Structural Studies on Spisulan: A Mucopolysaccharide from Clams

Spisulan, a novel type of acid mucopolysaccharide, has been isolated from clam tissues in purified form by relatively mild extraction procedures. The mucopolysaccharide is unusual in having a backbone peptide consisting of poly- threonine repeating units believed to be joined together by proline to form chains of relatively large size, as judged by viscosity and gel filtration results from Sephadex G-200. Chemical evidence indicates that short carbohydrate branches containing N-acetyl galactosamine, galactose and fucose are attached to the backbone peptide structure, presumably by glycosidic linkage to threonine. The sulfate content is sufficient to account for monosulfation of all carbohydrate groups and results from periodate oxidation are in agreement with this.     

Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

Introduction: Biologics drugs have succeeded in achieving a commercial dominance in the global market for new therapies and large pharmaceutical companies' interest remains strong through a continued commitment to pipeline development. It is not surprising, therefore, that next-generation biologics, particularly antibody-like scaffolds that offer many of the advantages of the original biologic drugs but in simplified formats, have entered the clinic as competing substitute therapeutic products, to capture market share.

Areas covered: Specifically, this paper will position shark-derived variable new antigen receptors (VNARs) within an overview of the existing biologics landscape including the growth, diversity and success to date of alternative scaffolds. The intention is not to provide a comprehensive review of biologics as a whole but to discuss the main competing single-domain technologies and the exciting therapeutic potential of VNAR domains as clinical candidates within this context.

Expert opinion: The inherent ability to specifically bind target and intervene in disease-related biological processes, while reducing off-site toxicity, makes mAbs an effective, potent and now proven class of therapeutics. There are, however, limitations to these ‘magic bullets’. Their size and complexity can restrict their utility in certain diseases types and disease locations. In contrast, a number of so-called alternative scaffolds, derived from both immunoglobulin- and non-immunoglobulin-based sources have been developed with real potential to overcome many of the shortcomings documented for mAb treatments. Unlike competing approaches such as Darpins and Affibodies, we now know that shark VNAR domains (like camel VHH nanobody domains), are an integral part of the adaptive immune system of these animals and have evolved naturally (but from very different starting molecules) to exhibit high affinity and selectivity for target. In addition, and again influenced by the environment in which they have evolved naturally, their small size, simple architecture, high solubility and stability, deliver additional flexibility compared to classical antibodies (and many non-natural alternative scaffolds), thereby providing an attractive basis for particular clinical indications where these attributes may offer advantages.     

Properties of a System of Public Idiotypes of Lupus Autoantibodies

We can conclude from the properties of the Id-16/6 system that a relatively restricted group of B cell clones is activated in systemic lupus erythematosus. Whether this is a property of the immunogeneic stimulus that causes the diseases (if indeed there is one), or whether the observations are due to an idiotypic network that favors the selection of Id-16/6-cxpressing B cells is not known. These alternatives are under investigation. Apart from these theoretical considerations, the high frequency of Id-16/6(+) autoantibodies, including pathogenic autoantibodies, in systemic lupus erythematosus may point to targets amenable to the specific therapy of the disease.     

Comparative Expression of Adult and Fetal V Gene Repertoires

A hallmark of the immune system is the extraordinary diversity associated with antibodies. This is made possible by a series of genetic rearrangements involving variable region gene segments. Considerable detail is known about these genetic mechanisms except for the enzymatic machinery involved. An important question in studies of the generation of diversity is whether V genes are selected for rearrangement mainly in a random manner or selected by particular developmental rules. Past studies have indicated that the acquisition of fetal and neonatal specificity repertoires is a nonrandom process. In this report, we review our studies that directly compare the adult and fetal/neonatal V gene repertoires. The evidence suggests that the adult repertoire is more diverse with indications of a random use of V_H gene families. However, whether V genes are indeed randomly used in the adult remains to be clarified at the V_H gene member level. The fetal repertoire, on the other hand, appears nonrandom in V gene usage. In addition, the fetal repertoire is mostly germline encoded with little evidence of junctional diversity. Taken together, the results indicate different rules for generation of the adult and fetal repertoires, findings most likely explain by distinct B cell subsets and B cell progenitors at early stages in ontogeny.     

Adequate sample size for developing prediction models is not simply related to events per variable

ObjectivesThe choice of an adequate sample size for a Cox regression analysis is generally based on the rule of thumb derived from simulation studies of a minimum of 10 events per variable (EPV). One simulation study suggested scenarios in which the 10 EPV rule can be relaxed. The effect of a range of binary predictors with varying prevalence, reflecting clinical practice, has not yet been fully investigated.Study Design and SettingWe conducted an extended resampling study using a large general-practice data set, comprising over 2 million anonymized patient records, to examine the EPV requirements for prediction models with low-prevalence binary predictors developed using Cox regression. The performance of the models was then evaluated using an independent external validation data set. We investigated both fully specified models and models derived using variable selection.ResultsOur results indicated that an EPV rule of thumb should be data driven and that EPV ≥ 20 ​ generally eliminates bias in regression coefficients when many low-prevalence predictors are included in a Cox model.ConclusionHigher EPV is needed when low-prevalence predictors are present in a model to eliminate bias in regression coefficients and improve predictive accuracy.