| 1. |
- Norberg, Maria, 1976-
(författare)
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In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups. In paper I-II, the in vitro activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil. An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect. In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells. A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers. In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C>A polymorphism does not appear to have any prognostic significance.
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| 2. |
- Brorsson, Anna Lena, 1964-, et al.
(författare)
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A person-centered education for adolescents with type 1 diabetes - a randomized controlled trial
- 2019
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 20:7, s. 986-996
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Young people with type 1 diabetes and their parents need to receive person-centred education to be able to manage their diabetes. Guided Self-Determination-Young (GSD-Y) is a person-centred communication and reflection education model that can be used in educational programmes for young people with type 1 diabetes.OBJECTIVE: To evaluate whether GSD-Y leads to improved glycaemic control, increased self-perceived health and health-related quality of life, fewer diabetes-related family conflicts, and improved self-efficacy in a group-based intervention for adolescents starting continuous subcutaneous insulin infusion (CSII) and their parents.METHODS: This randomized controlled trial included 71 adolescents starting CSII. Participants were followed for twelve months. The intervention group (n=37) attended seven group training sessions over a period of five months, using the GSD-Y model, the control group received standard care. Variables evaluated were HbA1c, self-perceived health, health-related quality of life, family conflicts, self-efficacy, and usage of continuous glucose monitoring.RESULTS: When adjusted for sex and family conflicts, there was a difference in glycaemic control between the groups at twelve months, favouring the intervention group (62 vs. 70 mmol/mol, p=0.009). When analyses were performed on boys and girls separately and adjusted for family conflicts, the only difference detected was for boys after twelve months (p=0.019). The intervention showed no effect on self-perceived health, health-related related quality of life, family conflicts, or self-efficacy.CONCLUSIONS: An intervention with GSD-Y may have an effect on glycaemic control. The content of the GSD-Y groups may serve as a model for person-centred care in adolescents with type 1 diabetes. This article is protected by copyright. All rights reserved.
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| 3. |
- Andersson, Johanna, 1990-, et al.
(författare)
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Depressive symptoms, functional impairment, and health-related quality of life in idiopathic normal pressure hydrocephalus : a population-based study
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background:Maximising quality of life is a central goal for all healthcare, especially when dealing with dementing disorders. In this study we aimed to compare health-related quality of life (HRQoL), depressive symptoms and functional impairment between individuals with and without idiopathic normal pressure hydrocephalus (iNPH) from the general population.Methods: A total of 122 individuals, 30 with iNPH (median age 75 years, 67 females) underwent neurological examinations and computed tomography of the brain with standardised rating of imaging findings and clinical symptoms. The participants completed the Geriatric Depression Scale (GDS-15) and the HRQoL instrument EQ5D-5L. In addition, the modified Rankin Scale (mRS) was used to evaluate functional impairment.Results: Compared with participants without iNPH, those with iNPH reported a higher score on GDS-15 (median 3 vs 1) and mRS (median 2 vs 1) (p < 0.05). Further, those with iNPH rated lower on EQ5D-5L (index 0.79, VAS 70) than those without iNPH (index 0.86, VAS 80) (p < 0.05). In logistic regression models, low HRQoL was associated with more depressive symptoms, a higher degree of iNPH symptoms, and lower functional status.Conclusions: In this population-based sample, those with iNPH had more depressive symptoms, lower functional status, and worse quality of life compared to those without iNPH. The strongest association with low HRQoL was found for depressive symptoms, functional level, and degree of iNPH symptoms. These results underline the value of shunt surgery because of its potential to reduce symptoms and disability in iNPH and therefore improve HRQoL.
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| 4. |
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| 5. |
- Andersson Norlén, Elina, et al.
(författare)
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Blood cultures with one venipuncture instead of two : a prospective clinical comparative single-center study including patients in the ICU, haematology, and infectious diseases departments
- 2023
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 55:9, s. 591-598
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Blood culture is a key method for diagnosing bloodstream infections. In this prospective study, we aimed to investigate whether blood cultures collected with the one-puncture method results in fewer contaminants, i.e. microorganisms from the skin or the environment, and the same detection of relevant pathogens compared to the two-puncture method. Further, we aimed to investigate if the time to blood culture positivity could be useful in evaluating contaminants.Methods: Patients planned for blood cultures were asked to participate in the study. From each recruited patient, six blood culture bottles were drawn, bottles 1–4 from the first venipuncture and bottles 5–6 from the second venipuncture. Within each patient, bottles 1–4 were compared to bottles 1, 2, 5, and 6 for contaminants and relevant pathogens. A sub-analysis was conducted on patients admitted to the ICU and those in the haematology department. We also assessed time-to-positivity for coagulase-negative staphylococci.Results: In the final analysis, 337 episodes from 312 patients were included. Relevant pathogens were identified in 62/337 (18.4%) episodes in both methods. Contaminants were detected in 12 (3.6%) and 19 episodes (5.6%) using the one-puncture and two-puncture method (p =.039), respectively. Corresponding results were observed in the sub-analysis. Notably, relevant coagulase-negative staphylococci demonstrated a shorter time-to-positivity compared to contaminant coagulase-negative staphylococci.Conclusion: Blood cultures obtained using the one-puncture method resulted in significantly fewer contaminants and detected relevant pathogens equally to the two-puncture method. Time-to-positivity may be a useful additive indicator for predicting coagulase-negative staphylococci contamination in blood cultures.
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| 6. |
- Dunder, Linda
(författare)
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Exposure to Bisphenol A (BPA) and Metabolic Disruption
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Metbolic disorders such as obesity, type 2 diabetes, liver lipid disorders and metabolic syndrome are increasing rapidly and have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence showing that other environmental factors, including environmental chemicals, may contribute to the rapid increase in the incidence of these metabolic diseases. Of particular growing concern is low-dose developmental exposure to endocrine disrupting chemicals (EDCs). The developing period is an extremely sensitive window of exposure to environmental stressors, including EDCs, and early life exposure has been linked to metabolic disorders later in life. Consistent with hormones, EDCs can act at very low serum concentrations and even small changes in the endocrine system may lead to extensive effects. The overall aim of this thesis has been to investigate potential metabolic disruption following exposure to Bisphenol A (BPA), which is a known EDC. The experimental animal study demonstrated that male and female rat offspring generally exhibited differential susceptibility to developmental exposure to BPA (0.5 µg/kg BW/day or 50 µg/kg BW/day). The main results showed that the lowest dose of BPA induced increased plasma triglyceride levels and increased adipocyte cell density in inguinal white adipose tissue in female offspring. Further, this low dose increased fatty acid indices and altered the fatty acid composition in male offspring and enhanced insulin secretion in pancreatic islets from male and female offspring and dams. Contrastingly, the higher BPA-dose decreased insulin secretion in pancreatic islets from male and female offspring and dams. The increased fatty acid indices, and the altered fatty acid composition together with enhanced insulin secretion may be early risk factors for insulin resistance. Furthermore, depending on the tissue, dose and sex, BPA altered the expression of genes involved in lipid and adipocyte homeostasis.The epidemiological study with a meta-analysis of data from the National Health and Nutrition Survey (NHANES) did not disclose any associations between urinary BPA and dyslipidemia. However, considering the cross-sectional nature of the present study, this should rather be investigated in carefully designed prospective cohort studies with repeated BPA measurements. Nonetheless, we hope that this paper can encourage researchers to evaluate NHANES data using meta-analyses instead of pooling of data.This thesis concludes that exposure to BPA, which is a known EDC, most likely is a contributor, along with genetic, social and behavioral factors, to the development of metabolic disorders.
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| 7. |
- Gezelius, Henrik, PhD, 1977-, et al.
(författare)
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Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening
- 2024
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Ingår i: NAR Genomics and Bioinformatics. - : Oxford University Press. - 2631-9268. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughput ex vivo drug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporates ex vivo treatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27 327 cells are freely available to extend to future scRNA-seq methodological comparisons.
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| 8. |
- Haas, Josephine, et al.
(författare)
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Time-trends in body mass index, and overweight and obesity as independent risk factors for diabetes angiopathy in young females with type 1 diabetes : A nationwide study in Sweden
- 2023
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227 .- 1872-8227. ; 204
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To examine time-trends in BMI-distributions of young females with and without type 1 diabetes (T1D), with focus on the upper half of the distribution i.e., the median and above, and to explore if overweight and obesity independently increase risk of diabetes angiopathy.Methods: Population-based cohort study of 3,473 females with T1D, 16-35 years, identified in the Swedish National Diabetes Registers, January 2005 to October 2015, and 8,487 females from the background population. BMI-distributions were examined using kernel density estimates and quantile regression. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for angiopathy in overweight/obese subjects were estimated with adjusted Cox regression.Results: The BMI-distribution in females with T1D was right shifted to that of the background population (p < 0.001). The 90th percentile and median BMI increased equally overtime in both groups, but females with T1D started from a higher baseline. In T1D, HRs were significantly increased for any angiopathy in individuals with obesity (adj HR 1.37 (CI 1.14-1.64)), and for retinopathy; adj HRs (CIs): overweight; 1.15 (1.02-1.29), obesity; 1.30 (1.08-1.56).Conclusions: Females with T1D have increasing BMI overtime and are heavier than females without T1D. Overweight and obesity are by themselves risk factors for angiopathy.
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| 9. |
- Hansson, Anna, 1984-, et al.
(författare)
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Biogas production in the industrial symbiosis context – facilitating collaboration through digitalization
- 2024
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Ingår i: 5THCESUST2024: 5TH SYMPOSIUM ON CIRCULAR ECONOMY AND SUSTAINABILITY.
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Konferensbidrag (refereegranskat)abstract
- Improving sustainability performance and adapting to circular economy principles in operational business strategies are becoming increasingly prioritized. In this pursuit, the concept of industrial symbiosis (IS) has become increasingly relevant. IS represents a collaborative approach where the interplay of material, residual waste, energy, and infrastructure exchanges aims to yield not only economic and environmental advantages for the participating companies but also substantial societal benefits by using resources more efficiently. Biogas production is such an example, it can reduce greenhouse gas emissions since it can produce heat and electricity, replace renewable fuel for vehicles, or be used as input material for industrial use. The digestate from biogas production can also be used as an effective agricultural fertilizer to replace chemical fertilizers which are produced using fossil energy.Digital tools and platforms in IS can be used to different extent depending on businesses levels of digital maturity (the extent to which businesses adapt to ongoing digital change and integrate digitalization). Digital tools and platforms hold a central role for developing various advantages in biogas-based IS, but since the digital maturity for IS focusing on biogas production is uncertain, the current efficiency obtained by tools and platforms is unknown. Therefore, through semi-structured interviews and study visits, this study assesses stakeholder collaboration and use of digital tools at five IS sites with biogas production in Sweden. It explores (i) current digital maturity and collaboration characteristics amongst established biogas-based IS, and (ii) needs amongst stakeholders for development of digital tools and platforms to promote digital maturity, monitoring, collaboration, and knowledge exchange in current and future IS structures.Preliminary results of the on-going study show that the use of digital tools varies depending on the character and size of resource flows that are included in the collaboration, and due to the internal digital maturity of the involved companies. In general, the use of digital tools for stakeholder interaction is on low or medium level, in which manual handling is required and little is automated. This complies with the sites being relatively small, and the number of stakeholders involved are relatively few. Moreover, the preliminary results show that the interest of future development of digital tools is found to be related to business development and expanded market opportunities through diversified raw material use, increased production, and new distribution channels. In addition, a demand of digital platforms for exchange of experience and competence supply has been identified.
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| 10. |
- Johansson, Jarkko, et al.
(författare)
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Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan
- 2023
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Ingår i: Cell Reports. - 2211-1247. ; 42:9
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Tidskriftsartikel (refereegranskat)abstract
- Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.
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