Decorin as a multivalent therapeutic agent against cancer.

Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combating solid malignancies

Miscibility in blends of poly(vinyl chloride) and chlorinated poly(vinyl chloride) with polycarbonates/

Blends of aromatic polycarbonates with poly(vinyl chloride) (PVC) and chlorinated poly(vinyl chloride) (CPVC) have been investigated. The polycarbonates include homopolymers and copolymers based on bisphenol-A derivatives. Polycarbonate/polycarbonate blends were also studied. The primary method for studying miscibility was differential scanning calorimetry. Dynamic mechanical analysis and infrared analysis were also utilized. Blends of high molecular weight bisphenol-A polycarbonate (BPC) and tetramethylbisphenol-A polycarbonate (TMPC) were found miscible in all proportions at temperatures exceeding 300\sp\circC. The phase behavior of BPC blended with tetrachlorobisphenol-A polycarbonate (TCPC) was found to depend strongly on the molecular weight of the homopolymers. Low molecular weight blends exhibit LCST behavior. The remaining binary combinations of BPC, TMPC, TCPC, hexafluorobisphenol-A polycarbonate (HFPC), and tetrabromobisphenol-A polycarbonate (TBPC) form two-phase blends at all blend compositions between 20 and 80% by weight. TCPC forms single-phase blends with PVC. Annealing temperatures up to 240\sp\circC did not affect phase separation in these blends. Infrared analysis in the carbonyl stretch region does not implicate the carbonate group as a significant factor affecting miscibility in these blends. Dynamic mechanical analysis shows that the two polymers retain their own secondary relaxations. TCPC is also miscible with solution-chlorinated PVCs (solution-CPVCs) having chlorine contents up to 70.2 weight percent, by weight, chlorine. Slurry-chlorinated PVCs were also miscible with TCPC. TBPC appears to be miscible with PVC and CPVCs, though it shows more an affinity for the chlorinated PVCs. Miscibility in these blends is favorable interactions with vinyl chloride monomer and/or a repulsive, intramolecular copolymer effect within the solution-CPVC. Segmental interaction parameters, X\sb{\rm ij}, were estimated using a binary interaction, mean field theory which can be applied to miscibility data from copolymer-containing blends. The boundaries of miscibility windows in polycarbonate-copolymer/solution-CPVC blends were used to calculate X\sb{\rm ij}\u27s. Miscibility windows were shown to be sensitive to small changes in the $X\sb{\rm ij}.

Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy.

Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein kinase (AMPK), a major decorin-activated energy sensor kinase, prevented decorin-evoked TFEB induction and nuclear localization. In conclusion, our findings indicate a non-canonical (nutrient- and energy-independent) mechanism underlying the pro-autophagic bioactivity of decorin via PEG3 and TFEB

Effect of Foreclosure Status on Residential Selling Price: Comment

In this comment we examine the conclusion by Forgey, Rutherford, and VanBuskirk (1994) "that the foreclosed properties sold at a 23% discount," using a sample of nearly 2,000 residential property sales from the Las Vegas, Nevada area. We found that when not controlling for location with a set of dummy variables for ZIP codes, HUD foreclosed properties sold for between 12.18% and 13.96% below a random sample of properties not within one block of foreclosed properties. When controlling for location, using a set of thirty-one dummy variables for ZIP codes, the foreclosure discount fell to between 8.45% and 9.72%. When controlling for the common characteristics between foreclosed properties and their neighbors, we found foreclosure discounts are very small (between 0.17% and 2.48%) and no longer statistically significant. We conclude that foreclosure does not provide an opportunity for arbitrage profits, and this study does reinforce the findings of other studies that conclude real estate markets operate efficiently.

Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature.

Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin protein ligase Parkin and the tumor suppressor mitostatin. Induction of both proteins required the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, we discovered that endorepellin evoked mitochondrial depolarization in endothelial cells via a specific interaction between its two proximal LG1/2 domains and VEGFR2. We also found that following loss of membrane potential, mitostatin and parkin interact and that mitostatin associates with the established Parkin receptor mitofusin-2. In conclusion, we have identified a critical role for endorepellin in remodeling the autophagic transcriptome and influencing mitochondrial homeostasis

Mini-Review: Decorin, a Guardian from the Matrix

Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor-β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of growth factors or directly via the antagonism of receptor tyrosine kinases. We propose that decorin can be considered a guardian from the matrix because of its innate ability to oppose pro-tumorigenic cues. © 2012 American Society for Investigative Pathology

Effect of foreclosure status on residential selling price: Comment

In this comment we examine the conclusion by Forgey, Rutherford and VanBuskirk (1994) “that the foreclosed properties sold at a 23% discount,” using a sample of nearly 2,000 residential property sales from the Las Vagas, Nevada area. We found that when not controlling for location with a set of dummy variables for zip codes, HUD foreclosed properties sold for between 12.18% and 13.96% below a random sample of properties not within one block of foreclosed properties. When controlling for location, using a set of thirty-one dummy variables for zip codes, the foreclosure discount fell to between 8.45% and 9.72%. When controlling for the common characteristics between foreclosed properties and their neighbors, we found foreclosure discounts are very small (between .17% and 2.58%) and no longer statistically significant. We conclude that foreclosure does not provide an opportunity for arbitrage profits, and this study does reinforce the findings of other studies that conclude real estate markets operate efficiently