No abstract

Melanomas frequently metastasize to distant organs and especially intracranial metastases still represent a major clinical challenge. Epigenetic reprogramming of intracranial metastases is thought to be involved in therapy failure, but so far only little is known about patient-specific DNA-methylation differences between intra- and extracranial melanoma metastases. Hierarchical clustering of the methylomes of 24 patient-matched intra- and extracranial melanoma metastases pairs revealed that intra- and extracranial metastases of individual patients were more similar to each other than to metastases in the same tissue from other patients. Therefore, a personalized analysis of each metastases pair was done by a Hidden Markov Model to classify methylation levels of individual CpGs as decreased, unchanged or increased in the intra- compared to the extracranial metastasis. The predicted DNA-methylation alterations were highly patient-specific differing in the number and methylation states of altered CpGs. Nevertheless, four important general observations were made: (i) intracranial metastases of most patients mainly showed a reduction of DNA-methylation, (ii) cytokine signaling was most frequently affected by differential methylation in individual metastases pairs, but also MAPK, PI3K/Akt and ECM signaling were often altered, (iii) frequently affected genes were mainly involved in signaling, growth, adhesion or apoptosis, and (iv) an enrichment of functional terms related to channel and transporter activities supports previous findings for a brain-like phenotype. In addition, the derived set of 17 signaling pathway genes that distinguished intra- from extracranial metastases in more than 50% of patients included well-known oncogenes (e.g. PRKCA, DUSP6, BMP4) and several other genes known from neuronal disorders (e.g. EIF4B, SGK1, CACNG8). Moreover, associations of gene body methylation alterations with corresponding gene expression changes revealed that especially the three signaling pathway genes JAK3, MECOM, and TNXB differ strongly in their expression between patient-matched intra- and extracranial metastases. Our analysis contributes to an in-depth characterization of DNA-methylation differences between patient-matched intra- and extracranial melanoma metastases and may provide a basis for future experimental studies to identify targets for new therapeutic approaches.

Companies invest significant sums of money in major Information Technology (IT) projects, yet success remains limited. Despite an abundance of IT Project Management (ITPM) resources available to project teams, such as the Project Management Institute (PMI) Body of Knowledge, IT standards and IT governance, a large percentage of IT projects continue to fail and ultimately get scrapped. Recent studies have shown an average of 66% IT project failure rate, with 52% of the projects being cancelled, and 82% being delivered late. The purpose of this research was to provide a way for uncovering potential causes of IT project failures by utilizing a systemic and holistic approach to identify critical success factors for project management. The holistic approach has enabled the development of an ITPM conceptual model, which provides a method to evaluate the critical success factors of a given project, and their alignment with each other. The adoption of the systemic methodology and its implementation increase the potential for IT project success, and alert project leaders of potential problems throughout the life of the project.

This chapter addresses the systemic integration of conceptual and empirical methods in Software Engineering (SWE) research in terms of the systems approach, where theory, empiricism, and pragmatics are combined as required in the research phases. The following themes form the framework of systemic integration during SWE research processes: Theme 1 - Research Planning (Problem Analysis & Literature Review); Theme 2 – Proposal Development; Theme 3 – Conceptualization; Theme 4 – Experimentation and Research Validation. An illustrative research example is provided in terms of the four themes. The purpose of this research example was to provide a way to uncover potential causes of Information Technology (IT) project failures by employing a systemic and holistic approach to identify critical success factors for Project Management (PM). This has enabled the development of an Information Technology Project Management approach, which provides a method to evaluate the critical success factors of a given project, and the alignment of these factors with each other. The systemic methodology and its implementation proposed in this research increase the potential for IT project success by alerting project leaders of potential problems throughout the life of the project.