Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

Background NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Results There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer

Offers of assistance in politician–constituent interaction

This paper was accepted in the journal Discourse Studies [© Sage] and the definitive version is available at http:dx.doi.org/10.1177/1461445615602376How do politicians engage with and offer to assist their constituents; the people who vote them into power? We address the question by analyzing a corpus of 80 interactions recorded at the office of a Member of Parliament (MP) in the United Kingdom, and comprising telephone calls between constituents and the MP’s clerical ‘caseworkers’ as well as face to face encounters with MPs in their fortnightly ‘surgeries’. The data were transcribed, then analysed using conversation analysis, focusing on the design and placement of offers of assistance. We identified three types of offers within a longer ‘offering’ sequence: 1) ‘proposal offers’, which typically appear first in any offering sequence, in which politicians and caseworkers make proposals to help their constituents using formats that request permission to do so, or check that the constituent does indeed want help (e.g., “do you want me to”; “we could…”); 2) ‘announcement offers’, which appear second, and indicate that something has been decided and confirm the intention to act (e.g., “I will do X”), and 3) ‘request offers’, which appear third, and take for form “let me do X”. Request offers indicate that the offer is available but cannot be completed until the current conversation is closed; they also appear in environments in which the constituent reissues their problems and appears dissatisfied with the offers so far. The paper contributes to what we know about making offers in institutional settings, as well as shedding the first empirical light on the workings of the constituency office: the site of engagement between everyday members of the public and their elected representatives