Small fragments of the extracellular matrix component hyaluronic acid (sHA) are typically produced at sites of inflammation and tissue injury and have been shown to be associated with tumor invasiveness and metastasis. Here we report that exposure of human melanoma cells to sHA leads to nuclear factor kB (NFk-B) activation followed by enhanced expression of matrix metalloprotease (MMP) 2 and interleukin (IL)-8, factors that can contribute to melanoma progression. At the receptor level, we found that Toll-like receptor (TLR) 4 is involved in this signalling pathway, similar to the case in dendritic and endothelial cells. Specifically, we found that melanoma cells expressed TLR4 on their surface in vivo and in vitro, and using specific siRNA, we could clearly demonstrate the functional importance of TLR4 in sHA-triggered activation of IL-8 expression in melanoma cells. Furthermore, we also found that sHA treatment enhanced the motility of melanoma cells, an effect that could again be blocked by TLR4-specific siRNA. Together, our results suggest that sHA in melanoma might promote tumor invasiveness by inducing MMPand cytokine-expression, in part in a TLR4-dependent manner, providing new insights into the relationship between cancer and innate immunity.Key words: hyaluronan -cytokine -metalloprotease -melanoma cells -TLR4Please cite this paper as: Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4.

Although many methods have been proposed for engineering service systems and customer solutions, most of these approaches give little consideration to recombinant service innovation. Recombinant innovation refers to reusing and integrating resources that were previously unconnected. In an age of networked products and data, we can expect that many service innovations will be based on adding, dissociating, and associating existing value propositions by accessing internal and external resources instead of designing them from scratch. The purpose of this paper is to identify if current service engineering approaches account for the mechanisms of recombinant innovation and to design a method for recombinant service systems engineering. In a conceptual analysis of 24 service engineering methods, the study identified that most methods (1) focus on designing value propositions instead of service systems, (2) view service independent of physical goods, (3) are either linear or iterative instead of agile, and (4) do not sufficiently address the mechanisms of recombinant innovation. The paper discusses how these deficiencies can be remedied and designs a revised service systems engineering approach that reorganizes service engineering processes according to four design principles. The method is demonstrated with the recombinant design of a service system for predictive maintenance of agricultural machines.

Business Process Management is a boundaryspanning discipline that aligns operational capabilities and technology to design and manage business processes. The Digital Transformation has enabled human actors, information systems, and smart products to interact with each other via multiple digital channels. The emergence of this hyper-connected world greatly leverages the prospects of business processes -but also boosts their complexity to a new level. We need to discuss how the BPM discipline can find new ways for identifying, analyzing, designing, implementing, executing, and monitoring business processes. In this research note, selected transformative trends are explored and their impact on current theories and IT artifacts in the BPM discipline is discussed to stimulate transformative thinking and prospective research in this field.

The aim of this study was to investigate the expression of thyroid hormone receptor β1 (THRβ1) by immunohistochemistry in breast cancer (BC) tissues and to correlate the results with clinico-biological parameters. In a well-characterized cohort of 274 primary BC patients, THRβ1 was widely expressed with a predominant nuclear location, although cytoplasmic staining was also frequently observed. Both nuclear and cytoplasmic THRβ1 were correlated with high-risk BC markers such as human epidermal growth factor receptor 2 (HER2), Ki67 (also known as MKI67), prominin-1 (CD133), and N-cadherin. Overall survival analysis demonstrated that cytoplasmic THRβ1 was correlated with favourable survival (p = 0.015), whereas nuclear THRβ1 had a statistically significant correlation with poor outcome (p = 0.038). Interestingly, in our cohort, nuclear and cytoplasmic THRβ1 appeared to be independent markers either for poor (p = 0.0004) or for good (p = 0.048) prognosis, respectively. Altogether, these data indicate that the subcellular expression of THRβ1 may play an important role in oncogenesis. Moreover, the expression of nuclear THRβ1 is a negative outcome marker, which may help to identify high-risk BC subgroups.

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