ser ut ur deras perspektiv. Vi kommer beskriva de problem de möter samt hur de går tillväga när de tävlar mot större aktörer. Vi har funnit att på grund av det faktum att kommunerna är bundna till vissa lagar och regler, kan dessa inte justeras för att passa små byggherrar. Något som kommunerna kan tänka sig att göra är att dela upp landområdet i mindre storlekar, vilket gör det möjligt för mindre aktörer att köpa dem. En annan intressant slutsats från denna studie är att små byggherrar tenderar att organisera sig i grupper med andra byggherrar med liknande storlek och förutsättningar. Genom att gå samman blir de starkare ekonomiskt och mer konkurrenskraftigt gentemot större utvecklare, och därmed få bättre möjligheter att köpa mark från kommunerna

Den lille byggherren – The underdog

This paper aims to describe how a small developer can survive in a market dominated by a few large developers. Plan monopoly gives municipalities’ absolute right to control land use. This often results in lowered prioritizing of innovation and new thinking, in favor of larger projects which are characterized by monotonous design. We have investigated how municipalities in the Stockholm area perceive smaller developers by performing interviews with several development managers. We have investigated what factors that plays a role when a developer wants to make his entrance into the market. Is the background just a complicated law to interpret, or is there any area where the municipalities can further assist small unproven developers? We have also interviewed some developers to understand what the reality looks like from their perspective. We will describe the problems they face and how they do when they compete against larger players. We have found that due to the fact that municipalities are bound to certain laws and regulations, they can’t adjust these to fit the small developer. They can however choose to divide the land area into smaller sizes which makes it possible for smaller developer to buy them. Another intriguing conclusion drawn from this study is that small developers tend to organize themselves into groups with other developers with similar size and condition. By joining together they become stronger financially and more competitive against larger developers, and hence get better options of buying land from the municipalities.Denna uppsats har till syfte att redogöra för hur en liten byggherre kan överleva på en marknad som domineras av ett fåtal stora aktörer. Planmonopolet ger kommunerna absolut rätt att bestämma över markanvändningen. Detta resulterar allt för ofta i att innovation och nytänkande bortprioriteras till förmån för stora projekt präglade av monoton utformning. Vi har undersökt hur kommuner kring Stockholms stad ser på de små byggherrarna genom att utföra intervjuer med exploateringskontoren där vi går in på vilka faktorer som spelar roll när en mindre aktör vill göra entré på marknaden. Är bakgrunden bara en krånglig lagstiftning eller finns det utrymme från kommunernas sida att ytterligare underlätta för små obeprövade aktörer. Vi har även intervjuat några byggherrar för att förstå hur verkligheten ser ut ur deras perspektiv. Vi kommer beskriva de problem de möter samt hur de går tillväga när de tävlar mot större aktörer. Vi har funnit att på grund av det faktum att kommunerna är bundna till vissa lagar och regler, kan dessa inte justeras för att passa små byggherrar. Något som kommunerna kan tänka sig att göra är att dela upp landområdet i mindre storlekar, vilket gör det möjligt för mindre aktörer att köpa dem. En annan intressant slutsats från denna studie är att små byggherrar tenderar att organisera sig i grupper med andra byggherrar med liknande storlek och förutsättningar. Genom att gå samman blir de starkare ekonomiskt och mer konkurrenskraftigt gentemot större utvecklare, och därmed få bättre möjligheter att köpa mark från kommunerna

It's not just a knee, but a whole life : A qualitative descriptive study on patients' experiences of living with knee osteoarthritis and their expectations for knee arthroplasty.

AIM: Knee arthroplasties are an increasingly common treatment for osteoarthritis (OA) and the main indication is pain. Previous research states, however, that 15-20% of the operated patients are dissatisfied and 20-30% have persistent pain after surgery. This study is aimed at describing patients' experiences of living with knee OA when scheduled for surgery and further their expectations for future life after surgery. METHODS: We interviewed 12 patients with knee OA scheduled for arthroplasty, using semi-structured qualitative interviews. The interviews were recorded and transcribed verbatim and analyzed using qualitative thematic analysis. FINDINGS: Three categories were formulated with an overriding theme: "It's not just a knee, but a whole life." The three categories were "Change from their earlier lives," "Coping with knee problems," and "Ultimate decision to undergo surgery." The main finding was that knee OA affects the whole body and self, ultimately affecting the patients' lives on many levels. Further findings were that knee OA was considered to be the central focus in the participants' lives, which limited their level of activity, their ability to function as desired, their quality of life, and their mental well-being. Although surgery was considered to be the only solution, the expectations regarding the outcome differed. CONCLUSIONS: The participants were forced to change how they previously had lived their lives resulting in a feeling of loss. Thus, the experienced loss and expectations for future life must be put into the context of the individual's own personality and be taken into account when treating individuals with knee OA. The experience of living with knee OA largely varies between individuals. This mandates that patients' assessment should be considered on individual basis with regard to each patient

Meanings of being a close relative of a family member treated with haemodialysis

AIMS AND OBJECTIVES: To describe and elucidate the meanings of being a close relative of a severely ill family member treated with maintenance haemodialysis approaching the end of life. BACKGROUND: End-stage renal disease together with comorbidities, haemodialysis treatment and high mortality rates also affects the lives of close relatives, who report burdens and impaired quality of life. To improve care, more understanding is needed of close relatives' experiences during these patients' end of life. DESIGN: This study has a qualitative interpretative design. METHODS: Fourteen retrospective qualitative interviews were conducted with close relatives (aged 48-93 years) of deceased patients who had been treated with haemodialysis. The interview text was interpreted using a phenomenological hermeneutical method in three phases. RESULTS: The findings of the structural analysis were formulated as six themes: Striving to be supportive and helpful without doing harm to the ill person's self; Needing increasing strength and support; Balancing the will to help with one's own ongoing life; Increasing responsibility involving dilemmas; Striving for a good life together in the present and Living with awareness of death. CONCLUSIONS: Close relatives strive for balance and well-being accompanying their ill family member through the end of life. They are facing moral dilemmas and growing demands as their responsibility increases with the deterioration of their family member. Support from and interaction with the healthcare professionals is then of significance. RELEVANCE TO CLINICAL PRACTICE: Findings challenge healthcare professionals in haemodialysis settings to identify close relatives' individual resources and needs towards the patients' end of life. Healthcare professionals in haemodialysis settings need to offer close relatives opportunities to talk about the future and what may be expected at end of life, with or without haemodialysis. They should also contact the closest relative after the death as they may need confirmation and closure