The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors

CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology

Enhancing Crowdsourcing Success: the Role of Creative and Deliberate Problem-Solving Styles

A growing number of firms are using crowdsourcing platforms to actively solicit the skills of external entities to help them solve innovation-related problems. Despite its increasing popularity, crowdsourcing has produced mixed success, because few external experts provide helpful solutions. The current research examines this issue by exploring why some external solvers are more successful than others. Grounded in dual-processing theory, this study combines survey and archival data to assess the impact of creative versus deliberate problem-solving styles on solving success. The results indicate that both styles can be effective, but their relative success depends on the amount of time a solver invests in a solution and his or her degree of contextual familiarity with the problem. Specifically, creative (deliberate) styles are more effective under conditions of high (low) contextual familiarity and shorter (longer) time investments. When solvers employ both styles, overall problem-solving success declines. Data source: surve

Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas

Pancreatic stellate cells (PSCs) play a central role as source of fibrogenic cells in pancreatic cancer and chronic pancreatitis. In contrast to quiescent hepatic stellate cells (qHSCs), a specific marker for quiescent PSCs (qPSCs) that can be used in formalin-fixed and paraffin embedded (FFPE) normal human pancreatic tissue has not been identified. The aim of this study was to identify a marker enabling the identification of qPSCs in normal human FFPE pancreatic tissue. Immunohistochemical (IHC), double-IHC, immunofluorescence (IF) and double-IF analyses were carried out using a tissue microarray consisting of cores with normal human pancreatic tissue. Cores with normal human liver served as control. Antibodies directed against adipophilin, α-SMA, CD146, CRBP-1, cytoglobin, desmin, GFAP, nestin, S100A4 and vinculin were examined, with special emphasis on their expression in periacinar cells in the normal human pancreas and perisinusoidal cells in the normal human liver. The immunolabelling capacity was evaluated according to a semiquantitative scoring system. Double-IF of the markers of interest together with markers for other periacinar cells was performed. Moreover, the utility of histochemical stains for the identification of human qPSCs was examined, and their ultrastructure was revisited by electron microscopy. Adipophilin, CRBP-1, cytoglobin and vinculin were expressed in qHSCs in the liver, whereas cytoglobin and adipophilin were expressed in qPSCs in the pancreas. Adipophilin immunohistochemistry was highly dependent on the preanalytical time interval (PATI) from removal of the tissue to formalin fixation. Cytoglobin, S100A4 and vinculin were expressed in periacinar fibroblasts (FBs). The other examined markers were negative in human qPSCs. Our data indicate that cytoglobin and adipophilin are markers of qPSCs in the normal human pancreas. However, the use of adipophilin as a qPSC marker may be limited due to its high dependence on optimal PATI. Cytoglobin, on the other hand, is a sensitive marker for qPSCs but is expressed in FBs as well.</p

Post-translational mechanisms of zinc signalling in cancer

Three groups of proteins are actively involved in the control of intracellular zinc, consisting of ZIP channels (SLC39A), ZnT transporters (SLC30A), and metallothioneins. Malfunctions of many zinc transport proteins, especially those belonging to the ZIP family which increase cytosolic zinc availability, have been associated with cancer. Importantly, post-translational modifications have been reported to play an increasing role in the functional control of ZIP channels. In this chapter, we therefore detail the established role of zinc signalling in cancer, with an emphasis on breast cancer, as well as demonstrate effects of post-translational modifications by phosphorylation and proteolytic cleavage