Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver

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Hepatocyte growth factor in human osteoarthritic cartilage

AbstractObjective Hepatocyte growth factor/scatter factor is a potent mitogen, morphogen and motogen for a variety of mainly epithelial cells. Hepatocyte growth factor is synthesized by mesenchymal cells and can be found in various tissues. The objective of this study was to investigate the expression and distribution patterns of this pleiotropic growth factor and its receptor, the product of the proto-oncogene c-met in normal and osteoarthritic human knee cartilage.Methods Five normal and 14 osteoarthritic human cartilage samples graded histomorphologically by Mankin Score, were studied by radioactive in-situ hybridization and immunohistochemistry for the expression of Hepatocyte growth factor and the c-met receptor.Results Hepatocyte growth factor could be found by immunohistochemistry in the territorial matrix surrounding the chondrocytes of calcified cartilage and within the deep zone of normal cartilage. Chondrocytes of these cartilage zones showed also positive c-met receptor-staining. Moreover, a small number of chondrocytes in the superficial and intermediate zone showed c-met staining. In accordance with the increased hepatocyte growth factor staining of osteoarthritic cartilage, an enhanced expression of hepatocyte growth factor-RNA by chondrocytes of the deep zone as well as the deeper mid zone was observed. Contrary to normal cartilage,c-met was identified immunohistochemically in osteoarthritic chondrocytes of all cartilage zones.Conclusion These results indicate that hepatocyte growth factor seems to be acting in an autocrine/paracrine manner in normal and osteoarthritic cartilage. The ubiquitous presence of the HGF/HGF-receptor complex in osteoarthritic chondrocytes suggests that hepatocyte growth factor may contribute to the altered metabolism in osteoarthritic cartilage.{copy

Fluorescence Correlation Spectroscopy Monitors the Fate of Degradable Nanocarriers in the Blood Stream

[Image: see text] The use of nanoparticles as carriers to deliver pharmacologically active compounds to specific parts of the body via the bloodstream is a promising therapeutic approach for the effective treatment of various diseases. To reach their target sites, nanocarriers (NCs) need to circulate in the bloodstream for prolonged periods without aggregation, degradation, or cargo loss. However, it is very difficult to identify and monitor small-sized NCs and their cargo in the dense and highly complex blood environment. Here, we present a new fluorescence correlation spectroscopy-based method that allows the precise characterization of fluorescently labeled NCs in samples of less than 50 μL of whole blood. The NC size, concentration, and loading efficiency can be measured to evaluate circulation times, stability, or premature drug release. We apply the new method to follow the fate of pH-degradable fluorescent cargo-loaded nanogels in the blood of live mice for periods of up to 72 h

Collagen type XVIII/endostatin is differentially expressed in primary and metastatic colorectal cancers and ovarian carcinomas

Collagen type XVIII (C18) is a nonfibrillar collagen of basement membranes. Its C-terminal fragment, endostatin, has been identified as an inhibitor of angiogenesis. C18 is predominantly expressed by hepatocytes of normal, cirrhotic and neoplastic liver. We compared the patterns of C18 RNA-expression in colonic adenocarcinoma metastases, which represent the most frequently occurring liver tumours, to normal colon mucosa, to primary colon cancers and to ovarian cancers which are often morphologically similar to colonic cancer or metastasis. Two C18-specific RNA-probes were generated to perform in situ hybridization combined with immunohistochemistry for cytokeratin, vimentin and the endothelial marker CD31, in order to characterize the C18-expressing cells. C18/endostatin protein was localized by immunohistology. In colorectal carcinomas and their liver metastases high levels of C18 transcripts were observed in endothelial cells and fibroblasts/myofibroblasts, whereas C18 RNA was virtually absent from carcinoma cells. Ovarian carcinomas displayed high C18 RNA expression both in carcinoma and stromal cells, indicating that induction of C18 transcription in tumour stromal cells is independent of the ability of carcinoma cells to express C18. While the role of tumour cell derived C18 in cancer growth regulation remains unknown, stimulation of proteolysis of the locally strongly expressed C18 to endostatin could offer an attractive approach for a targeted antineoplastic therapy. © 2001 Cancer Research Campaign   http://www.bjcancer.co

SAT-based Explicit LTL Reasoning

We present here a new explicit reasoning framework for linear temporal logic (LTL), which is built on top of propositional satisfiability (SAT) solving. As a proof-of-concept of this framework, we describe a new LTL satisfiability tool, Aalta\_v2.0, which is built on top of the MiniSAT SAT solver. We test the effectiveness of this approach by demonnstrating that Aalta\_v2.0 significantly outperforms all existing LTL satisfiability solvers. Furthermore, we show that the framework can be extended from propositional LTL to assertional LTL (where we allow theory atoms), by replacing MiniSAT with the Z3 SMT solver, and demonstrating that this can yield an exponential improvement in performance

Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease

Biomarkers are increasingly important in the clinical management of complex diseases, yet our ability to discover new biomarkers remains limited by our dependence on endogenous molecules. Here we describe the development of exogenously administered `synthetic biomarkers' composed of mass-encoded peptides conjugated to nanoparticles that leverage intrinsic features of human disease and physiology for noninvasive urinary monitoring. These protease-sensitive agents perform three functions in vivo: target sites of disease, sample dysregulated protease activities and emit mass-encoded reporters into host urine for multiplexed detection by mass spectrometry. Using mouse models of liver fibrosis and cancer, we show that they can noninvasively monitor liver fibrosis and resolution without the need for invasive core biopsies and can substantially improve early detection of cancer compared with clinically used blood biomarkers. This approach of engineering synthetic biomarkers for multiplexed urinary monitoring should be broadly amenable to additional pathophysiological processes and to point-of-care diagnostics