Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the ‘gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

SUMMARY1. Extracellular recordings were made from 123 synaptically activated neurones in the nucleus tractus solitarius of the chloralose-anaesthetized cat.2. Ninety-one neurones were activated by electrical stimulation of cardiac or pulmonary vagal branches and thirty-two by stimulation of the aortic nerve.3. lonophoretic application of GABA abolished or markedly reduced the evoked or spontaneous activity of each neurone tested. These inhibitory effects were antagonized by the simultaneous ionophoretic application of bicuculline.4. Glycine inhibited the evoked activity of 60 % of neurones tested. This inhibition could be antagonized by the simultaneous application of strychnine.5. Application of bicuculline alone increased the evoked or spontaneous activity of a large proportion of the neurones; strychnine alone had no significant effect on the evoked or spontaneous activity of the neurones.6. These results are consistent with the hypothesis that GABA acts as an inhibitory transmitter substance within the nucleus tractus solitarius.

Medical innovation is fundamental to improved patient care. EBUS can potentially reduce morbidity for lung cancer patients and save health community costs. However, with PbR the service provider delivers this at a loss as the tariffs do not reflect innovation and because of coding inaccuracies. We suggest tariffs for innovative procedures need to reflect the true cost.

SUMMARYThe location, within the brain stem, of vagal efferent neurones with axons in the cardiac and pulmonary branches of the cat, and the cardiac branch of the dog, have been defined. Horseradish peroxidase was applied to the cut central ends of these vagal branches and, after an appropriate time, sections of the brain stem were examined for labelled cell bodies. Labelled cell bodies were found ipsilaterally in the dorsal motor vagal nucleus, the nucleus ambiguus and in the reticular formation between these two nuclei. We suggest that the dual location for cell bodies of vagal axons may represent a separation of somata with myelinated and non-myelinated vagal axons to the nucleus ambiguus and the dorsal motor vagal nucleus respectively.