Definite Descriptions are Directly Referential

Amongst those who have analysed definite descriptions as referential, most have considered them to be indirectly referential. In contrast, I will argue that definite descriptions are directly referential, in the sense of Kaplan (1980). In other words, the informational contents of utterances of definite descriptions are identical to their referents. In this thesis, I will first present a semantic framework inspired primarily by Kaplan (1980) with additions from Russell (2008) and Salmon (1986). I will then present a semantic analysis of definite descriptions whereby they are directly referential expressions. This analysis will also concur with Lewis’ (1979) suggestion that the referents of definite description utterances are determined by comparative salience. I will argue that this analysis provides the most theoretically virtuous explanation of the various semantic properties of definite descriptions. I will also examine a series of problem cases for this analysis and argue that they can be resolved through independently justified means. Firstly, I will discuss Frege’s Puzzle, as presented by Salmon (1986), as it relates to the directly referential analysis of definite descriptions, as well as the related problem of de dicto indirect speech and propositional attitude reports. I will suggest that Salmon’s approach to these problems in the case of proper names will also apply in the case of directly referential definite descriptions. Secondly, I will argue that Kripke’s (1977) analysis of the phenomena discussed by Donnellan (1966) is compatible with the directly referential analysis of definite descriptions. Thirdly, I will provide an ambiguous analysis of modal operators to account for de dicto modal claims. I will conclude by discussing possible links between this analysis and analyses of other singular terms

Formal Representations of Salience in Dynamic Semantics

Lewis’ (1973; 1979) salience analysis of definite description reference suggests that an utterance of ‘the F’ refers to the most salient F, according to a contextual salience ranking. This analysis was created to account for referring improper definite descriptions. As shown by von Heusinger (2004), the salience analysis can also be used to explain anaphoric definite descriptions. Any formalization of the salience analysis will require a method for formally representing salience, such as Lewis’ order-theoretic method or von Heusinger’s choice-theoretic method. In this thesis, I will argue that the order-theoretic method explains certain features of salience that the choice-theoretic method does not, and therefore the order-theoretic method should be favored. I will also show how von Heusinger’s Dynamic Semantics with Choice Functions can be adapted to utilize the order-theoretic method, thus providing a formal modeling of the context change described by the salience explanation of anaphoric definite descriptions.Master of Art

Corpus Analysis in Philosophical Semantics

The topic of this dissertation is corpus analysis: the use of computational techniques to search through large collections of real-world texts (called corpora) to discover facts about language use which hold throughout the collection. I examine how corpus analysis can be used as an empirical methodology within philosophy of language to confirm semantic analyses of philosophically important expressions. I begin by discussing the philosophical importance of analyzing the ordinary meaning of people's language use, as through that we can come to understand how they categorize the world around them. Specifically, I am concerned with philosophical semantics: the study of the meaning of expressions for which different theories of their meaning will have different philosophical upshots. After discussing the kind of meaning relevant to this subject area (namely operative concepts: the concepts that actually determine how we apply expressions to cases), I rationally reconstruct and analyze existing methods of confirmation in philosophical semantics, including intuitive methods and questionnaire methods from experimental philosophy. I then critique these methods in terms of the strength of evidence they can offer.Next, I introduce corpus analysis, and explain how it can be used as a method of confirmation in philosophical semantics. I pay special attention to the question of how corpus analysis can be used to discover the 'deep', semantic, representational features of text relevant for confirming semantic analyses, and offer several techniques to perform this task.I argue that corpus analysis has many benefits over existing methods of confirmation in philosophical semantics, given that it studies (i) actual, rather than imagined, instances of language use, and (ii) the language use of the actual communities whose meanings we are interested in, rather than just that of philosophers.The dissertation concludes with a case study of the use of corpus analysis to confirm a theory of the reference conditions of definite descriptions over a rival theory with different philosophical upshots. This is the first corpus study in philosophical semantics to make use of an annotated corpus, which is a technique with lot of promise within this field.Doctor of Philosoph

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation

Emergence of High-Avidity Melan-A–Specific Clonotypes as a Reflection of Anti–PD-1 Clinical Efficacy

International audienceTherapeutic strategies using anti-PD-1-blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti-PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A-specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti-PD-1. We observed amplification of Melan-A-specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti-PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti-PD-1 therapy, our work describes the emergence of high-avidity Melan-A-specific clonotypes as a surrogate marker of treatment efficacy

Chemotherapy efficacy after first-line immunotherapy in 18 advanced melanoma patients

International audienceIn BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure. This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included. Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%. Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy