Discovery of novel molecular and biochemical predictors of response and outcome in diffuse large B-cell lymphoma

PhDDiscovery of Novel Molecular and Biochemical Predictors of Response and Outcome in Diffuse Large B-cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the commonest form of non-Hodgkin lymphoma and responds to treatment with a 5-year overall survival (OS) of 40-50%. Predicting outcome using the best available method, the International Prognostic Index (IPI), is inaccurate and unsatisfactory. This thesis describes research undertaken to discover, explore and validate new molecular and biochemical predictors of response and long-term outcome with the aims of improving on the inaccurate IPI and of suggesting novel therapeutic approaches. Two strategies were adopted: a rational and an empirical approach. The rational strategy used gene expression profiling to identify transcriptional signatures that correlated with outcome to treatment and from which a model of 13-genes accurately predict long-term OS. Two components of the 13-gene model, PKC and PDE4B, were studied using inhibitors in lymphoma cell-lines and primary cell cultures. PKC inhibition using SC-236 proved to be cytostatic and cytotoxic in the cell-lines examined and to a lesser extent in primary tumours. PDE4 inhibition using piclamilast and rolipram had no effect either alone or in combination with chemotherapy. The empirical approach investigated the trace element selenium in presentation serum and found that it was a biochemical predictor of response and outcome to treatment. In an attempt to provide evidence of a causal relationship as an explanation for the associations between presentation serum selenium, response and outcome, two selenium compounds, methylseleninic acid (MSA) and selenodiglutathione (SDG) were studied in vitro in the same lymphoma cell-lines and primary cell cultures. Both MSA and SDG exhibited cytostatic and cytotoxic activity and caspase-8 and caspase-9 driven apoptosis. For SDG reactive oxygen species generation was important for its activity in three of the four cell-lines. In conclusion, molecular and biochemical predictors of response and survival were discovered in DLBCL that led to viable targets for drug intervention being validated in vitro

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements