| 1. |
- Nilsson, Johanna, 1986-
(författare)
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Between Political Party and Armed Group : Understanding Renamo as a Hybrid Party
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis explores the concept of hybridity within the context of rebel-to-party transformation, with a particular focus on Renamo during the period of 2015-2017 in Mozambique. This timeframe was marked by a resurgence of organised systematic violence, disrupting the relative peace that had prevailed in Mozambique since 1992. The central conflict revolved around the issue of local self-governance, with Renamo asserting its claim to govern in six out of Mozambique's ten provinces. During this period, Renamo operated both as a political party with a significant presence in parliament and as an armed group engaged in systematic violence.The rebel-to-party literature has sparked discussions about groups that seem to retain elements of their violent past while transitioning into political parties, leading to the emergence of the concept of hybrid parties. However, this concept remains relatively undefined and underexplored. This thesis seeks to contribute to this discussion through an in-depth qualitative study of Renamo's elite-level politicians, aiming to enhance our understanding of hybrid parties.The study, conducted during the conflict years, closely examines how elite politicians in Renamo navigate their dual roles. It encompasses 14 months of fieldwork from February 2015 to January 2017, drawing on elite interviews, elite-level public statements, and elite observations of parliament, enriched by ethnographic sensibility. The analysis is grounded in a theoretical framework that allows for an exploration of Renamo's behaviour and perceptions as both an armed group and a political party, particularly concerning the issue of local self-governance. Through this analysis, the study aims to elucidate the intersections, thereby advancing our comprehension of how hybridity manifests.The main findings suggest that Renamo's hybridity predominantly manifests through processes related to contemporaneity in behaviour, elite-level legitimisation, and one key political issue. Furthermore, I argue that the hybridity is maintained through narratives of democracy and a charismatic leader. The thesis advocates for a deeper exploration of these processes to enhance both empirical understanding and the theoretical discussion surrounding hybrid parties.
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| 2. |
- Olsson, Hans
(författare)
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Stage T1 Urinary Bladder Carcinoma : Investigation of A Population-Based Cohort
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Approximately 2 300 new cases of urinary bladder carcinoma (UBC) are diagnosed every year in Sweden. This type of cancer is characterized as a long-standing disease with a high risk of recurrence and progression from an indolent to a more aggressive course. UBC occurs in a non-muscle-invasive form (stages Ta and T1), which is treated mainly with local resection and BCG instillation, and a muscle-invasive form (stage ≥ T2), for which the treatment of choice is irradiation or cystectomy.The aim of the research underlying this thesis was to explore the factors involved in tumor development and progression, and to find prognostic markers for recurrence and progression in patients with primary stage T1 urothelial carcinoma of the bladder (UCB).Tumor tissue in archived paraffin blocks from patients diagnosed with that type of malignancy was used in the four studies that were conducted. This was a population-based project, because all of the patients had been reported to the cancer center in the Southeast Healthcare Region in Sweden from 1992 to 2001. The follow-up time was comparable long in the cases included and was intended to be at least 10 years.The hospital records were reviewed to gather information on clinical characteristics of the tumors, such as size and multiplicity, as well as treatment modalities, recurrence and/or progression, and eventual death from UBC. The original tumor slides were re-evaluated. These two initial activities yielded a study population comprising 211 well-characterized patients with primary T1 UCB. Some of the originally selected patients were excluded due to missing paraffin blocks or poor quality of the tumor material, the latter being particularly important in the genetic analyses conducted in the fourth study.Ordinary light microscopy was performed to evaluate specific tumor characteristics, such as lymphovascular tumor infiltration, and for T1 sub-staging. Immunohistochemistry was carried out to, among other things, analyze cell cycle regulators. Furthermore, pyrosequencing, single-strand conformation analysis (SSCA), and Sanger sequencing were conducted in the fourth study to assess mutations in the p53 gene and murine double minute 2 SNP309 promoter polymorphism. Statistical analyses to estimate the risk of tumor recurrence and progression were carried out in all four investigations.Conclusions: This population-based cohort of patients with well-characterized T1 tumors of the urinary bladder showed high rates of recurrence (80%) and progression (39%), and the aggressiveness is underlined by the fact that 32% died from the disease. Lymphovascular tumor infiltration and abnormal immunohistochemical staining for p16 were found to be associated with tumor progression, and in the future analysis of these parameters might be used in treatment decisions regarding T1 bladder tumors. No other clinical or pathological variable or cell cycle regulator was associated with progression, and none of the genetic analyses conducted in the current studies were helpful in predicting outcome or explaining the mechanisms of tumor development.
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| 3. |
- Crnalic, Sead, 1960-
(författare)
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Metastatic spinal cord compression in prostate cancer : clinical and morphological studies
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established. Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases. Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry. Results: Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival. Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice. Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression. Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected. Conclusion: Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.
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| 4. |
- Kühnemund, Malte
(författare)
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Single Molecule Detection : Microfluidic Automation and Digital Quantification
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Much of recent progress in medical research and diagnostics has been enabled through the advances in molecular analysis technologies, which now permit the detection and analysis of single molecules with high sensitivity and specificity. Assay sensitivity is fundamentally limited by the efficiency of the detection method used for read-out. Inefficient detection systems are usually compensated for by molecular amplification at the cost of elevated assay complexity.This thesis presents microfluidic automation and digital quantification of targeted nucleic acid detection methods based on padlock and selector probes and rolling circle amplification (RCA). In paper I, the highly sensitive, yet complex circle-to-circle amplification assay was automated on a digital microfluidic chip. In paper II, a new RCA product (RCP) sensing principle was developed based on resistive pulse sensing that allows label free digital RCP quantification. In paper III, a microfluidic chip for spatial RCP enrichment was developed, which enables the detection of RCPs with an unprecedented efficiency and allows for deeper analysis of enriched RCPs through next generation sequencing chemistry. In paper IV, a smart phone was converted into a multiplex fluorescent imaging device that enables imaging and quantification of RCPs on slides as well as within cells and tissues. KRAS point mutations were detected (i) in situ, directly in tumor tissue, and (ii) by targeted sequencing of extracted tumor DNA, imaged with the smart phone RCP imager. This thesis describes the building blocks required for the development of highly sensitive low-cost RCA-based nucleic acid analysis devices for utilization in research and diagnostics.
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| 5. |
- Niinivirta, Marjut
(författare)
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Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is no established predictive marker for the treatment of metastatic renal cell cancer (mRCC) patients. With a predictive marker, patients unlikely to respond could be selected upfront and offered other therapy options. Thereby, unnecessary toxicity could be avoided and costs would be reduced. Tyrosine kinase inhibitors (TKI) are the cornerstone in the treatment of mRCC. The aim of the thesis was to evaluate and hopefully define tumoral predictive markers for treatment with the common TKIs sunitinib and sorafenib.The studies are based on immunohistochemical analyses of renal cancer tissues from 139 primary tumors sampled in a tissue microarray. Three proteins with a specific and differential expression in RCC were chosen in co-operation with the Human Protein Atlas project. Since TKIs block vascular endothelial growth factor receptors (VEGFR) on tumor vessels, angiogenesis associated proteins were also analysed as putative predictive biomarkers.In two studies, the renal proteins cubilin (CUBN) and pyruvate kinase L/R (PKLR) were investigated. Our results indicate that these membranous proteins are positive predictive factors for sunitinib and sorafenib therapies. Patients with high membranous expressions of CUBN and PKLR respectively experienced significantly longer progression free survivals (PFS) and overall survivals (OS) compared to the other patients. Combining CUBN and PKLR negative tumors, a patient group with a particularly short PFS could be defined, possibly consisting of patients not benefitting at all from treatment with sunitinib or sorafenib.Studies of tumoral annexin A1 (ANXA1) and epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) demonstrated predictive potential for sunitinib but not for sorafenib treatment. A low cytoplasmic expression of ANXA1 was significantly associated with longer PFS and OS in patients treated with sunitinib. A combined analysis with CUBN and ANXA1 expression indicated a higher predictive value than the expressions of either marker alone. We further observed that a high vascular endothelial expression of ELTD1 is predictive for a longer PFS and OS in sunitinib treated patients. The expressions of CD34 which is a marker of the number of vessels and the sunitinib target VEGFR2 failed to demonstrate significant associations with PFS.To conclude, our real world studies indicate that CUBN, PKLR, ANXA1 and ELTD1 are potential tumoral biomarkers, to predict benefit from treatment with sunitinib (all four proteins) and sorafenib (CUBN and PKLR) in patients suffering from mRCC.
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| 6. |
- Papworth, Karin, 1964-
(författare)
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Prognostic factors in renal cell carcinoma : evaluation of erythropoietin and its receptor, carbonic anhydrase IX, parathyroid hormone-related protein and osteopontin
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A prognostic factor is a marker or a feature that can be used to estimate the risk of recurrence of disease, metastatic spread and clinical outcome. Despite intensive search for more sophisticated markers in renal cell carcinoma (RCC), few have added prognostic information to earlier described factors like stage of disease, nuclear grade, tumour type, and in metastatic disease; performance status, anaemia, hypercalcaemia and increased erythrocyte sedimentation. In the dominating tumour type, clear cell renal RCC (cRCC), hypoxia is common, leading to an up-regulation of hypoxia inducible factor (HIF). The majority of cRCC have a mutation in the von Hippel Lindau gene (VHL-gene), which regulates HIF and in turn leads to up-regulation of a number of target genes for potential growth factors. The aim of the study was to evaluate the possible prognostic information of a few factors associated to pVHL/HIF, anemia and/or hypercalcaemia in RCC; erythropoietin (EPO) and it´s receptor (EPO-R), carbonic anhydrase IX (CA IX), parathyroid hormone-related protein (PTHrP) and osteopontin (OPN). Patients diagnosed with RCC between 1982-2007 were included in the studies. The tumour tissue expressions of EPO, EPO-R and PTHrP were assessed using immunohistochemistry. Serum/plasma levels of EPO, CA IX, PTHrP and OPN were also analyzed using immunometric methods. Our study demonstrated that the expression of EPO and EPO-R were related, and the expressions differed significantly between RCC types. The serum EPO levels did not associate to the tumour expression of EPO or EPO-R, indicating that circulating EPO derives from other sources than tumour cells. Erythropietin receptor expression was more frequent in advanced stages of disease, but neither EPO, nor EPO-R, were independent prognostic factors for survival. Serum CA IX levels were higher in cRCC compared to papillary RCC (pRCC). In cRCC, the CA IX serum levels correlated positively to TNM stage, but serum CA IX did not add independent prognostic information. Parathyroid hormone-related protein is a cause of hypercalcaemia in malignancy, and we observed that circulating PTHrP related to hypercalcaemia in RCC. The tumour expression of PTHrP associated positively to serum PTHrP, but not to serum calcium. We found an association between PTHrP and OPN in plasma, and both plasma PTHrP and OPN were positively associated to TNM stage. Neither serum/plasma PTHrP nor tumour expression of PTHrP were independent prognostic factors for survival. The serum OPN levels were higher in pRCC but no impact on survival was observed in this RCC type. In contrast, plasma/serum OPN was an independent prognostic factor for disease-specific survival in cRCC. Our results support a role for these factors in RCC. The expressions vary between tumour types, which can be explained by different gene aberrations. Some of the factors have a close relation to para-malignant symptoms like hypercalcaemia. Most of the factors correlate positively to TNM-stage, reflecting a relation to advanced disease. Although expression of EPO, EPO-R, PTHrP and CA IX did not add independent prognostic information, the results might contribute to greater understanding of important mechanisms and associations in RCC. Osteopontin is a strong independent prognostic factor in cRCC, and should be further evaluated as a tool in the clinic when treating RCC patients.
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| 7. |
- Rosestedt, Maria
(författare)
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Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The HER3 receptor plays a strong role in disease progression and resistance to therapies in several cancer types. Due to its endogenous expression and low overexpression in malignant tumours, it is a particularly challenging target. The primary aim of this thesis project was to develop, evaluate and characterize affibody molecules for theranostic applications in HER3-expressing malignant tumours.Paper I investigated the in vivo targeting properties and therapeutic efficacy of a bivalent affibody construct fused with an albumin binding domain, ZHER3-ABD-ZHER3. This construct could slow down the growth of HER3-expressing tumour xenografts without causing health problems or side effects in mice.Paper II compared the in vitro and in vivo properties of two HER3-targeting affibody molecules (Z08698 and Z08699) to select an imaging probe for HER3 diagnostics. While the two constructs had similar properties, Z08698 demonstrated better blood clearance and better radioactivity retention in tumours.Paper III and IV present the development of a HER3 imaging probe for PET using gallium and cobalt isotopes. We demonstrated that imaging of HER3 expression could be obtained as soon as 3 h pi using gallium-68. Additionally, we demonstrated that affibody molecules labelled with a neutral cobalt-NOTA complex had a lower radioactivity uptake in the liver than molecules radiolabelled with a positive gallium-NOTA complex. Imaging contrast increased over time. As the dose of the injected protein increased, the activity uptake in normal organs decreased, whereas the tumour uptake remained the same, which improved the imaging contrast and allowed discrimination between xenografts with high and low HER3 expression. This modification did not influence tumour activity uptake.Paper V presents the HER3-targeting affibody molecule trimer as a tool to block hepatic uptake in order to increase the imaging contrast in the liver. The trimer demonstrated its ability to bind to endogenous receptors in the liver, which decreased the hepatic uptake of the radiolabelled monomer. This phenomenon enabled the monomer to pass the liver barrier, which increased tumour radioactivity uptake and improved imaging contrast.
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| 8. |
- Sundqvist, Nicolas, 1993-
(författare)
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Mathematical Modelling of Cerebral Metabolism : From Ion Channels to Metabolic Fluxes
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The brain is the most metabolically active organ in the human body and therefore rely on a continuous supply of oxygen and glucose. Neuronal stimulation in specific regions of the leads to the firing of action potentials, a process facilitated by voltage-gated ion channels in the neurons’ cell membranes. This activation of the ion channels significantly elevates the brain’s metabolic energy demand, compelling neurons to ramp up their metabolic activity in response. Concurrently, this neuronal activation also initiates a signalling cascade that induces vasodilation and increases blood flow, thereby ensuring that regions with elevated neural activity are adequately supplied with oxygen and nutrients. This dynamic interplay between neuronal activity and cerebral blood flow (CBF) regulation constitutes the neurovascular coupling (NVC). The NVC is a cornerstone in interpreting functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level-Dependent (BOLD) responses. The BOLD response is an indirect, non-invasive, and highly sensitive indicator of neuronal activity, reflecting changes in blood oxygenation and flow associated with the neuronal and metabolic activity in the brain. By examining these responses, we can gain insights into the complex interactions between neuronal activity, energy metabolism, and CBF.Additionally, techniques such as 13C Metabolic Flux Analysis (13C MFA) makes it possible to gain further insight into the cerebral metabolism. This method enables a detailed examination of metabolic pathways and fluxes by tracking the incorporation of 13C-labelled substrates into various metabolites. By using 13C MFA, researchers can quantify the flow of substrates through metabolic networks, offering a deeper understanding of how cell such as neurons adapt their metabolism during different functional states and conditions.Central to exploring these multifaceted aspects of cerebral metabolism is the use of mathematical modelling and systems biology. These disciplines provide a framework for integrating diverse biological data, allowing for the simulation and prediction of complex neurovascular interactions under various physiological and pathological conditions. Mathematical models can encapsulate the dynamics of ion channel kinetics, metabolic pathways, and neurovascular coupling, offering a comprehensive view of the interplay between neuronal activity, metabolism, and cerebral blood flow. This approach is instrumental in bridging the gap between molecular-scale events and observable physiological phenomena, enhancing our understanding of cerebral metabolism and its critical role in the brain’s function.Paper I sets the foundation by developing a mechanistic model that integrates the mechanisms of the NVC with the metabolism. This model connects cerebral regulation of blood flow and metabolism, using small mechanistic model to represent the central metabolism. By integrating experimental data based on nuclear magnetic resonance spectroscopy (NMRS), the model successfully captures the dynamics of metabolites in response to neuronal stimuli, providing a crucial link between metabolic changes and NVC.Paper II extends the investigation to the realm of ion channel kinetics. By developing a generic model structure for voltage-gated ion channels, this paper explores how ion channel activity, a fundamental aspect of neuronal function, influences cerebral metabolism. The model, validated against experimental data and existing kinetic models, accurately predicts various channel behaviours and action potential characteristics. It includes mechanisms like voltage sensor movements and rate constants dependent on membrane voltage, offering a universal approach for studying all types of voltage-gated ion channels in neural networks and other applications.Paper III further explores the neurovascular relationship by examining the influence of inhibitory neurons on CBF and metabolism. This study introduces an expanded mathematical model that integrates the effects of γ-aminobutyric acid(GABA)ergic inhibitory neurons on vascular responses, aligning with new experimental evidence and enhancing understanding of neurovascular coupling (NVC). The model, validated with data from various studies, not only captures vascular changes triggered by inhibitory neuron activation but also reveals how these neurovascular responses vary with stimulation frequency, underscoring the important role of inhibitory neuron in the NVC.Paper IV tackles the critical aspect of accurately measuring metabolic fluxes in cells, focusing on 13C MFA. This study introduces a novel approach for model selection in MFA, ensuring that the chosen models accurately represent the underlying metabolic processes. This method enhances our ability to identify and understand key metabolic pathways and reactions, providing deeper insights into various metabolic conditions. Connecting back to the cerebral metabolism, application of 13C MFA to neuronal systems offers a powerful tool for studying metabolically linked neuropathology such as the development of Alzheimer’s disease.In Conclusion, this thesis establishes key components for understanding the mechanisms of the cerebral metabolism. The integration of mathematical modelling across different scales, from ion channels to cerebral blood flow, is used to provide a comprehensive perspective on how cerebral metabolism is regulated and how it interacts with other physiological processes. This work not only advances our basic scientific knowledge but also holds significant potential for improving our understanding of neurological disorders where metabolism and neurovascular function are impaired.
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| 9. |
- Thomasson, Marcus, 1973-
(författare)
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Expression and prognostic value of LRIG1 and the EGF-receptor family in renal cell and prostate cancer
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The epidermal growth factor receptor (EGFR) family consists of four (EGFR, ErbB2, Erbb3, and ErbB4) receptor tyrosine kinases (RTK) whose signalling is important for physiological and malignant cellular functions such as proliferation, survival, migration, and differentiation. EGFR and ErbB2 in particular are established oncogenes in many solid tumours and are targets for anti-cancer treatment. LRIG1 (leucine-rich repeats and immunoglobulin-like domains-1) is a protein that negatively regulates the EGFR-family, and other RTKs and is a proposed tumour suppressor. This thesis examines the expression of the EGFR-family members and LRIG1 in renal cell carcinoma (RCC) and in prostate cancer (PC). In RCC, up-regulation of EGFR was shown for all RCC types analysed: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC). ErbB2 was down-regulated in ccRCC. ErbB3 expression was low in non-neoplastic kidney and not significantly altered in RCC. ErbB4 was strongly down-regulated in the vast majority of RCCs of all types. LRIG1 was down-regulated in ccRCC. No prognostic value was found for any of these factors in RCC. In prostate cancer cells, LRIG1 was shown to be up-regulated by androgen stimulation and suppressed the growth of prostate cancer cells. In prostate cancer, the expression and prognostic value of LRIG1 was investigated in two patient series, one with untreated patients and one with patients who had undergone prostatectomy. In the untreated patient series, LRIG1 correlated with malignancy grade (Gleason score) and poor outcome for patients (both cancer specific and overall survival), being an independent prognostic factor. In contrast, in the series of patients who had undergone prostatectomy, LRIG1 expression correlated with a good outcome (overall survival). Thus in RCC, there were alterations in gene-expression of the EGFR-family members and LRIG1 between kidney cortex and RCC and between the RCC types. Despite few associations with clinical factors, these alterations are likely to be of biological importance. In prostate cancer LRIG1 was up-regulated by androgen stimulation and inhibited cell proliferation. LRIG1 expression had prognostic value in prostate cancer, maybe as a secondary marker of androgen receptor activation or because of growth inhibition of prostate cancer cells. Contradicting findings in untreated patients and patients treated with prostatectomy poses the question of whether the prognostic value of LRIG1 and other markers vary depending on the specific biological and clinical circumstances in the materials studied.
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| 10. |
- Gustiené, Prima, 1955-
(författare)
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Development of a new service-oriented modelling method for information systems analysis and design
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis presents a new modelling method for information systems analysis and design, where the concept of service and the principles of service orientation are used for integrated modelling and reasoning about information systems architectures across organisational and technical systems boundaries. The concept of service enables cohesion of the intersubjective and objective modelling traditions by using a single type of diagram that facilitates detection of semantic inconsistency, incompleteness, ambiguity and discontinuity between the static and dynamic aspects of information systems specifications. The thesis is focused on three research topics, which are fundamental to the development of a new service-oriented modelling method. The first research topic concerns a pragmatic-driven specification of information systems. It clarifies answers to the research question: How can a conceptual modelling process be driven by pragmatic considerations? The second research topic provides a service-oriented modelling foundation for information systems analysis and design. It answers the research questions: How can the concept of service be used explicitly for the analysis and design of information systems and how can the static and dynamic aspects of information systems specifications be integrated at the conceptual level? The third research topic presents transition principles to implementation-specific design and answers the research question: How can service-oriented conceptual representations be aligned with implementation-specific design? The thesis contributes with a new knowledge to the area of conceptual modelling of information systems. The service-oriented modelling method consists of the modelling process, modelling language and techniques for the analysis and design of information systems on three levels of abstraction: pragmatic, semantic and syntactic. These three levels are necessary for a holistic understanding of enterprise architecture by stakeholders. The advantage of the service-oriented modelling method is that it can help to control traceability from information system design to original requirements. The method facilitates the semantic integration of the structural, behavioural and interactive aspects of information systems conceptual representations by using a single diagram type. The modelling language provides service-oriented constructs that are fundamental to building the major systems analysis patterns. The service-oriented modelling process contributes with seven steps of incremental design, which justifies various information systems components. The method provides the basis for a gradual and systematic way of modelling and an understanding of how pragmatic, semantic and logical information system requirements are linked together. The possibility to detect and eliminate undesirable characteristics of service-oriented diagrams can help to improve communication among stakeholders. Service-oriented specifications are computation-neutral and therefore they are more comprehensible for business analysis experts in comparison to implementation specific graphical representations of information systems. Finally, this thesis presents the challenges for future research, one of which is the development of the automated tools for the alignment of business models with implementation-specific information systems specifications.
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