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Extracellular matrix (ECM) molecules play important roles in regulating processes such as cell proliferation, migration, differentiation and survival. Decorin is a proteoglycan that binds to ('decorates') collagen fibrils in the ECM. Decorin also interacts with many growth factors and their receptors, the most notable of these interactions being its inhibitory activity on TGF-β, the growth factor responsible for fibrosis formation. We have generated a recombinant, multi-functional, fusion-protein consisting of decorin as a therapeutic domain and a vascular homing and cell-penetrating peptide as a targeting vehicle. This recombinant decorin (CAR-DCN) accumulates at the sites of the targeted disease at higher levels and, as a result, has substantially enhanced biological activity over native decorin. CAR-DCN is an example of how molecular engineering can give a compound the ability to seek out sites of disease and enhance its therapeutic potential. CAR-DCN will hopefully be used to treat severe human diseases. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc., (© 2018 The British Pharmacological Society.)

The molecular mechanisms of pulmonary arterial hypertension (PAH) remain ill-defined. The aims of this study were to obtain sequential endoarterial biopsy samples in a surgical porcine model of PAH and assess changes in histology and mRNA expression during the disease progression. Differentially expressed genes were then analyzed as potential pharmacological targets. Four Yucatan micro-pigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Endovascular samples were obtained with a biopsy catheter at baseline (before surgery) and from the left lung 7, 60, and 180 days after surgery. RNA was isolated from biopsy samples, amplified and analyzed. Dysregulated genes were linked to drugs with potential to treat or prevent PAH. With the development of PAH in our model, we identified changes in histology and in the expression of several genes with known or investigational inhibitors and several novel genes for PAH. Gene dysregulation displayed time-related variations during disease progression. Endoarterial biopsy provides a new method of assessing pulmonary vascular histology and gene expression in PAH. This analysis could identify novel applications for existing and new PAH drugs. The detection of stage- and disease-specific variation in gene expression could lead to individualized therapies.

Iron oxide nanoparticles (IONPs) are used in various MRI applications as negative contrast agents. A major challenge is to distinguish regions of signal void due to IONPs from those due to low signal tissues or susceptibility artifacts. To overcome this limitation, several positive contrast strategies have been proposed. Relying on IONP T(1) shortening effects to generate positive contrast is a particularly appealing strategy because it should provide additional specificity when associated with the usual negative contrast from effective transverse relaxation time (T(2)*) effects. In this article, ultrashort echo time imaging is shown to be a powerful technique which can take full advantage of both contrast mechanisms. Methods of comparing T(1) and T(2)* contrast efficiency are described and general rules that allow optimizing IONP detection sensitivity are derived. Contrary to conventional wisdom, optimizing T(1) contrast is often a good strategy for imaging IONPs. Under certain conditions, subtraction of a later echo signal from the ultrashort echo time signal not only improves IONP specificity by providing long T(2)* background suppression but also increases detection sensitivity, as it enables a synergistic combination of usually antagonist T(1) and T(2)* contrasts. In vitro experiments support our theory, and a molecular imaging application is demonstrated using tumor-targeted IONPs in vivo., (Copyright © 2010 Wiley-Liss, Inc.)

Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli. We have shown that TGF-beta 1 is unique in regulating the production of proteoglycans and matrix glycoproteins by glomerular cells in vitro. In an experimental model of glomerulonephritis in rats we found increased proteoglycan and fibronectin synthesis by cultured nephritic glomeruli, which was greatly reduced by addition of antiserum to TGF-beta 1. Conditioned media from glomerular cultures induced elevated proteoglycan synthesis when added to normal cultured mesangial cells. This stimulation was blocked by addition of TGF-beta antiserum. Glomerular histology showed mesangial matrix expansion with a time course that roughly paralleled that of the elevated proteoglycan synthesis by the nephritic glomeruli was increased. Administration of anti-TGF-beta 1 at the time of induction of glomerulonephritis suppressed the elevated extracellular matrix production and dramatically attenuated histological manifestations of the disease. Our results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.

MG-63 human osteosarcoma cells were selected for attachment and growth in increasing concentrations of a synthetic peptide containing the cell attachment-promoting Arg-Gly-Asp (RGD) sequence derived from the cell-binding region of fibronectin. Cells capable of attachment and growth in 5 mM concentrations of a peptide having the sequence Gly-Arg-Gly-Asp-Ser-Pro overproduce the cell surface receptor for fibronectin. No increase in fibronectin receptor gene copy number was detected by Southern blot analysis. The peptide-resistant MG-63.3A cells look very different from the MG-63 cells and resemble osteocytes. The resistant cells also grow more slowly than MG-63 cells. The enhanced expression of the fibronectin receptor on the resistant cells indicates that cells can regulate the amount of this receptor on their surface in response to environmental factors and that this may affect the phenotypic properties of the cell. MG-63.3A cells differ from MG-63 cells in their ability to form a calcified matrix in vitro and in their increased synthesis of type I collagen. The MG-63.3A cells synthesize 50-100-fold less prostaglandin E2, a mediator of bone resorption, than MG-63 cells. There is an overall down-regulation of chondroitin sulphate proteoglycans in MG-63.3A cells. These results are consistent with the hypothesis that such proteoglycans interfere with calcium phosphate deposition and with the observation that chondroitin sulphate is increased in a wide variety of neoplasms but is absent or in small amounts in normal tissue. We conclude that MG-63.3A cells represent a more differentiated cell type with osteoblast-like properties.

Circulating carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) levels were measured by radioimmunoassay in 53 patients with carcinoma of the ovary, 16 patients with other malignant genital tumors, and 31 women with nonmalignant diseases of the genital tract. The serum CEA concentration was elevated (greater than 5 ng/ml) in 11 patients with ovarian cancer, 2 patients with endometrial cancer, 1 patient with carcinoma of the cervix, and 1 patient with a benign embryonal cystic teratoma. Elevated CEA levels were found only in patients with advanced malignant disease, while early stages were associated with normal CEA concentrations. AFP levels were normal in all but 1 patient. Both CEA and AFP levels were markedly raised in a case of advanced genital carcinoma arising probably from the ovary. Ascitic fluid of another patient with ovarian cancer contained a high concentration of CEA, giving an identical reaction in immunodiffusion with CEA from colon cancer. The present results indicate that while the increased expression of carcinofetal components takes place in some malignant tumors of the female genital tract, it is usually a late phenomenon.

A wide variety of malignancies have associated tumor antigens. Two which have proven useful in the clinical detection and management of cancer are alphafetoprotein (AFP) and the carcinoembryonic antigen (CEA). These materials have been determined both by radioimmunoassay and by a newer technique employing enzymes to replace radioisotopea as markers. The interpretation of these immune assay results and the factors governing the shape of the standard curve are discussed. The advantages of 57Co over 22Na as a volume marker in radioimmunoassay are presented.

Recombinant DNA methods have been used to analyse core proteins of two different proteoglycans, one from a rat yolk sac tumour and the other from human fibroblasts and fetal membrane tissue. The processed core protein of the yolk sac tumour proteoglycan is a 104-amino acid polypeptide. This polypeptide contains a 49-amino acid serine-glycine repeat which clearly serves as the chondroitin sulphate attachment region. Genomic and mRNA blots suggest that this core protein is a member of a multigene family the members of which share the Ser-Gly repeat. The fibroblast/fetal membrane proteoglycan has a 329-amino acid core protein which is also processed from a larger precursor. This core protein contains three individual Ser-Gly dipeptides, one of which is known to be substituted with a chondroitin/dermatan sulphate side-chain. The availability of proteoglycan cDNA clones will facilitate gene transfer studies aimed at identifying the recognition sequences for the addition of the glycosaminoglycan. Gene transfer should also allow studies on the effects of proteoglycan expression on cellular properties such as adhesion and tumorigenicity.