363 research outputs found

    The reflective practitioner: In creation of PEGASYS

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    This paper discusses the framework of a presence-generating art system (PEGASYS) in development as part of practice-based research. The interactive audio-visual panoramic computer-based system provides engagement with a natural terrain, incorporating site-specific performance and augmented characters made possible through the design, production and implementation of a tetradecagon (14 sided) camera plate. A gaze-based interface facilitates a biotechnological interaction that utilizes our ability to see in a human-computer orientation. The co-joining of eye-gaze technology with human strengths produces an outcome that facilitates engagements that can be deeply rewarding, embedding participants in new relationships with remote natural habitats

    Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

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    Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

    Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

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    Aims/hypothesis: Our aims were to compare osteoclastic activity between patients with acute Charcot's osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods: Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results: In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p=0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p<0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264±0.06% to 41.6±8.1%, p<0.0001) and diabetic control (0.000±0.00% to 14.2±16.5%, p<0.0001) patients, and also in healthy control participants (0.004±0.01% to 10.5±1.9%, p0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6±8.1% to 5.9±2.4%, p=0.001), this suppression was not as complete as in diabetic control patients (14.2±16.5% to 0.45±0.31%, p=0.001) and in healthy control participants (from 10.5±1/9% to 0.00±0.00%, p<0.0001). Conclusions/interpretation: These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot's osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway
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