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- Israelsson, Pernilla, et al.
(författare)
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Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary
- 2019
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Ingår i: International Journal of Gynecological Cancer. - : BMJ Publishing Group Ltd. - 1048-891X .- 1525-1438. ; 29, s. A138-A138
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Background Tumor establishment, metastatic spreading and poor survival in ovarian cancer is strongly associated with progressive derangement of the patient‘s immune system. Accumulating evidence suggests that immune impairment is influenced by the production and presence of cytokines in the tumor microenvironment.Methodology Cytokine mRNA profiles in tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed in patients with high grade serous carcinoma (HGSC) of the ovary and compared it to patients with benign ovarian conditions and controls with normal ovaries. Cytokine assessment was done by real-time quantitative RT-PCR and specific primers and probes for 12 cytokines-IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, TNF-β/LTA, TGF-β1, and GM-CSF chosen to distinguish between cytotoxic Th1, humoral Th2, regulatory Th3/Tr1 and inflammatory responses.Results The cytokine mRNA response in the HGSC patients was significantly up regulated compared to patients with benign ovarian conditions and normal ovary controls confirming the immunogenicity of HGSC and implying immune recognition and reaction locally in the tumor microenvironment and systemically in the peripheral blood.There was an up-regulation of inflammatory and inhibitory cytokine mRNA promoting tumor progression, T-regulatory cell priming and T-regulatory cell-mediated immune suppression. In contrast, there was an inability to mount the crucially important IFN gamma response needed for upregulation of the cytotoxic anti-tumor response in the local microenvironment. In addition, systemic IL-4- mediated Th2 response prevailed in the peripheral blood deviating the systemic defense towards humoral immunity.Conclusion Taken together, these results suggest local and systemic cytokine cooperation promoting tumor survival, progression and immune escape. Our study confirms and extends previous investigations and contributes to the evaluation of potential cytokine candidates for diagnostic cytokine mRNA profiles and for future therapeutic interventions based on cytokine inhibition.
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- Andersson, Charlotta, 1976-
(författare)
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Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Wilms’ tumor gene 1 (WT1) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally WT1 was described as a tumor suppressor gene, but later studies have shown oncogenic properties of WT1 in a variety of tumors. Because of its dual functions in tumorigenesis, WT1 has been described as a chameleon gene. In this thesis, the significance of WT1 as a biomarker was investigated in acute myeloid leukemia (AML), clear cell renal cell carcinoma (ccRCC), ovarian carcinoma (OC) and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).Previous studies have suggested that expression of WT1 is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of WT1 as an MRD marker in AML. In adult AML patients, we found that a reduction of WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis was associated with an improved overall survival (OS) and freedom from relapse (FFR). In peripheral blood, a reduction of WT1 expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR.WT1 harbor pathogenic genetic variants in a considerable proportion of AML and T-lymphoblastic leukemia (T-ALL), but mutations have not been reported in BCP-ALL. We aimed to evaluate the clinical impact of WT1 mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the WT1 gene were rarely seen in childhood BCP-ALL. However, five WT1 SNPs were identified. In survival analyses, WT1 SNP rs1799925 was found to be associated with worse OS, indicating that WT1 SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether WT1 mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in WT1 were associated with WT1 expression and clinical outcome. Sequencing analysis revealed that none of the previously reported WT1 mutations were found in ccRCC; however, we identified six different WT1 SNPs. Our data suggest that pathogenic WT1 mutations are not involved in ccRCC, and the prognostic significance of WT1 SNPs in ccRCC is considerably weak. However, a favorable OS and disease-specific survival were found in the few cases harboring the homozygous minor allele.OC has a poor prognosis, and early effective screening markers are lacking. Serous OCs are known to express the WT1 protein. Overexpressed oncogenic proteins can be considered potential candidate antigens for cancer vaccines and T-cell therapy. It was therefore of great interest to investigate whether anti-WT1 IgG antibody (Ab) measurements in plasma could serve as biomarkers of anti-OC response. We found limited prognostic impact, but the results indicated that anti-WT1 IgG Ab measurements in plasma and WT1 staining in tissue specimens could be potential biomarkers for patient outcome in the high-risk subtypes of OCs.In conclusion, the results of this thesis indicate that WT1 gene expression can provide information about MRD of patients with AML, and WT1 SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of WT1 SNPs is weak and limited to the subgroup of patients that are homozygous for the minor allele. In OCs anti-WT1 IgG Ab measurement in plasma and WT1 staining in tissue specimens could possibly be used as biomarkers for predicting patient outcome in the high-risk subtypes of OCs.
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- Berglund, Leo, 1986-
(författare)
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Kritiskt tänkande som utbildningsmål : Från modernistisk filosofi till policy för högre utbildning
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The goal of critical thinking in higher education is paradoxical, since it implies a form of education that both directs the student towards a pre-defined goal, and commands the student to be autonomous. This paradox is studied in four contexts, as to investigate what pedagogical contradictions the goal of critical thinking generates, and how they transform pedagogical thinking. 1) In the 1930s, European logical positivists cooperated with American pragmatists to "unify science". For Dewey, the realisation of this ideal depended on individuals adopting a "scientific attitude", which could be cultivated in schools and universities. Dewey’s position influenced a pedagogical discourse of critical thinking as the spirit of rational and democratic citizenship. 2) In the 1980s, the Critical Thinking Movement (CTM) addressed the issue on how to make logical thinking applicable in everyday life. Understanding critical thinking as individuals’ problem-solving skills, the CTM essentially inverted the collectivist political orientation of Dewey and the neo-positivists. 3) In the Swedish 1968 governmental investigation of higher education (U 68), a sociologically informed conception of critical thinking, that involved the student in the project of social planning, was promoted. However, educational experts perceived critical thinking as a vague goal, which could not be operationalised. In the 1990s, critical thinking reappeared as part of the doctrine of learning, but only as a generic term used to signify advanced cognitive operations in relation to different subject matters. 4) In contemporary courses in critical thinking held at Swedish universities, radically diverse conceptions are being taught. An analysis of three courses identified three subjectivities "called" by the arrangements and bodies of literature in the courses: the critical thinker as reason, intellect, and moral consciousness. Each of the subjectivities, however, comprises inconsistencies and contradictions, since they are all to be both produced by and autonomous from the orders that the educational institution represents. The dissertation is concluded by a discussion on critical thinking as both a goal and a by-product of education.
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- Brorström-Lundén, Eva, et al.
(författare)
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Dioxins in atmospheric deposition: comparison of samplers
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Persistent organic pollutants (POPs) such as polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs /PCDFs) have great potential for atmospheric long-range transport and deposition. The atmosphere is an important pathway for these contaminants to both aquatic and terrestrial environments. The Swedish national monitoring program for organic contaminants in air and precipitation includes, except PCDD/PCDFs, a large number of different substances/group of substances which differ in chemical and physical properties which not only affect their behaviour in the atmosphere and the deposition process but also the requirements on sampling methods used. This leads to great demands on the type of deposition sampler to be used in a monitoring program where the aim is to monitor several different organic substances and compromises are necessary when choosing sampler type.The overall aim of this study is to compare two different types of deposition samplers for sampling of PCDDs/PCDFs. These two samplers, the IVL-sampler and the MONAS sampler, have quite different sampling characteristics. In addition, brominated dioxins/furans were included in the measurements in order to get an idea of their occurrence in deposition at the Swedish west coast.The sampling program lasted for one year with 4 sampling periods with a sampling duration of 3 months. This gives results showing seasonal variation and the opportunity to estimate the annual deposition.The overall results from this study show that:• Differences in measured deposition fluxes were found between the two samplers with a variation in magnitude between different sampling occasions. A greater amount of dioxins/furans in deposition was measured with the MONAS sampler at three out of the four periods.• The annual dioxin/furan deposition was about 25 % higher with the MONAS sampler compared to the IVL sampler, when LOD (limit of detection) was replaced with zero for all non-detected congeners in the sum of the congeners.•The results from the sampling comparison for the two samplers gave a difference of 25%on annual basis which should be assessed in relation to the given analytical uncertainty which was +/-29% for all samples.The results found here are in agreement with other comparison studies when deposition samplers with different sampling characteristics were used (Brorström-Lundén, 1995). From this and other studies we can conclude that sampling of dioxins/furans as well as for other POPs gives different deposition fluxes when using samplers with different sampling characteristics. The collection efficiency differs not only among e.g. different congeners but also between sampling occasions which differ in ambient conditions such as amounts of precipitation, ambient air temperature and atmospheric particle concentrations. The choice of the type of deposition sampler to be used must therefore depend on the purpose of the measurements and the results should be discussed in relation to the sampling methods.
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