Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

Maximum likelihood estimation of noise covariance matrices for state estimation of autonomous hybrid systems

A critical aspect of developing Bayesian state estimators for hybrid systems, that involve a combination of continuous and discrete state variables, is to have a reasonably accurate characterization of the stochastic disturbances affecting their dynamics. Recently, Bavdekar et al. (2011) have proposed a maximum likelihood (ML) based framework for estimation of the noise covariance matrices from operating input-output data when an EKF is used for state estimation. In this work, the ML framework is extended to estimation of the noise covariance matrices associated with autonomous hybrid systems, and, to a wider class of recursive Bayesian filters. Under the assumption that the innovations generated by an estimator form a white noise sequence, the proposed ML framework computes the noise covariance matrices such that they maximize the log-likelihood function of the estimator innovations. The efficacy of the proposed scheme is demonstrated through the simulation and experimental studies on the benchmark three-tank system. (C) 2016 Elsevier Ltd. All rights reserved

Comparative in vitro cytotoxic, anti-inflammatory and anti-microbiological activities of two indigenous Venda medicinal plants

Department of MicrobiologyBackground: The Vhembe region of the Limpopo province has a rich tradition of medicinal plants use. Traditionally, boiled roots of Ziziphus mucronata are used in the treatment of boils, general swelling and other skin infections. A combination of leaf paste and root infusion treats measles, dysentery, chest complains, and gland swelling. Pterocarpus angolensis is famous for the treatment of menorrhagia, infertility in women, wounds and pain management. The purpose of the present study was to compare the cytotoxicity, anti-inflammatory potential and anti-microbial activities of Ziziphus mucronata and Pterocarpus angolensis from the Vhembe region. Method: U937, MeWo, Vero and RAW 264.7 cells were treated to various concentrations (50, 100, or 125 or 250 μg/ml depending on assays) of Ziziphus mucronata and Pterocarpus angolensis. Cytotoxicity assay was done using MTT; Antiinflammatory activity was assessed using NO production; Anti-bacterial activity was done using the Micro-Broth dilution method and Anti-mycobacteria activity was determined using the Alamar Blue Method while RT activity was measured by ELISA. Results: Cytotoxicity results showed that Pterocarpus was more toxic than Ziziphus as observed in the Vero and MeWo cells; however both displayed toxicity towards a Human cancer cell line. Both extracts did not inhibit nitrate production but induced significant increase in macrophage activation. The plant extracts have shown anti-tuberculosis activity at concentrations >500 μg/ml and there was moderation inhibition of HIV replication. Conclusions: The results obtained indicated that the extracts have pro-inflammatory properties, and the observed toxicity on malignant cell lines must be investigated further for promising anti-cancer drug therapy.University of Venda, Research and Innovation Directorate(S/15/MBY10

More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments

Sarcomas are a diverse group of cancers with mesenchymal origin. Although sarcomas comprise less than 1% of cancers, there are more than 50 different subtypes that are quite different from one another in terms of both their biology and clinical behavior. Historically, the need for adequate patient numbers in clinical trials has pushed sarcoma researchers to lump these very different malignancies together and treat the patients using a "one-size-fits-all" approach. However, with improvements in our scientific understanding, we are finally ready for a histology-tailored therapeutic approach to these complex diseases. In this review, we discuss key advances in our understanding of the biology underlying selected sarcoma subtypes and how targeting these subtypes is relevant therapeutically with respect to both molecularly targeted agents as well as immunotherapy