Quantification and Clinical Relevance of Cystatin C

An aging population and increasing rates of diabetes mellitus contribute to a high prevalence of kidney dysfunction – approximately 10 percent of adults in developed countries have chronic kidney disease (CKD). CKD is a progressive loss of kidney function and this remains permanent. Early recognition of this condition is important for prevention or impeding severe adverse cardiac and renal outcomes. Cystatin C is a low molecular weight cysteine protease inhibitor that has emerged as a biomarker of kidney function. The special potential of plasma cystatin C in this setting is related to its independency of muscle mass, which is a remarkable limitation of the traditional marker creatinine. Cystatin C is a sensitive marker in diagnosing mild and moderate CKD, especially in small children, in the elderly and in conditions where muscle mass is affected. Cystatin C is quantified with immunoassays, mainly based on particle-enhanced nephelometry (PENIA) or turbidimetry (PETIA). The aim of this study was to develop a rapid and reliable assay for quantification of human cystatin C in plasma or serum by utilizing time-resolved fluorescence-based immunoassay methods. This was accomplished by utilizing different antibodies, including polyclonal and 7 monoclonal antibodies against cystatin C. Different assay designs were tested and the best assay was further modified to a dry-reagent double monoclonal assay run on an automated immunonalyzer. This assay was evaluated for clinical performance in estimating reduced kidney function and in predicting risk of adverse outcomes in patients with non-ST elevation acute coronary syndrome. Of the tested assay designs, heterogeneous non-competitive assay had the best performace and was chosen to be developed further. As an automated double monoclonal assay, this assay enabled a reliable measurement of clinically relevant cystatin C concentrations. It also showed a stronger concordance with the reference clearance method than the conventional PETIA method in patients with reduced kidney function. Risk of all-cause mortality and combined events, defined by death and myocardial infarction, increased with higher cystatin C and cystatin C remained an independent predictor of death and combined events after adjustment to nonbiochemical baseline factors. In conclusion, the developed dry-reagent double monoclonal assay allows rapid and reliable quantitative measurement of cystatin C. As measured with the developed assay, cystatin C is a potential predictor of adverse outcomes in cardiac patients.

Theoretical background for market emergence framework : Case: Electricity Distribution Industry

Both the competitive environment and the internal structure of an industrial organization are typically included in the processes which describe the strategic management processes of the firm, but less attention has been paid to the interdependence between these views. Therefore, this research focuses on explaining the particular conditions of an industry change, which lead managers to realign the firm in respect of its environment for generating competitive advantage. The research question that directs the development of the theoretical framework is: Why do firms outsource some of their functions? The three general stages of the analysis are related to the following research topics: (i) understanding forces that shape the industry, (ii) estimating the impacts of transforming customer preferences, rivalry, and changing capability bases on the relevance of existing assets and activities, and emergence of new business models, and (iii) developing optional structures for future value chains and understanding general boundaries for market emergence. The defined research setting contributes to the managerial research questions “Why do firms reorganize their value chains?”, “Why and how are decisions made?” Combining Transaction Cost Economics (TCE) and Resource-Based View (RBV) within an integrated framework makes it possible to evaluate the two dimensions of a company’s resources, namely the strategic value and transferability. The final decision of restructuring will be made based on an analysis of the actual business potential of the outsourcing, where benefits and risks are evaluated. The firm focuses on the risk of opportunism, hold-up problems, pricing, and opportunities to reach a complete contract, and finally on the direct benefits and risks for financial performance. The supplier analyzes the business potential of an activity outside the specific customer, the amount of customer-specific investments, the service provider’s competitive position, abilities to revenue gains in generic segments, and long-term dependence on the customer.

Market entry patterns of Finnish SMEs entering China

In 2011 China became the world’s second largest economy overtaking Japan. With its rapidly growing middle class buying diverse goods from consumption products to sophisticated technology and luxury products, it is also the fastest growing export market in the world. The purpose of this study is to examine what types of market entry modes Finnish SMEs use in China, which factors affect on their decisions and whether they have switched or combined the strategies after entering China. The goal is to understand the relevance of the entry mode choice related to the internationalization process and to evaluate how well it suits the Chinese business environment. The empirical part of the study is a semi structured qualitative analysis of six case companies that represent different industry fields. The cases were selected based on the recent literature about the Finnish industry fields China is interested in to gain knowledge and expertise from. Companies included in the study are an architect office, two pharmaceutical development companies, an ICT company, a plastic mechanics company and a clean tech company. The results of this study indicated that the market entry patterns of Finnish SMEs in China differ from each other based on the factors related to company’s background, mode concerns and Chinese market influences.

An Assessment ofFatigue Strength of Load Carrying Welded Joints with Lack of Penetration

On yleisesti tiedossa, että väsyttävän kuormituksen alaisena olevat hitsatut rakenteet rikkoutuvat juuri hitsausliitoksista. Täyden tunkeuman hitsausliitoksia sisältävien rakenteiden asiantunteva suunnittelu janykyaikaiset valmistusmenetelmät ovat lähes eliminoineet väsymisvauriot hitsatuissa rakenteissa. Väsymislujuuden parantaminen tiukalla täyden tunkeuman vaatimuksella on kuitenkin epätaloudellinen ratkaisu. Täyden tunkeuman hitsausliitoksille asetettavien laatuvaatimuksien on määriteltävä selkeät tarkastusohjeet ja hylkäämisperusteet. Tämän diplomityön tarkoituksena oli tutkia geometristen muuttujien vaikutusta kuormaa kantavien hitsausliitosten väsymislujuuteen. Huomio kiinnitettiin pääasiassa suunnittelumuuttujiin, joilla on vaikutusta väsymisvaurioiden syntymiseen hitsauksen juuren puolella. Nykyiset määräykset ja standardit, jotka perustuvat kokeellisiin tuloksiin; antavat melko yleisiä ohjeita hitsausliitosten väsymismitoituksesta. Tämän vuoksi muodostettiin kokonaan uudet parametriset yhtälöt sallitun nimellisen jännityksen kynnysarvon vaihteluvälin, ¿¿th, laskemiseksi, jotta vältettäisiin hitsausliitosten juuren puoleiset väsymisvauriot. Lisäksi, jokaiselle liitostyypille laskettiin hitsin juuren puolen väsymisluokat (FAT), joita verrattiin olemassa olevilla mitoitusohjeilla saavutettuihin tuloksiin. Täydentäviksi referensseiksi suoritettiin useita kolmiulotteisia (3D) analyysejä. Julkaistuja kokeellisiin tuloksiin perustuvia tietoja käytettiin apuna hitsausliitosten väsymiskäyttäytymisen ymmärtämiseksi ja materiaalivakioiden määrittämiseksi. Kuormaa kantavien vajaatunkeumaisten hitsausliitosten väsymislujuus määritettiin käyttämällä elementtimenetelmää. Suurimman pääjännityksen kriteeriä hyödynnettiin murtumiskäyttäytymisen ennakoimiseksi. Valitulle hitsatulle materiaalille ja koeolosuhteille murtumiskäyttäytymistä mallinnettiin särön kasvunopeudella da/dN ja jännitysintensiteettikertoimen vaihteluvälillä, 'K. Paris:n yhtälön numeerinen integrointi suoritettiin FRANC2D/L tietokoneohjelmalla. Saatujen tulosten perusteella voidaan laskea FAT tutkittavassa tapauksessa. ¿¿th laskettiin alkusärön jännitysintensiteettikertoimen vaihteluvälin ja kynnysjännitysintensiteettikertoimen, 'Kth, perusteella. ¿Kth arvoa pienemmällä vaihteluvälillä särö ei kasva. Analyyseissäoletuksena oli hitsattu jälkikäsittelemätön liitos, jossa oli valmis alkusärö hitsin juuressa. Analyysien tulokset ovat hyödyllisiä suunnittelijoille, jotka tekevät päätöksiä koskien geometrisiä parametreja, joilla on vaikutusta hitsausliitosten väsymislujuuteen.

Effects of Cytochrome P450 Enzyme Inhibitors on the Pharmacokinetics of Nonsteroidal Anti-inflammatory Drugs and Venlafaxine

Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs. Inhibition of CYP enzymes usually increases the plasma concentrations of their substrate drugs and can thus alter the safety and efficacy of these drugs. The metabolism of many widely used nonsteroidal antiinflammatory drugs (NSAIDs) as well as the metabolism of the antidepressant venlafaxine is nown to be catalyzed by CYP enzymes. In the present studies, the effect of CYP inhibition on the armacokinetics and pharmacodynamics of NSAIDs and venlafaxine was studied in clinical trials with healthy volunteers and with a crossover design, by using different antifungal agents as CYP inhibitors. The results of these studies demonstrate that the inhibition of CYP enzymes leads to increased concentrations of NSAIDs. In most cases, the exposure to ibuprofen, diclofenac, etoricoxib, and meloxicam was increased 1.5to 2 fold when they were used concomitantly with antifungal agents. CYP2D6 inhibitor, terbinafine, substantially increased the concentration of parent venlafaxine, whereas the concentration of active moiety of venlafaxine (parent drug plus active metabolite) was only slightly increased. Voriconazole, an inhibitor of the minor metabolic pathway of venlafaxine, produced only minor changes in the pharmacokinetics of venlafaxine. These studies show that an evident increase in the concentrations of NSAIDs may be expected, if they are used concomitantly with CYP inhibitors. However, as NSAIDs are generally well tolerated, use of single doses of NSAIDs concomitantly with CYP inhibitors is not likely to adversely affect patient safety, whereas clinical relevance of longterm concomitant use of NSAIDs with CYP inhibitors needs further investigation. CYP2D6 inhibitors considerably affect the pharmacokinetics of venlafaxine, but the clinical significance of this interaction remains unclear.

Success factors of customer and supplier master data system

Especially in global enterprises, key data is fragmented in multiple Enterprise Resource Planning (ERP) systems. Thus the data is inconsistent, fragmented and redundant across the various systems. Master Data Management (MDM) is a concept, which creates cross-references between customers, suppliers and business units, and enables corporate hierarchies and structures. The overall goal for MDM is the ability to create an enterprise-wide consistent data model, which enables analyzing and reporting customer and supplier data. The goal of the study was defining the properties and success factors of a master data system. The theoretical background was based on literature and the case consisted of enterprise specific needs and demands. The theoretical part presents the concept, background, and principles of MDM and then the phases of system planning and implementation project. Case consists of background, definition of as is situation, definition of project, evaluation criterions and concludes the key results of the thesis. In the end chapter Conclusions combines common principles with the results of the case. The case part ended up dividing important factors of the system in success factors, technical requirements and business benefits. To clarify the project and find funding for the project, business benefits have to be defined and the realization has to be monitored. The thesis found out six success factors for the MDM system: Well defined business case, data management and monitoring, data models and structures defined and maintained, customer and supplier data governance, delivery and quality, commitment, and continuous communication with business. Technical requirements emerged several times during the thesis and therefore those can’t be ignored in the project. Conclusions chapter goes through these factors on a general level. The success factors and technical requirements are related to the essentials of MDM: Governance, Action and Quality. This chapter could be used as guidance in a master data management project.

Role of ErbB2 and ErbB4 in Cancer Growth, Prognosis and as Targets for Immunotherapy

ErbB receptors (EGFR, ErbB2, ErbB3 and ErbB4) are growth factor receptors that regulate signals of cell differentiation, proliferation, migration and survival. Inappropriate activation of these receptors is associated with the development and severity of many cancers and has prognostic and predictive value in cancer therapy. Drugs, such as therapeutic antibodies, targeted against EGFR and ErbB2, are currently used in therapy of breast, colorectal and head and neck cancers. The role of ErbB4 in tumorigenesis has remained relatively poorly understood. Alternative splicing produces four different isoforms of one ErbB4 gene. These isoforms (JM-a, JM-b, CYT-1 and CYT-2) are functionally dissimilar and proposed to have different roles in carcinogenesis. The juxtamembrane form JM-a undergoes regulated intramembrane proteolysis producing a soluble receptor ectodomain and an intracellular domain that translocates into the nucleus and regulates transcription. Nuclear signaling via JM-a isoform stimulates cancer cell proliferation. This study aimed to develop antibodies targeting the proposed oncogenic ErbB4 JM-a isoform that show potential in inhibiting ErbB4 dependent tumorigenesis. Also, the clinical relevance of ErbB4 shedding in cancer was studied. The currently used monoclonal antibody trastuzumab, targeting ErbB2, has shown efficacy in breast cancer therapy. In this study novel tissues with ErbB2 amplification and trastuzumab sensitivity were analyzed. The results of this study indicated that a subpopulation of breast cancer patients demonstrate increased shedding and cleavage of ErbB4. A JM-a isoform-specific antibody that inhibited ErbB4 shedding and consequent activation of ErbB4 had anti-tumor activity both in vitro and in vivo. Thus, ErbB4 shedding associates with tumor growth and specific targeting of the cleavable JM-a isoform could be considered as a strategy for developing novel ErbB-based cancer drugs. In addition, it was demonstrated that ErbB2 amplification is common in intestinal type gastric cancers with poor clinical outcome. Trastuzumab inhibited growth of gastric and breast cancer cells with equal efficacy. Thus, ErbB2 may be a useful target in gastric cancer.

The Role of an Oncoprotein CIP2A in Breast Cancer

Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein expressed in several human cancer types. Previously, CIP2A has been shown to promote proliferation of cancer cells. Mechanistically, CIP2A is known to inhibit activity of a tumor suppressor protein phosphatase 2A (PP2A) towards an oncoprotein MYC, further stabilizing MYC in human cancer. However, the molecular mechanisms how CIP2A expression is induced during cellular transformation are not well known. Also, expression, functional role and clinical relevance of CIP2A in breast cancer had not been studied before. The results of this PhD thesis work demonstrate that CIP2A is highly expressed in human breast cancer, and that high expression of CIP2A in tumors is a poor prognostic factor in a subset of breast cancer patients. CIP2A expression correlates with inactivating mutations of tumor suppressor p53 in human cancer. Notably, we demonstrate that p53 inactivation up-regulates CIP2A expression via increased expression of an oncogenic transcription factor E2F1. Moreover, CIP2A promotes expression of E2F1, and this novel positive feedback loop between E2F1 and CIP2A is demonstrated to regulate sensitivity to both p53-dependent and -independent senescence induction in breast cancer cells. Importantly, in a CIP2A deficient breast cancer mouse model, abrogation of CIP2A attenuates mammary tumor formation and progression with features of E2F1 inhibition and induction of senescence. Furthermore, we demonstrate that CIP2A expression defines the cellular response to a senescence-inducing chemotherapy in breast cancer. Taken together, these results demonstrate that CIP2A is an essential promoter of breast cancer tumor growth by inhibiting senescence. Finally, this study implicates inhibition of CIP2A as a promising therapy target for breast cancer.

Roles of leadership in complex environments : Enhancing Knowledge Flows in Organisational Constellations through Practice-Based Innovation Processes

Global challenges, complexity and continuous uncertainty demand development of leadership approaches, employees and multi-organisation constellations. Current leadership theories do not sufficiently address the needs of complex business environments. First of all, before successful leadership models can be applied in practice, leadership needs to shift from the industrial age to the knowledge era. Many leadership models still view leadership solely through the perspective of linear process thinking. In addition, there is not enough knowledge or experience in applying these newer models in practice. Leadership theories continue to be based on the assumption that leaders possess or have access to all the relevant knowledge and capabilities to decide future directions without external advice. In many companies, however, the workforce consists of skilled professionals whose work and related interfaces are so challenging that the leaders cannot grasp all the linked viewpoints and cross-impacts alone. One of the main objectives of this study is to understand how to support participants in organisations and their stakeholders to, through practice-based innovation processes, confront various environments. Another aim is to find effective ways of recognising and reacting to diverse contexts, so companies and other stakeholders are better able to link to knowledge flows and shared value creation processes in advancing joint value to their customers. The main research question of this dissertation is, then, to seek understanding of how to enhance leadership in complex environments. The dissertation can, on the whole, be characterised as a qualitative multiple-case study. The research questions and objectives were investigated through six studies published in international scientific journals. The main methods applied were interviews, action research and a survey. The empirical focus was on Finnish companies, and the research questions were examined in various organisations at the top levels (leaders and managers) and bottom levels (employees) in the context of collaboration between organisations and cooperation between case companies and their client organisations. However, the emphasis of the analysis is the internal and external aspects of organisations, which are conducted in practice-based innovation processes. The results of this study suggest that the Cynefin framework, complexity leadership theory and transformational leadership represent theoretical models applicable to developing leadership through practice-based innovation. In and of themselves, they all support confronting contemporary challenges, but an implementable method for organisations may be constructed by assimilating them into practice-based innovation processes. Recognition of diverse environments, their various contexts and roles in the activities and collaboration of organisations and their interest groups is ever-more important to achieving better interaction in which a strategic or formal status may be bypassed. In innovation processes, it is not necessarily the leader who is in possession of the essential knowledge; thus, it is the role of leadership to offer methods and arenas where different actors may generate advances. Enabling and supporting continuous interaction and integrated knowledge flows is of crucial importance, to achieve emergence of innovations in the activities of organisations and various forms of collaboration. The main contribution of this dissertation relates to applying these new conceptual models in practice. Empirical evidence on the relevance of different leadership roles in practice-based innovation processes in Finnish companies is another valuable contribution. Finally, the dissertation sheds light on the significance of combining complexity science with leadership and innovation theories in research.

Membrane properties of structurally modified ceramides : effects on lipid lateral distribution and sphingomyelin-interactions in artificial bilayer membranes

Ceramides comprise a class of sphingolipids that exist only in small amounts in cellular membranes, but which have been associated with important roles in cellular signaling processes. The influences that ceramides have on the physical properties of bilayer membranes reach from altered thermodynamical behavior to significant impacts on the molecular order and lateral distribution of membrane lipids. Along with the idea that the membrane physical state could influence the physiological state of a cell, the membrane properties of ceramides have gained increasing interest. Therefore, membrane phenomena related to ceramides have become a subject of intense study both in cellular as well as in artificial membranes. Artificial bilayers, the so called model membranes, are substantially simpler in terms of contents and spatio-temporal variation than actual cellular membranes, and can be used to give detailed information about the properties of individual lipid species in different environments. This thesis focuses on investigating how the different parts of the ceramide molecule, i.e., the N-linked acyl chain, the long-chain sphingoid base and the membrane-water interface region, govern the interactions and lateral distribution of these lipids in bilayer membranes. With the emphasis on ceramide/sphingomyelin(SM)-interactions, the relevance of the size of the SMhead group for the interaction was also studied. Ceramides with methylbranched N-linked acyl chains, varying length sphingoid bases, or methylated 2N (amide-nitrogen) and 3O (C3-hydroxyl) at the interface region, as well as SMs with decreased head group size, were synthesized and their bilayer properties studied by calorimetric and fluorescence spectroscopic techniques. In brief, the results showed that the packing of the ceramide acyl chains was more sensitive to methyl-branching in the mid part than in the distal end of the N-linked chain, and that disrupting the interfacial structure at the amide-nitrogen, as opposed to the C3-hydroxyl, had greater effect on the interlipid interactions of ceramides. Interestingly, it appeared that the bilayer properties of ceramides could be more sensitive to small alterations in the length of the long-chain base than what was previously reported for the N-linked acyl chain. Furthermore, the data indicated that the SM-head group does not strongly influence the interactions between SMs and ceramides. The results in this thesis illustrate the pivotal role of some essential parts of the ceramide molecules in determining their bilayer properties. The thesis provides increased understanding of the molecular aspects of ceramides that possibly affect their functions in biological membranes, and could relate to distinct effects on cell physiology.

Evaluating the Strategic Objectives of Cameroonian Higher Education: An application of the Balanced Scorecard

Contemporary higher education operates in an environment of dwindling and parsimonious resources; the increasing need for accountability and relevance to varying stakeholders with differing expectations. These relatively new trends in higher education have been faced by business organizations which have developed different ways of operating in response. This study outlines one way by which business organizations have addressed similar circumstances to show how the Cameroon higher education (HE) could learn from business organizations to manage strategic objectives. The balanced scorecard (BSC) has been used by business organizations to address similar trends. This study evaluates the strategic objectives of Cameroonian higher education using the balanced scorecard. The system level is used to identify the general strategic objectives and one state university is used to represent the translation and implementation of the objectives at the institution level. The BSC principles used include: operational strategic objectives; organizational alignment to the strategy; making strategy everyone’s everyday job; making strategy continual and; mobilizing the leadership for change. The underlying concepts in these principles are communication, consensus, relevance, and a participatory approach. The study employs data from policy documents, relevant literature, websites and semi-structured interviews. The research approach is qualitative and the analyses are done by making meaning of phenomena in their natural contexts. The results show that there is a general knowledge of the strategic objectives but there is disagreement on the relevance of these objectives to HE and on the type of approaches used in implementing the objectives. It was also found that the relevant stakeholders are known, but not all the respondents agree on the importance of these stakeholders. All stakeholders do not have the same level of influence-the state is the most influential. Reporting is sufficiently done but there are insufficient provisions for feedback from stakeholders. The study concludes that the BSC principles can be applied to the management of strategic objectives in Cameroon HE. For Cameroonian higher education, it is recommended that the focus should be first, on developing tools for strategy before the strategy itself. Even though the need for the BSC is confirmed the context does not seem sufficiently ready to implement the BSC as a strategic management tool. The proposed BSC framework can only be used as a communication tool. The barriers to managing strategic objectives in Cameroon HE are related to the communication, consensus, clarity and relevance. However, the system has prospects for improved management and eventual adoption of the BSC as both a strategic management and communication tool. In line with other BSC applications to higher education, this study concluded that it is more feasible to apply the balanced scorecard to a single higher education institution than to a higher education system. The study makes a contribution to the BSC by showing how its principles can be used in a non-business context. The study also opens up possibilities for future research on the same topic in a different context or the same context with a wider scope (more institutions and respondents); the same study with a deeper focus on the interrelationships between the different strategic objectives (strategy maps). The study could also be extended by including the perspectives of the identified stakeholders who are not directly part of the higher education system but constitute the environment in which higher education operates.