| 11. |
- Abdulla, Maysaa
(författare)
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Prognostic signficance of tumor cell markers in diffuse large B-cell lymphoma with special emphasis on lymphoma localization
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade B-cell lymphoma with different clinical, morphological, immunophenotypical, and molecular features. DLBCL is curable in 60-70% of patients when treated with standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).The main aim of this thesis is to identify prognostic factors in DLBCL by studying tumor markers (paper I and II), site of disease (paper III) and tumor microenvironment markers in primary DLBCL of the CNS (PCNSL) (paper IV) in order to better identify different risk groups of DLBCL patients.In papers I-III, we studied DLBCL patients treated homogeneously with R-CHOP. The negative prognostic impact of double protein expression of MYC and BCL2 so called “double-expressor lymphoma” (DEL) was a common finding in the three papers. In paper I, we detected DEL in 27% of patients, distributed with no significant difference between the germinal center derived B-cell subgroup (GCB) in 52% of cases and the non-GCB subgroup in 37% of cases. There was no significant difference in survival between GCB and non-GCB patients. The diagnosis in most of the patients with DEL was made on core needle biopsy in this paper. This finding was more thoroughly investigated in paper III with attention paid to the site of biopsy. In paper II, we evaluated the concordance of cell of origin (COO) assignment between gene expression profile (GEP) and immunohistochemistry (IHC) to identify the best predictor of survival in a DLBCL cohort including patients from Sweden and Denmark. The overall concordance between the two methods was 83%. We found that ABC/non-GCB subtype identified by both GEP and IHC is associated with the worst outcome. This finding indicates the importance of precise risk stratification in the era of precision medicine. DEL was more common in ABC patients categorized by GEP. In paper III, we identified abdominal lymph node involvement by radiological examination in 63% of DLBCL patients with an inferior survival, adverse clinical characteristics and significantly more frequent DEL. These findings may indicate a distinct biological behavior in patients with abdominal nodal disease. In paper IV, we demonstrated a significant association between IDO1 and PD-L1 in PCNSL patients. This finding indicates the crucial immunosuppressive role of these two molecules. In addition, in PCNSL low frequencies of MYC and BCL2 translocations and high frequency of BCL6 translocation was observed and DEL was detected in 49% of cases. Contrary to our results in systemic DLBCL in papers I-III, there was no significant prognostic impact of DEL in PCNSL.
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| 12. |
- Abeid, Muzdalifat, 1973-
(författare)
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Improving Health-seeking Behavior and Care among Sexual Violence Survivors in Rural Tanzania
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to assess the effects of providing community education and training to healthcare workers to improve community response, healthcare and support for rape survivors in the Kilombero district of Tanzania. The overall design of the project was to begin with an exploratory study (Paper I) to establish the community’s perceptions towards sexual violence and their perceived recommendations to address this issue. Using a structured questionnaire, the community’s knowledge and attitudes towards sexual violence were determined along with their associations with demographic factors (Paper II). Papers III and IV assessed the effect of healthcare workers’ training and a community information package, respectively, using a controlled quasi-experimental design. The findings highlighted the social norms and variety of barriers that impacted negatively on the survivors’ care-seeking from support services and health outcomes. Increasing age and higher education were associated with better knowledge and less accepting attitudes towards sexual violence. Training on the management of sexual violence was effective in improving healthcare workers’ knowledge and practice but not attitude. Knowledge on sexual violence among the communities in the intervention and comparison areas increased significantly over the study period; from 57.3% to 80.6% in the intervention area and from 55.5% to 71.9% in the comparison area. In the intervention area, women had significantly less knowledge than men at baseline (53% Vs 64%, p<.001).There was a reduction, though not significantly, in acceptance attitudes from 28.1% to 21.8% in favor of women. In conclusion, the current intervention provides evidence that healthcare workers’ training and community education is effective in improving knowledge but not attitudes towards sexual violence. The findings have potential implications for interventions aimed at preventing and responding to violence. The broader societal norms that hinder rape disclosure need to be re-addressed.
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| 13. |
- Abelson, Anna-Karin, 1978-
(författare)
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Genetic Risk Factors for Systemic Lupus Erythematosus : From Candidate Genes to Functional Variants
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors. Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America. These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.
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| 14. |
- Abelson, Klas, 1976-
(författare)
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Acetylcholine in Spinal Pain Modulation : An in vivo Study in the Rat
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The spinal cord is an important component in the processing and modulation of painful stimuli. Nerve signals from the periphery are relayed and further conducted to the brain (nociception) in the spinal cord, and the most essential modulation of painful information (antinociception) occurs here. Several neurotransmitters are involved in spinal pain modulation, among them acetylcholine. However, the role of acetylcholine has previously been little investigated. In the present thesis, the acetylcholine release in the spinal cord was studied in vivo. By using spinal microdialysis on anaesthetised rats, the effects on the intraspinal acetylcholine release of various receptor ligands and analgesic agents were examined. This, together with pain behavioural tests and in vitro pharmacological assays, was used to evaluate the role of acetylcholine in spinal pain modulation. The four studies in this thesis resulted in the following conclusions: An increased release of spinal acetylcholine is associated with an elevated pain threshold, while a decreased acetylcholine release is associated with hyperalgesia, as seen after systemic treatment with a muscarinic agonist and an antagonist. Lidocaine is a potent analgesic when given systemically. It was found to produce an increase of intraspinal acetylcholine after intravenous injection of analgesic doses. This effect was attenuated after muscarinic, and abolished after nicotinic, receptor blockade. Various a2-adrenergic ligands, associated with nociceptive or antinociceptive effects, were found to affect intraspinal acetylcholine release via action on nicotinic receptors. Finally, the involvement of spinal acetylcholine in the analgesic effects of aspirin and paracetamol was examined. It was found that spinal acetylcholine could participate in the analgesic effects of aspirin, but not of paracetamol. The present thesis provides data that clearly demonstrate a relationship between intraspinal acetylcholine and antinociception, and elucidate interactions between acetylcholine and other mechanisms that mediate antinociception in the spinal cord.
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| 15. |
- Abrahamsson, Niclas, 1976-
(författare)
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On the Impact of Bariatric Surgery on Glucose Homeostasis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2.In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery.In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS).In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms.In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response.In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.
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| 16. |
- Abramenkovs, Andris, 1989-
(författare)
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Induction and repair of clustered DNA damage sites after exposure to ionizing radiation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.
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| 17. |
- Abu Hamdeh, Sami, 1982-
(författare)
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Clinical Consequences of Axonal Injury in Traumatic Brain Injury
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traumatic brain injury (TBI), mainly caused by road-traffic accidents and falls, is a leading cause of mortality. Survivors often display debilitating motor, sensory and cognitive symptoms, leading to reduced quality of life and a profound economic burden to society. Additionally, TBI is a risk factor for future neurodegenerative disorders including Alzheimer’s disease (AD). Commonly, TBI is categorized into focal and diffuse injuries, and based on symptom severity into mild, moderate and severe TBI. Diffuse axonal injury (DAI), biomechanically caused by rotational acceleration-deceleration forces at impact, is characterized by widespread axonal injury in superficial and deep white substance. DAI comprises a clinical challenge due to its variable course and unreliable prognostic methods. Furthermore, axonal injury may convey the link to neurodegeneration since molecules associated with neurodegenerative events aggregate in injured axons.The aim of this thesis was to study clinical consequences of axonal injury, its detection and pathological features, and potential link to neurodegeneration in severe TBI patients treated at the neurointensive care unit at Uppsala University Hospital. In paper I and IV DAI patients were studied for the relation of elevated intracranial pressure (ICP) and poor outcome to axonal injury on magnetic resonance imaging. In paper II, soluble amyloid-beta aggregates (oligomers and protofibrils), characteristic of AD pathology, were investigated in surgically resected brain tissue from severe TBI patients, using highly-selective Enzyme-Linked ImmunoSorbent Assays. In paper III, brain tissue biopsy samples from TBI patients with either focal injury or DAI were examined for differential proteome profiles using mass spectrometry-based proteomics.The results provide evidence that axonal injury, located in the central brain stem, in substantia nigra and the mesencephalic tegmentum, is particularly related to poor outcome and increased ICP during neurointensive care of DAI patients. A novel classification system for prognostication after DAI is proposed. Furthermore, the thesis shows that severe TBI induces rapid accumulation of neurotoxic soluble amyloid-beta oligomers and protofibrils. In addition, DAI initiates unique proteome profiles different from that of focal TBI in structurally normal-appearing brain. These findings have implication for the clinical management of DAI patients, and provide new insight in the neuropathological consequences of axonal injury.
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| 18. |
- Abu Sabaa, Amal
(författare)
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Clinical and Molecular Studies of Diffuse Large B-cell Lymphoma
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance.
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| 19. |
- Acosta Ruiz, Vanessa, 1987-
(författare)
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CT Guided Ablation of T1 Renal Tumors
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The widespread use of medical imaging contributes to the increased detection of incidentally detected small renal tumors, a majority which are often indolent masses found in elderly patients with preexisting chronic kidney disease. In Sweden, partial nephrectomy with minimal invasive surgical approach is the current standard for removing these tumors, although another option is percutaneous image-guided tumor ablation that allows treatment of elderly patients with comorbidities for who surgery is a risk. Due to the lack of long-term follow-up studies and prospective randomized trials, ablation is still considered an alternative option to surgery in Sweden. The aim of this thesis was to evaluate treatment of T1 renal tumors with CT guided radiofrequency (RFA) and microwave ablation (MWA).Factors affecting the efficacy rate of complete tumor ablation with RFA after a single session were evaluated (Paper I). Optimal electrode placement and a long tumor distance to the collecting system were associated with an increased primary efficacy. Renal tumor RFA was compared with laparoscopic partial nephrectomy (LPN: Papers II-III): both methods had comparable secondary efficacy rates, but RFA involved several treatment sessions. Total session times and hospitalization times were shorter and complications less frequent for RFA than for LPN (Paper II). After treatment, renal function impact was assessed by evaluation of both renal function quantity and quality through determination of the split renal function (SRF: Paper III). Standard renal function measurements were assessed and both RFA and LPN were nephron sparing when treating small renal tumors and did not affect creatinine or GFR. However, LPN involved greater SRF reduction in the affected kidney than RFA. Initial experience with microwave ablation was evaluated and this new ablation technique demonstrated high efficacy rates with fewer complications, and was comparable with the mid-term results of now established ablation techniques (Paper IV).In conclusion, CT guided RFA and MWA are safe and effective treatments for the removal of T1 renal tumors. This thesis provides further insights into the field of thermal ablation of small renal masses, which can aid future treatment selection and patient management.
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| 20. |
- Adamsson, Viola
(författare)
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A Healthy Nordic Diet and Cardiometabolic Risk Factors : Intervention Studies with Special Emphasis on Plasma Lipoproteins
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A healthy diet is important in the prevention of cardiovascular disease (CVD). Several risk factors, modifiable by diet, are involved in the development of CVD, e.g. hyperlipidaemia, hyperglycaemia, insulin resistance, obesity and hypertension. Little data however exist on diets composed of foods originating from the Nordic countries, and their potential to reduce CVD risk.This thesis aimed to investigate whether an ad libitum healthy Nordic diet (ND), either provided as a whole diet, or as a prudent breakfast (PB) alone, could influence CVD risk factors in healthy, mildly hypercholesterolemic men and women. Another aim was to describe the nutrient and food composition of the ND, both by using self-reported data and serum biomarkers of dietary fat quality.The primary clinical outcome measure was LDL-cholesterol, and other cardiometabolic risk factors were secondary outcomes.Two parallel, randomised, controlled intervention studies were conducted in free-living subjects. Clinical and dietary assessments were performed at baseline and at the end of dietary interventions. All foods were provided to subjects randomised to ND, whereas only breakfast items were supplied to subjects randomised to PB. Control groups followed their habitual diet/breakfast.Compared with controls, ND reduced body weight and improved several CVD risk factors including LDL-cholesterol, insulin sensitivity and blood pressure. Several, but not all effects were probably partly mediated by diet-induced weight loss. ND accorded with Nordic nutrition recommendations and was defined as “a plant-based diet, where animal products are used sparingly as side dishes”. Compared with average Swedish diet, ND was high in dietary fibre, but low in sodium, meat, high-fat dairy products, sweets and alcohol. A decreased intake of saturated fat and increased intake of n-3 PUFA during ND was partly reflected in serum lipids. Eating a PB without other dietary changes did not improve lipid or glucose metabolism, but decreased markers of visceral fat and inflammation, without influencing body weight.This thesis suggests that a whole ND, but not PB alone, promotes weight loss and improves multiple CVD risk factors in healthy subjects after 6 weeks. These results suggest that ND could have a potential role in the prevention of cardiometabolic diseases.
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