This thesis investigates the nature of grammatical patterns through an in-depth study of resultative constructions in Mandarin and Thai. At the heart of the thesis lies the proposal that event structure templates - complex, meaning-based grammatical patterns - must be recognised as primary objects of linguistic analysis. As content-theoretic objects that are independent of form, event structure templates abstract away from language- specific surface encoding of cross-linguistic resultative constructions while providing the toolkit for a language- independent characterisation of the generalisations that exist. As a result, the pattern-theoretic approach developed here provides a happy compromise between mainstream generative approaches, which are typically criticised for focusing on broad cross-linguistic generalisations at the expense of complete descriptions of particular languages, and Construction Grammar approaches, which have been criticised for the complementary problem, i.e. focusing on the complete descriptions of particular languages at the expense of cross-linguistic generalisations. The thesis develops a balance between these proposals by exploring three independent, but interdependent, dimensions of resultative constructions that are crucial for a pattern-theoretic analysis of these constructions: predication relations, argument realisation, and surface encoding. It provides a survey of the myriad patterns of predication relations instantiated by resultative constructions, and carefully and critically evaluates competing theoretical proposals in this well- examined domain. Through a close and fine-grained analysis of Mandarin and Thai resultatives, it argues for a pattern -theoretic approach in which patterns of predication relations are represented in terms of families of event structure templates. It also investigates the regularities governing the alignment between semantic arguments of event structures and grammatical relations in the syntax, and proposes to capture these generalisations by embedding event structures within a correspondence-based theory of argument realisation. Finally, it considers the cross- linguistic variation in the surface encoding of resultative constructions and provides a formal model of how the same event structure template can be realised by different surface encoding strategies in different languages. Treating event structures as complex grammatical patterns provides an insightful way of characterising cross-linguistically recurrent, yet variant, construction types, such as resultative, and identifies a typological research programme with the potential to uncover implicational relations that hold within languages

Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.