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  • tropisetron It is technically challenging to extract

    2018-11-14

    It is technically challenging to extract proteins of interest from bone due to the abundance of collagens and minerals. A pilot study using HCl/Urea extraction identified 119 proteins in OA subchondral bone with only 7 proteins shared between the low and high damage regions. This data suggests that signalling pathways in the corresponding subchondral bone region may relate to OA severity (). However, validation is required with the authors acknowledging that the regional variations could be due to experimental error. Bone–cartilage communication models are needed to elucidate soluble mediators. Previously we have employed a cartilage explant model system to investigate the secretome of cartilage in response to inflammatory stimuli (). A similar model system is required using osteochondral co-cultured explants to identify novel soluble factors released in response to inflammation or loading when the bone-cartilage juncture is intact. Recently an three-dimensional microsystem that models the osteochondral unit was developed. Osteogenic and chondrogenic tissues were produced using mesenchymal stem cells seeded within biomaterial scaffolds in a multichamber bioreactor (). Tissue-specific gene expression, matrix production and a basophilic developing tidemark were detected. Introduction of interleukin-1β (IL-1β) to either the chondral or osseous medium induced strong degradative responses both locally and in the opposing tissue type. IL-1β treatment of the osseous compartment resulted in a stronger catabolic response in the chondral layer than direct IL-1β application to the chondral component. This study provides evidence for active biochemical communication across the bone-cartilage interface and supports the osteochondral nature of OA (). Development of cell based model systems will allow investigation into the release of soluble factors by stimulated osteoblasts/osteocytes that can induce a pro-catabolic phenotype in chondrocytes. An iTRAQ secretome analysis revealed that a soluble protein (14-3-3ε) was differentially present when a mechanical stress was applied on osteoblasts and that these secreted mediators could activate chondrocytes to produce metalloproteinases ().
    Hepatitis B is an old disease and the possibility to successfully vaccinate against infection by hepatitis B virus (HBV) was first shown 36years ago in a convincing trial (). Thus, it may appear unspectacular when in this issue of , a small clinical trial with a new type of hepatitis B vaccine is described (). Do we really need this? But the significance of the paper should not be underestimated. The classical hepatitis B vaccine is produced in genetically transformed yeast cells and consists of 20-nm-large particles formed by the small (S) protein of hepatitis B surface antigen (HBsAg). The tropisetron against conformational epitopes of HBsAg (anti-HBs) neutralize the infectivity of hepatitis B virus (HBV) in vitro and indicate protection in vivo. However, the classical vaccine has some shortcomings. In spite of multiple injections some persons remain unprotected, particularly those with a weakened immune response. Furthermore, asymptomatic infections by heterologous HBV genotypes with transient viremia are frequent in vaccinated subjects with low or moderate anti-HBs titers (for review see ). While the WHO, public health authorities and the main producers of hepatitis B vaccines still consider these tropisetron drawbacks as insignificant, an enhanced protective capacity against a wider HBV genotype spectrum would not hurt. A weakness of the current HBV vaccines is that they were designed at a time when the S protein was believed to be the only component of the viral envelope. Soon after, two related, larger HBV envelope proteins (L for large and M for middle) were discovered (). L protein consists of the S sequence and an amino-terminal preS part which is further divided into preS1 and preS2. PreS2 forms the aminoterminal part of M. The preS1 domain of L was identified as the species-, liver- and differentiation-specific attachment site of HBV to liver cells (). Currently, a not widely used vaccine is available which is expressed in mammalian cell cultures and contains small amounts of M and L protein as minor components of S-HBsAg particles. It has superior immunogenicity (), but it remains open whether this is due to the preS components or to better immunogenicity of the S part. Isolated preS antigen without HBsAg had generated neutralizing antibodies in experimental animals () but was never administered to human recipients as a vaccine until the study performed by Cornelius et al. It is an irony of medicine history that this study was not intended to improve immunization against HBV but is a side product during the development of an immunotherapy against grass pollen allergy. The Valenta group fused DNA sequences encoding grass pollen allergen-specific peptides to the preS sequence, expressed this construct in , and obtained after purification a vaccine called BM32. This vaccine was adsorbed to aluminum hydroxide and given in doses of 10–40μg (similar to the classical hepatitis B vaccine) to 30 human subjects. BM32 satisfied the expectations as grass pollen allergy immunotherapeutic, but the question of the current paper was: what was the effect of the preS carrier protein? Soluble monomeric proteins like the preS antigen are usually weak immunogens, but the data suggest that the antibody and T-cell responses against preS partial peptides are comparable to those against the classical HBsAg although no direct comparison was done. It remains open whether the allergen components changed the immune response against preS. It should be noted that a partial lipopeptide of preS1 linked with aminoterminal myristic acid is able to compete with natural HBV for its receptor and is used as the candidate drug Myrcludex in clinical studies for patients with chronic HBV and hepatitis delta virus infection (); but this drug candidate is not a vaccine.