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  • Adamo, Hanibal Hani, 1984- (författare)
  • TINT Tumor Indicating Normal Tissue new field of diagnostic biomarkers for prostate cancer
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background: </strong>Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue).</p><p> <strong>Methods: </strong>In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting.</p><p><strong> </strong><strong>Results: </strong>Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis.</p><p> <strong>Conclusions: </strong>Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients. </p>
  • Adjeiwaah, Mary, 1980- (författare)
  • Quality assurance for magnetic resonance imaging (MRI) in radiotherapy
  • 2017
  • Licentiatavhandling (övrigt vetenskapligt)abstract
    • <p>Magnetic resonance imaging (MRI) utilizes the magnetic properties of tissues to generate image-forming signals. MRI has exquisite soft-tissue contrast and since tumors are mainly soft-tissues, it offers improved delineation of the target volume and nearby organs at risk. The proposed Magnetic Resonance-only Radiotherapy (MR-only RT) work flow allows for the use of MRI as the sole imaging modality in the radiotherapy (RT) treatment planning of cancer. There are, however, issues with geometric distortions inherent with MR image acquisition processes. These distortions result from imperfections in the main magnetic field, nonlinear gradients, as well as field disturbances introduced by the imaged object. In this thesis, we quantified the effect of system related and patient-induced susceptibility geometric distortions on dose distributions for prostate as well as head and neck cancers. Methods to mitigate these distortions were also studied.</p><p><strong>In Study I,</strong> mean worst system related residual distortions of 3.19, 2.52 and 2.08 mm at bandwidths (BW) of 122, 244 and 488 Hz/pixel up to a radial distance of 25 cm from a 3T PET/MR scanner was measured with a large field of view (FoV) phantom. Subsequently, we estimated maximum shifts of 5.8, 2.9 and 1.5 mm due to patient-induced susceptibility distortions. VMAT-optimized treatment plans initially performed on distorted CT (dCT) images and recalculated on real CT datasets resulted in a dose difference of less than 0.5%.</p><p> The magnetic susceptibility differences at tissue-metallic,-air and -bone interfaces result in local B<sub>0</sub> magnetic field inhomogeneities. The distortion shifts caused by these field inhomogeneities can be reduced by shimming.  <strong>Study II</strong> aimed to investigate the use of shimming to improve the homogeneity of local  B<sub>0</sub> magnetic field which will be beneficial for radiotherapy applications. A shimming simulation based on spherical harmonics modeling was developed. The spinal cord, an organ at risk is surrounded by bone and in close proximity to the lungs may have high susceptibility differences. In this region, mean pixel shifts caused by local B<sub>0</sub> field inhomogeneities were reduced from 3.47±1.22 mm to 1.35±0.44 mm and 0.99±0.30 mm using first and second order shimming respectively. This was for a bandwidth of 122 Hz/pixel and an in-plane voxel size of 1×1 mm<sup>2</sup>.  Also examined in Study<strong> II</strong> as in <strong>Study I</strong> was the dosimetric effect of geometric distortions on 21 Head and Neck cancer treatment plans. The dose difference in D<sub>50</sub> at the PTV between distorted CT and real CT plans was less than 1.0%.</p><p>In conclusion, the effect of MR geometric distortions on dose plans was small. Generally, we found patient-induced susceptibility distortions were larger compared with residual system distortions at all delineated structures except the external contour. This information will be relevant when setting margins for treatment volumes and organs at risk.  </p><p>The current practice of characterizing MR geometric distortions utilizing spatial accuracy phantoms alone may not be enough for an MR-only radiotherapy workflow. Therefore, measures to mitigate patient-induced susceptibility effects in clinical practice such as patient-specific correction algorithms are needed to complement existing distortion reduction methods such as high acquisition bandwidth and shimming.</p>
  • Ahmed Hassan Ahmed, Osama, 1972- (författare)
  • Rift Valley fever challenges and new insights for prevention and control using the “One Health” approach
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Rift Valley fever (RVF) is an emerging viral zoonosis that causes frequent outbreaks in east Africa and on the Arabian Peninsula. The likelihood of RVF global expansion due to climate change and human anthropogenic factors is an important issue. The causative agent, RVF virus, is an arbovirus that is transmitted by several mosquito species and is able to infect a wide range of livestock as well as people. The infection leads to mass abortions and death in livestock and a potentially deadly hemorrhagic fever in humans. RVF has severe socio-economic consequences such as animal trade bans between countries, disruption of food security, and economic disaster for farmers and pastoralists as well as for countries. Human behavior such as direct contact with infected animals or their fluids and exposure to mosquito bites increases the risk for contracting the disease.</p><p>To better understand the challenges associated with RVF outbreaks and to explore prevention and control strategies, we used the One Health approach. The local community had to be involved to understand the interaction between the environment, animals, and humans. We focused on Sudan, Saudi Arabia, and Kenya. First, we systematically reviewed the literature and then we performed cross sectional community-based studies using a special One Health questionnaire. Climatic and remote sensing data were used in combination with statistics to develop a sub-region predictive model for RVF.</p><p>For both Saudi Arabia and Sudan, the ecology and environment of the affected areas were similar. These areas included irrigation canals and excessive rains that provide an attractive habitat for mosquito vectors to multiply. The surveillance systems were unable to detect the virus in livestock before it spread to humans. Ideally, livestock should serve as sentinels to prevent loss of human lives, but the situation here was reversed. Differences between countries regarding further spread of RVF was mainly determined by better economic and infrastructure resources.</p><p>In Sudan, there was a lack of knowledge and appropriate practices at the studied community regarding RVF disease symptoms and risk factors for both animals and humans. The community was hesitant in notifying the authorities about RVF suspicion in livestock due to the lack of a compensation system. The perceived role of the community in controlling RVF was fragmented, increasing the probability of RVF transmission and disease.</p><p>In Kenya, our study found that better knowledge about RVF does not always translate to more appropriate practices that avoid exposure to the disease. However, the combination of good knowledge, attitudes, and practices may explain why certain communities were less affected. Strategies to combat RVF should consider socio-cultural and behavioral differences among communities. We also noticed that RVF outbreaks in Kenya occurred in regions with high livestock density exposed to heavy rains and wet soil fluxes, which could be measured by evapotranspiration and vegetation seasonality variables. We developed a RVF risk map on a sub-regional scale. Future outbreaks could be better managed if such relevant RVF variables are integrated into early warning systems.</p><p>To confront RVF outbreaks, a policy is needed that better incorporates ecological factors and human interactions with livestock and environment that help the RVF pathogen spread. Early detection and notification of RVF is essential because a delay will threaten the core of International Health Regulations (IHR), which emphasizes the share of information during a transboundary disease outbreak to avoid unnecessary geographical expansion.</p>
  • Al-Alawi, Kamila, 1974- (författare)
  • Team-based approach in the management of diabetes at primary health care level in Muscat, Oman challenges and opportunities
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Introduction: The growth of type 2 diabetes is considered an alarming epidemic in Oman. The efficient team-based approach to diabetes management in primary health care is an essential component for providing ideal diabetic care. This thesis aimed to explore the current situation related to team-based management of type 2 diabetes in public Primary Health Care Centres (PHCCs) under the Ministry of Health (MOH) in Oman, including the various challenges associated with diabetes management and the most preferable Human Resources for Health (HRH) management mechanism, and to examine how this could be optimized from provider and patient perspectives.</p><p>Materials and methods: The entire project was conducted in Muscat Governorate and was based on one quantitative and three qualitative studies. In the quantitative study, 26 public PHCCs were approached through cross-sectional study. The core diabetes management team recommended by the MOH for PHCCs in Oman was explored in terms of their competencies, values, skills, and resources related to the team-based approach to diabetes management. For the qualitative studies, five public purposely-selected PHCCs were approached. The diabetes consultations conducted by the core members and other supportive members involved in diabetes management were observed and later the Primary Health Care Providers (PHCPs) were interviewed. The different approaches explored challenges related to diabetes management and the most preferable HRH mechanism by PHCPs. Seven type 2 diabetes patients with different gender, employment status, and education were consequently interviewed to explore their perceptions towards the current diabetes management service and their opinions towards nurse-led clinics.</p><p>Results: The survey provided significant and diverse perceptions of PHCPs towards their competencies, values, skills, and resources related to diabetes management. Physicians considered themselves to have better competencies than nurses and dieticians. Physicians also scored higher on team-related skills and values compared with health educators. In terms of team-related skills, the difference between physicians and nurses was statistically significant and showed that physicians perceived themselves to have better skills than nurses. Confusion about the leadership concept among PHCPs with a lack of pharmacological, technical, and human resources was also reported. The observations and interviews with PHCPs disclosed three different models of service delivery at diabetes management clinics. The challenges explored involved PHCCs’ infrastructure, nurses’ knowledge, skills, and non-availability of technical and pharmaceutical support. Other challenges that evolved into the community were cultural beliefs, traditions, health awareness, and public transportation. Complete implementation of task-sharing mechanisms within the team-based approach was selected by all PHCPs as the most preferable HRH mechanism. The selection was discussed in the context of positive outcomes, worries, and future requirements. The physicians stated that nurses’ weak contribution to the team within the selected mechanism could be the most significant aspect. Other members supported the task-sharing mechanism between physicians and nurses. However, type 2 diabetes patients’ non-acceptance of a service provided by the nurses created worries for the nurses. The interviews with type 2 diabetes patients disclosed positive perceptions towards the current diabetes management visits; however, opinions towards nurse-led clinics varied among the patients.</p><p>Conclusions and recommendations: The team-based approach at diabetes management clinics in public PHCCs in Oman requires thoughtful attention. Diverse presence of the team members can form challenges during service delivery. Clear roles for team members must be outlined through a solid HRH management mechanism in the context of a sharp leadership concept. Nurse-led clinics are an important concept within the team; however, their implementation requires further investigation. The concept must involve clear understandings of independence and interdependence by the team members, who must be educated to provide a strong gain for team-based service delivery.</p>
  • Al-Amiry, Bariq, 1976- (författare)
  • Radiological measurements in total hip arthroplasty
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Varje år opereras ungefär 1 miljon patienter runt om i världen och 20,000 patienter i Sverige med en total höftledsprotes (THA). Höftledsprotesoperation anses vara en av de mest framgångsrika, säkra och kostnadseffektiva kirurgiska åtgärderna med ett syfte att smärtlindra, återställa rörligheten och förbättra livskvaliteten. Höftleden drabbas av artros, åldersrelaterad sjukdom som orsakar destruktion av leden. Vid operation med THA är det viktigt att återställa de biomekaniska krafterna runt höftleden med en adekvat så kallad femoral offset (FO), avståndet mellan höftens rörelsecentrum och mitten av bäckenet, postoperativ benlängdsskillnad (BLS) och ett tillfredsställande komponentläge. Den preoperativa planeringen och den postoperativa röntgenbedömningen av dessa parametrar kräver god tillförlitlighet, det vill säga validitet och reproducerbarhet både mellan olika bedömare och vid upprepade mätningar av samma bedömare. Således är radiologiska mätningar före och efter THA oerhört viktiga för att få bästa resultat efter THA. Det finns inte tillräckligt med information i litteraturen om effekten av den preoperativa radiologiska artrosgraden och symptomduration av artrosen på utfallet av THA. Dessutom behövs ytterligare forskning för att studera effekten av obesitas på de radiologiska mätningarna efter THA.</p>
  • Alenius Dahlqvist, Jenny, 1972- (författare)
  • Heart rate variability and pacemaker treatment in children with Fontan circulation
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Background: Fontan surgery is performed in children with univentricular heart defects. Arrhythmias are frequent complications, occasionally requiring pacemaker treatment. Previous data regarding indications and risk factors for pacemaker treatment in Fontan patients is limited and conflicting. Heart rate variability (HRV) reflects autonomous nervous activity controlling the sinus node and has been associated with tachyarrhythmias in both adults and children, as well as in adults with sinus node dysfunction (SND).</p><p>Aim: To study HRV, arrhythmia and pacemaker treatment  in children with Fontan circulation— with the purpose of contributing to the reduction of long term complications in this patient group.</p><p>Methods: We have retrospectively reviewed pacemaker therapy in all Swedish patients who underwent Fontan surgery from 1982 to 2017 (n=599). We have also analysed HRV from 24-hour Holter ECG recordings in 112 children with Fontan circulation and in children with univentricular heart defects before bidirectional Glenn (BDG) procedure (n=47), before and on completion of Fontan surgery (n=47 and 45 respectively). Analysis was performed by power spectral analysis and Poincaré method, and results compared with healthy controls. Furthermore, HRV was analysed in Fontan patients who later required a pacemaker due to severe SND. Results were compared with Fontan patients who had SND, without indication for pacemaker treatment, with patients with Fontan circulation without SND and healthy controls. In addition we evaluated the possibility to analyse arrhythmias and HRV in 27 Fontan children using intermittent ECG recordings with a handheld devices at home during a 14-day period.</p><p>Results: After a mean follow-up of 12 years, 13% (78/599) of patients with Fontan circulation had received a pacemaker. Patients operated with the extracardiac conduit (EC) had a significantly lower prevalence of pacemaker implantation (6%) than patients with a lateral tunnel (LT) (17%). The most common pacemaker indication in patients with Fontan circulation was SND (64%). Children with Fontan circulation showed significant reductions in several HRV parameters, compared with controls. No significant differences were found between patients operated with LT versus EC (paper I). After BDG the RR interval and SD2 (representing changes in heart rate over 24-hours) significantly increased compared to pre-BDG. Compared with healthy controls, patients post-BDG, had significantly longer RR intervals and reduced overall HRV. P<sub>HF</sub> (reflecting parasympathetic control of the heart) was significantly reduced after TCPC as compared to before (paper II). Fontan patients with SND showed significantly elevated SD2 (representing changes in heart rate over 24-hours), somewhat reduced in patients that later required a pacemaker (Paper V). Handheld ECG analysis revealed frequent ventricular extra systoles in one patient and episodes of supraventricular tachycardia in another. Seven Fontan patients showed reduced HRV recorded with the handheld device over a 14-day period (paper III).</p><p>Conclusions: Overall HRV was reduced in patients with univentricular heart defects during the different surgical stages of Fontan surgery, compared to healthy controls. HRV was reduced in both patients with LT and EC with no significant difference between them. After BDG heart rate was significantly reduced as compared to before. P<sub>HF, </sub>reflecting the parasympathetic innervation of the heart was reduced after as compared to before TCPC. Pacemaker treatment is commonly needed in patients with Fontan circulation, and SND was the most prevalent indication for implantation. The prevalence of Fontan patients requiring pacemaker treatment was significantly lower in patients with EC. HRV analysis can contribute to management when following-up patients with Fontan circulation.</p><p> </p><p> </p>
  • Aléx, Jonas, 1975- (författare)
  • Cold exposure and thermal comfort among patients in prehospital emergency care innovation research in nursing
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Background</p><p>Patients’ cold exposure is a neglected problem in prehospital emergency care. Cold stress increases pain and anxiety and contributes to fear and an overall sense of dissatisfaction. When left untreated, cold stress disturbs vital body functions until ultimately reaches hypothermia.</p><p>Aim</p><p>The overall aim was to investigate patients’ experiences of thermal comfort and reactions to cold exposure in prehospital emergency care and to evaluate the effects of an intervention using active warming from underneath.</p><p>Method</p><p>Study I:</p><p>Persons (n=20) injured in a cold environment in the north of Sweden were interviewed. Active heat was given to 13 of them.</p><p>Study II:</p><p>In wintertime, 62 patients were observed during prehospital emergency care. The field study was based on observations, questions about thermal discomfort, vital signs, and temperature measurements.</p><p>Study III:</p><p>Healthy young persons (n=23) participated in two trials each. Data were collected inside and outside a cold chamber. In one trial, the participants were lying on a regular ambulance stretcher and in a second trial on a stretcher supplied with a heated mattress. Outcomes were the Cold Discomfort Scale (CDS), back, finger, and core body temperature, four statements from the State-TraitAnxiety-Inventory (STAI), vital signs, and short notes about their experiences of the two stretchers.</p><p>Study IV:</p><p>A quantitative intervention study was conducted in prehospital emergency care in the north of Sweden. The patients (n=30) in the intervention group were transported in an ambulance supplemented with a heated mattress on the stretcher, whereas only a regular stretcher was used in the ambulance for the patients (n=30) in the control group. Outcomes were the CDS, finger, core body, and air temperature, and questions about cold experiences.</p><p>Results</p><p>Study I:</p><p>Patients suffered more because of the cold than from the pain of their injuries. The patients were in a desperate need of heat.</p><p>Study II:</p><p>Patients are exposed to cold stress due to cold environments. There was a significant decrease from the first measurement in finger temperature of patients who were indoors when the ambulance arrived, compared to the measurement taken in the ambulance. In the patient compartment of the ambulance, 85% of the patients had a finger temperature below the comfort zone and almost half of them experienced the patient compartment in the ambulance to be cold. The regular mattress surface temperature at the ambulance ranged from -22.3 to 8.4 ºC.</p><p>Study III:</p><p>A statistical increase of the participants’ back temperature was found between those lying on the heated mattress compared to those lying on the regular mattress. The heated mattress was experienced as warm, comfortable, providing security, and easy to relax on.</p><p>Study IV:</p><p>Thermal comfort increased for the patients in the intervention group and decreased in the control group. A significant higher proportion of the participants rated the stretcher as cold to lie on in the control group compared to the intervention group.</p><p>Conclusion</p><p>The ambulance milieu is too cold to provide thermal comfort. Heat supply from underneath increased comfort and might prevent cold stress and hypothermia</p><p></p>
  • Anderl, Ines, 1973- (författare)
  • Activation of the Cellular Immune Response in <em>Drosophila melanogaster</em> Larvae
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>During the last 40 years, <em>Drosophila melanogaster</em> has become an invaluable tool in understanding innate immunity. The innate immune system of <em>Drosophila </em>consists of a humoral and a cellular component. While many details are known about the humoral immune system, our knowledge about the cellular immune system is comparatively small. Blood cells or hemocytes constitute the cellular immune system. Three blood types have been described for <em>Drosophila</em> larvae. Plasmatocytes are phagocytes with a plethora of functions. Crystal cells mediate melanization and contribute to wound healing. Plasmatocytes and crystal cells constitute the blood cell repertoire of a healthy larva, whereas lamellocytes are induced in a demand-adapted manner after infection with parasitoid wasp eggs. They are involved in the melanotic encapsulation response against parasites and form melanotic nodules that are also referred to as tumors.</p><p>In my thesis, I focused on unraveling the mechanisms of how the immune system orchestrates the cellular immune response. In particular, I was interested in the hematopoiesis of lamellocytes.</p><p>In Article I, we were able to show that ectopic expression of key components of a number of signaling pathways in blood cells induced the development of lamellocytes, led to a proliferative response of plasmatocytes, or to a combination of lamellocyte activation and plasmatocyte proliferation.</p><p>In Article II, I combined newly developed fluorescent enhancer-reporter constructs specific for plasmatocytes and lamellocytes and developed a “dual reporter system” that was used in live microscopy of fly larvae. In addition, we established flow cytometry as a tool to count total blood cell numbers and to distinguish between different blood cell types. The “dual reporter system” enabled us to differentiate between six blood cell types and established proliferation as a central feature of the cellular immune response. The combination flow cytometry and live imaging increased our understanding of the tempo-spatial events leading to the cellular immune reaction.</p><p>In Article III, I developed a genetic modifier screen to find genes involved in the hematopoiesis of lamellocytes. I took advantage of the gain-of-function phenotype of the <em>Tl<sup>10b</sup></em> mutation characterized by an activated cellular immune system, which induced the formation blood cell tumors. We screened the right arm of chromosome 3 for enhancers and suppressors of this mutation and uncovered <em>ird1</em>.</p><p>Finally in Article IV, we showed that the activity of the Toll signaling pathway in the fat body, the homolog of the liver, is necessary to activate the cellular immune system and induce lamellocyte hematopoiesis.</p>
  • Andersson, Christopher, 1987- (författare)
  • Regulatory pathways and virulence inhibition in <em>Listeria monocytogenes</em>
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><em>Listeria monocytogenes</em> is a rod-shaped Gram positive bacterium. It generally exist ubiquitously in nature, where it lives as a saprophyte. Occasionally it however enters the food chain, from where it can be ingested by humans and cause gastro-intestinal distress. In immunocompetent individuals <em>L. monocytogenes</em> is generally cleared within a couple of weeks, but in immunocompromised patients it can progress to listeriosis, a potentially life-threatening infection in the central nervous system. If the infected individual is pregnant, the bacteria can cross the placental barrier and infect the fetus, possibly leading to spontaneous abortion.</p><p>The infectivity of <em>L. monocytogenes</em> requires a certain set of genes, and the majority of them is dependent on the transcriptional regulator PrfA. The expression and activity of PrfA is controlled at several levels, and has traditionally been viewed to be active at 37 °C (virulence conditions) where it bind as a homodimer to a “PrfA-box” and induces the expression of the downstream gene.</p><p>One of these genes is ActA, which enables intracellular movement by recruiting an actin polymerizing protein complex. When studying the effects of a blue light receptor we surprisingly found an effect of ActA at non-virulent conditions, where it is required for the bacteria to properly react to light exposure.</p><p>To further study the PrfA regulon we tested deletion mutants of several PrfA-regulated virulence genes in chicken embryo infection studies. Based on these studies we could conclude that the chicken embryo model is a viable complement to traditional murine models, especially when investigating non-traditional internalin pathogenicity pathways. We have also studied the effects of small molecule virulence inhibitors that, by acting on PrfA, can inhibit <em>L. monocytogenes</em> infectivity in cell cultures with concentrations in the low micro-molar range.</p>
  • Andersson, Charlotta, 1976- (författare)
  • Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Wilms’ tumor gene 1 (<em>WT1</em>) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally <em>WT1</em> was described as a tumor suppressor gene, but later studies have shown oncogenic properties of <em>WT1</em> in a variety of tumors. Because of its dual functions in tumorigenesis, <em>WT1</em> has been described as a chameleon gene. In this thesis, the significance of <em>WT1 </em>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).</p><p>Previous studies have suggested that<em> </em>expression of<em> WT1</em> is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of <em>WT1</em> as an MRD marker in AML. In adult AML patients, we found that a reduction of <em>WT1</em> 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 <em>WT1</em> expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR.</p><p><em>WT1</em> 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 <em>WT1</em> mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the <em>WT1</em> gene were rarely seen in childhood BCP-ALL. However, five <em>WT1</em> SNPs were identified. In survival analyses, <em>WT1</em> SNP rs1799925 was found to be associated with worse OS, indicating that <em>WT1</em> SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether <em>WT1</em> mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in <em>WT1</em> were associated with <em>WT1</em> expression and clinical outcome. Sequencing analysis revealed that none of the previously reported <em>WT1</em> mutations were found in ccRCC; however, we identified six different <em>WT1 </em>SNPs. Our data suggest that pathogenic <em>WT1</em> mutations are not involved in ccRCC, and the prognostic significance of <em>WT1</em> 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.</p><p>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.</p><p>In conclusion, the results of this thesis indicate that <em>WT1</em> gene expression can provide information about MRD of patients with AML, and <em>WT1</em> SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of <em>WT1</em> 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.</p>
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