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Rigosertib is a novel benzyl styryl sulfone that inhibits the growth of a wide variety of human tumor cells in vitro and in vivo and is currently in Phase III clinical trials. We recently provided structural and biochemical evidence to show that rigosertib acts as a RAS-mimetic by binding to Ras Binding Domains (RBDs) of the RAF and PI3K family proteins and disrupts their binding to RAS. In a recent study, Jost et al (2017) attributed the mechanism of action of rigosertib to microtubule-binding. In these studies, rigosertib was obtained from a commercial vendor. We have been unable to replicate the reported results with clinical grade rigosertib, and hence compared the purity of clinical grade and commercially sourced rigosertib. We find that the commercially sourced rigosertib contains a p p r o xi m a t e l y 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical grade rigosertib, which is free of this impurity, does not exhibit tubulin binding activity. In vivo, cell lines that express mutant b-tubulin (TUBBL240F) were also reported to be resistant to the effects of rigosertib. However, our studies showed that both wild-type and TUBBL240F-expressing cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Morphologically, we find that rigosertib, at lethal concentrations, induced a senescence-like phenotype in the small percentage of both wild-type and TUBBL240F-expressing cells that survive in the presence of rigosertib.Our results suggest that TUBBL240F expressing cells are more prone to undergo senescence in the presence of rigosertib as well as BI2536, an unrelated ATP-competitive pan-PLK inhibitor.The appearance of these senescent cells could be incorrectly scored as resistant cells in flow cytometric assays using short term cultures.

The details of the various parameters were of great help in evolving this modus operandi. The clinical as well as histopathologic features of lupus miliaris disseminatus faciei are fairly distinct and facilitate visualizing the entity as a spectrum comprising early, fully developed, and late lesions. Further studies are called for.

The pancreas comprises exocrine and endocrine compartments, with the latter comprising the pancreatic islet with its endocrine cells. In both type1 and type2 diabetes, several morphological changes occur in the pancreas, but the predominant feature of beta cell loss. Our aim of this study is to find out of histopathological changes in pancreas due to diabetes and correlate it with clinical findings. Methods: A prospective study was done on 50 autopsy specimens of pancreas. Specimens were fixed in formalin and tissue was adequately processed. The sections were stained with routine haematoxylene and eosin stain. Results: In our study 86% cases were of T1DM and 14% of T2DM. Most common age group was between 40-60 years (62% cases). 68% cases had duration of DM of 10-20 years. On histopathological examination, 85% Cases of T1DM revealed cytolysis and inflammation in exocrine pancreas. In cases of T2DM cytolysis was seen in 32% cases, inflammation in 25% and fibrosis in 16% cases.. Fibrosis was present in 14% cases of T1DM and 25% cases of T2DM in endocrine pancreas. Insulitis in endocrine pancreas was seen in 85% cases of T1DM and 34% cases of T2DM. Thus, the most common finding was reduced beta cell mass in T2DM and insulitis in T1DM. Findings were correlated with age, sex and duration of diabetes. Conclusion: With increasing incidence of diabetes knowledge of pathogenesis of changes due to diabetes in pancreas may lead to research of further targeted therapy in better management of diabetes in future. Changes that occur in pancreas due to diabetes are more evident in long standing diabetes and early changes are not evident in routine histopathological sections.

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