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Background Breast cancer is the most common malignancy in female patients worldwide. Because of its heterogeneity in terms of prognosis and therapeutic response, biomarkers with the potential to predict survival or assist in making treatment decisions in breast cancer patients are essential for an individualised therapy. Epigenetic alterations in the genome of the cancer cells, such as changes in DNA methylation pattern, could be a novel marker with an important role in the initiation and progression of breast cancer. Method DNA methylation and RNA-seq datasets from The Cancer Genome Atlas (TCGA) were analysed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox model. Applying gene ontology (GO) and single sample gene set enrichment analysis (ssGSEA) an epigenetic signature associated with the survival of breast cancer patients was constructed that yields the best discrimination between tumour and normal breast tissue. A predictive nomogram was built for the optimal strategy to distinguish between high- and low-risk cases. Results The combination of mRNA-expression and of DNA methylation datasets yielded a 13-gene epigenetic signature that identified subset of breast cancer patients with low overall survival. This high-risk group of tumor cases was marked by upregulation of known cancer-related pathways (e.g. mTOR signalling). Subgroup analysis indicated that this epigenetic signature could distinguish high and low-risk patients also in different molecular or histological tumour subtypes (by Her2-, EGFR- or ER expression or different tumour grades). Using Gene Expression Omnibus (GEO) the 13-gene signature was confirmed in four external breast cancer cohorts. Conclusion An epigenetic signature was discovered that effectively stratifies breast cancer patients into low and high-risk groups. Since its efficiency appears independent of other known classifiers (such as staging, histology, metastasis status, receptor status), it has a high potential to further improve likely individualised therapy in breast cancer.

Background Mesenchymal stem cells (MSCs) are attracting increasing interest for cell-based therapies, making use of both their immuno-modulating and regenerative potential. For such therapeutic applications, a massive in vitro expansion of donor cells is usually necessary to furnish sufficient material for transplantation. It is not established to what extent the long-term genomic stability and potency of MSCs can be compromised as a result of this rapid ex vivo expansion. In this study, we investigated the DNA damage response and chromosomal stability (indicated by micronuclei induction) after sub-lethal doses of gamma irradiation in murine MSCs at different stages of their in vitro expansion. Methods Bone-marrow-derived tri-potent MSCs were explanted from 3-month-old female FVB/N mice and expanded in vitro for up to 12 weeks. DNA damage response and repair kinetics after gamma irradiation were quantified by the induction of γH2AX/53BP1 DSB repair foci. Micronuclei were counted in post-mitotic, binucleated cells using an automated image analyzer Metafer4. Involvement of DNA damage response pathways was tested using chemical ATM and DNA-PK inhibitors. Results Murine bone-marrow-derived MSCs in long-term expansion culture gradually lose their ability to recognize endogenous and radiation-induced DNA double-strand breaks. This impaired DNA damage response, indicated by a decrease in the number of γH2AX/53BP1 DSB repair foci, was associated with reduced ATM dependency of foci formation, a slower DNA repair kinetics, and an increased number of residual DNA double-strand breaks 7 h post irradiation. In parallel with this impaired efficiency of DNA break recognition and repair in older MSCs, chromosomal instability after mitosis increased significantly as shown by a higher number of micronuclei, both spontaneously and induced by γ-irradiation. Multifactorial regression analysis demonstrates that in vitro aging reduced DNA damage recognition in MSCs after irradiation by a multiplicative interaction with dose ( p  < 0.0001), whereas the increased frequency of micronuclei was caused by an additive interaction between in vitro aging and radiation dose. Conclusion The detrimental impact of long-term in vitro expansion on DNA damage response of MSCs warrants a regular monitoring of this process during the ex vivo growth of these cells to improve therapeutic safety and efficiency.

In an economy increasingly dominated by digital platforms, incumbent firms are trying to launch platforms associated with their original products in an attempt to remain relevant and create additional value propositions. Yet, evidence shows that digital platform design from within a non-digital product company is not straightforward and many failures have been observed. As previous research is scarce to explain the root causes of this lack of platform success, we conducted a Delphi study with global experts in the automotive industry to identify those factors that can explain why these incumbents are failing with their digital platform initiatives. We identified six categories that complement the established body of knowledge on failure factors with digital platforms. Based on that, we suggest an integrative framework to explain typical failures in digital platforms by incumbents.

This paper takes a first step in aiding researchers to improve the relevance of their research to practice. By proposing that Information Systems researchers conduct applicability checks with practitioners on the research objects (for example, theories, models, frameworks, processes, technical artifacts, or other theoretically based IS artifacts) they either produce or use in theory-focused research, our paper presents an actionable, systematic approach to evaluating, establishing, and further improving research relevance. Furthermore, because it is an approach that can be conducted as an additional step either at the beginning or the end of the traditional research life cycle, it leaves untouched the rigorous methods used to conduct the study, that is, it does not compromise traditional research models. The approach we propose is based on the analyses of three dimensions of relevance that are critical to practitioners' attempts to internalize IS research findings (importance, accessibility, and suitability), and a comprehensive set of solutions that can be used to address them. Our analysis reveals that the most critical dimension for practice is the importance of the research to the needs of practice. The solution we propose to address that need is to conduct an applicability check on the research objects of interest. The applicability check forms an integral part of the research process, either prior to or following engagement in a typical research process. We present principles and criteria for the conduct and evaluation of an applicability check, which is primarily based on the focus group method, and secondarily on a modified nominal group technique.

Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell‐based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome‐based pathway analysis of in vitro‐expanded human bone marrow‐derived mesenchymal stem cell (hBM‐MSCs), supplemented with cellular assays focusing on DNA double‐strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (γ‐H2AX + 53BP1 foci) and repair (pBRCA1 + γ‐H2AX foci) of X‐ray‐induced DNA DSBs in hBM‐MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3‐ to fourfold reduction of their mRNA expression by qRT‐PCR. We conclude that the in vitro expansion of hMSCs can lead to aging‐related impairment of the recognition and repair of DNA breaks. During the process of their in vitro expansion, primary human BM‐MSCs experience a gradual impairment of their ability to recognize DNA double‐strand breaks. A reduced DNA damage response (fewer γ‐H2AX + 53BP1 foci) was associated with a downregulation of BRCA1‐related DNA repair by homologous recombination and chromosomal replication pathways, suggesting that in vitro aged hMSCs could be affected by reduced genetic stability.

Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure.

Digitization provides entirely new affordances for our economies and societies. This leads to previously unseen design opportunities and complexities as systems and their boundaries are re-defined, creating a demand for appropriate methods to support design that caters to these new demands. Conceptual modeling is an established means for this, but it needs to be advanced to adequately depict the requirements of digitization. However, unlike the actual deployment of digital technologies in various industries, the domain of conceptual modeling itself has not yet undergone a comprehensive renewal in light of digitization. Therefore, inspired by the notion of Industry 4.0, an overarching concept for digital manufacturing, in this commentary paper, we propose Modeling 4.0 as the notion for conceptual modeling mechanisms in a digital environment. In total, 12 mechanisms of conceptual modeling are distinguished, providing ample guidance for academics and professionals interested in ensuring that modeling techniques and methods continue to fit contemporary and emerging requirements.

Purpose - This paper summarizes typical pitfalls as they can be observed in larger process modeling projects.Design methodology approach - The identified pitfalls have been derived from a series of focus groups and semi-structured interviews with business process analysts and managers of process management and modeling projects.Findings - The paper provides a list of typical characteristics of unsuccessful process modeling. It covers six pitfalls related to strategy and governance (1-3) and the involved stakeholders (4-6). Further issues related to tools and related requirements (7-10), the practice of modeling (11-16), the way we design to-be models (17-19), and how we deal with success of modeling and maintenance issues (19-21) will be discussed in the second part of this paper.Research limitations implications - This paper is a personal viewpoint, and does not report on the outcomes of a structured qualitative research project.Practical implications - The provided list of total 22 pitfalls increases the awareness for the main challenges related to process modeling and helps to identify common mistakes.Originality value - This paper is one of the very few contributions in the area of challenges related to process modeling.

Purpose - This second part of the paper summarizes typical pitfalls as they can be observed in larger process modeling projects.Design methodology approach - The identified pitfalls have been derived from a series of focus groups and semi-structured interviews with business process analysts and managers of process management and modeling projects.Findings - The article continues the discussion of the first part. It covers issues related to tools and related requirements (7-10), the practice of modeling (11-16), the way we design to-be models (17-19), and how we deal with success of modeling and maintenance issues (19-21). Potential pitfalls related to strategy and governance (1-3) and the involved stakeholders (4-6) were discussed in the first part of this paper.Research limitations implications - This paper is a personal viewpoint, and does not report on the outcomes of a structured qualitative research project.Practical implications - The provided list of intotal 22 pitfalls increases the awareness for the main challenges related to process modeling and helps to identify common mistakes.Originality value - This paper is one of the very few contributions in the area of challenges related to process modeling.

Business Process Management (BPM) has become one of the most widely used approaches for the design of modern organizational and information systems. The conscious treatment of business processes as significant corporate assets has facilitated substantial improvements in organizational performance but is also used to ensure the conformance of corporate activities. This Handbook presents in two volumes the contemporary body of knowledge as articulated by the world's leading BPM thought leaders. This second volume focuses on the managerial and organizational challenges of BPM such as strategic and cultural alignment, governance and the education of BPM stakeholders. As such, this book provides concepts and methodologies for the integration of BPM. Each chapter has been contributed by leading international experts. Selected case studies complement their views and lead to a summary of BPM expertise that is unique in its coverage of the most critical success factors of BPM.The second edition of this handbook has been significantly revised and extended. Each chapter has been updated to reflect the most current developments. This includes in particular new technologies such as in-memory data and process management, social media and networks. A further focus of this revised and extended edition is on the actual deployment of the proposed theoretical concepts. This volume includes a number of entire new chapters from some of the world's leading experts in the domain of BPM.