Evaluation of a gas sensor array and pattern recognition for the identification of bladder cancer from urine headspace.

Previous studies have indicated that volatile compounds specific to bladder cancer may exist in urine headspace, raising the possibility that headspace analysis could be used for diagnosis of this particular cancer. In this paper, we evaluate the use of a commercially available gas sensor array coupled with a specifically designed pattern recognition algorithm for this purpose. The best diagnostic performance that we were able to obtain with independent test data provided by healthy volunteers and bladder cancer patients was 70% overall accuracy (70% sensitivity and 70% specificity). When the data of patients suffering from other non-cancerous urological diseases were added to those of the healthy controls, the classification accuracy fell to 65% with 60% sensitivity and 67% specificity. While this is not sufficient for a diagnostic test, it is significantly better than random chance, leading us to conclude that there is useful information in the urine headspace but that a more informative analytical technique, such as mass spectrometry, is required if this is to be exploited fully

Discovery of novel irreversible inhibitors of IL-2 inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket

IL-2 inducible tyrosine kinase (Itk) plays a key role in antigen receptor signalling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted Cysteine442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by X-ray crystallography and enzymology, whilst demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models