Leukocyte Heparanase: A Double-Edged Sword in Tumor Progression

Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate, a complex glycosaminoglycan found ubiquitously throughout mammalian cells and tissues. Heparanase has been strongly associated with important pathological processes including inflammatory disease and tumor metastasis, through its ability to promote various cellular functions such as cell migration, invasion, adhesion, and cytokine release. A number of cell types express heparanase including leukocytes, cells of the vasculature as well as tumor cells. However, the relative contribution of heparanase from these different cell sources to these processes is poorly defined. It is now well-established that the immune system plays a critical role in shaping tumor progression. Intriguingly, leukocyte-derived heparanase has been shown to either assist or impede tumor progression, depending on the setting. This review covers our current knowledge of heparanase in immune regulation of tumor progression, as well as the potential applications and implications of exploiting or inhibiting heparanase in cancer therapy

Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis

The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors

A general formulation for a mathematical pem fuel cell model

Abstract A general formulation for a comprehensive fuel cell model, based on the conservation principle is presented. The model formulation includes the electro-chemical reactions, proton migration, and the mass transport of the gaseous reactants and liquid water. Additionally, the model formulation can be applied to all regions of the PEM fuel cell: the bipolar plates, gas flow channels, electrode backing, catalyst, and polymer electrolyte layers. The model considers the PEM fuel cell to be composed of three phases: reactant gas, liquid water, and solid. These three phases can co-exist within the gas flow channels, electrode backing, catalyst, and polymer electrolyte layers. The conservation of mass, momentum, species, and energy are applied to each phase, with the technique of volume averaging being used to incorporate the interactions between the phases as interfacial source terms. In order to avoid problems arising from phase discontinuities, the gas and liquid phases are considered as a mixture. The momentum interactions between the fluid and solid phases are modeled by the Darcy-Forchheimer term. The electro-oxidation of H 2 and CO, the reduction of O 2 , and the heterogeneous oxidation of H 2 and CO are considered in the catalyst layers. Due to the small pore size of the polymer electrolyte layer, the generalized Stefan-Maxwell equations, with the polymer considered as a diffusing species, are used to describe species transport. One consequence of considering the gas and liquid phases as a mixture is that expressions for the velocity of the individual phases relative to the mixture must be developed. In the gas flow channels, the flow is assumed homogeneous, while the Darcy and Schlögl equations are used to describe liquid water transport in the electrode backing and polymer electrolyte layers. Thus, two sets of equations, one for the mixture and another for the solid phase, can be developed to describe the processes occurring within a PEM fuel cell. These equations are in a conservative form, and can be solved using computational fluid dynamic techniques

5' triphosphorylated small interfering RNAs control replication of hepatitis B virus and induce an interferon response in human liver cells and mice.

Approved therapies for chronic hepatitis B include systemic administration of interferon (IFN)-alfa and inhibitors of hepatitis B virus (HBV) reverse-transcription. Systemic application of IFN-alfa is limited by side effects. Reverse-transcriptase inhibitors effectively control HBV replication, but rarely eliminate the virus and can select drug-resistant variants. We aimed to develop an alternative therapeutic approach that combines gene silencing with induction of IFN in the liver. METHODS:To stimulate an immune response while inhibiting HBV activity, we designed 3 small interfering (si)RNAs that target highly conserved sequences and multiple HBV transcripts of all genotypes. A 5'-triphosphate (3p) was added to the siRNAs, turning them into a ligand for the cytosolic helicase retinoic acid-inducible protein I, which becomes activated and induces expression of type-I IFNs. Antiviral activity was investigated in cell lines that replicate HBV, in HBV-infected primary human hepatocytes, and in HBV transgenic mice. RESULTS: 3p-double-stranded RNA (3p-RNA) activated retinoic acid-inducible protein I, induced a strong type I IFN response (expression of IFN-β) in liver cells and showed transient but strong antiviral activity. Bifunctional, HBV-specific, 3p-siRNAs controlled replication of HBV more efficiently and for longer periods of time than 3p-RNAs without silencing capacity or siRNAs that targeted identical sequences but did not contain 3p. CONCLUSIONS: HBV-specific 3p-siRNAs are bifunctional antiviral molecules that induce production of type I IFNs in the liver and target HBV RNAs to inhibit viral replication