Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

BACKGROUND: Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways. METHODS: Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR. RESULTS: IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration. CONCLUSIONS: IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies

Context Dependence, MOPs,WHIMs and procedures Recanati and Kaplan on Cognitive Aspects in Semantics

After presenting Kripke’s criticism to Frege’s ideas on context dependence of thoughts, I present two recent attempts of considering cognitive aspects of context dependent expressions inside a truth conditional pragmatics or semantics: Recanati’s non-descriptive modes of presentation (MOPs) and Kaplan’s ways of having in mind (WHIMs). After analysing the two attempts and verifying which answers they should give to the problem discussed by Kripke, I suggest a possible interpretation of these attempts: to insert a procedural or algorithmic level in semantic representations of indexicals. That a function may be computed by different procedures might suggest new possibilities of integrating contextual cognitive aspects in model theoretic semanti

Monsters in Kaplan’s Logic of Demonstratives

Kaplan (1989a) insists that natural languages do not contain displacing devices that operate on character-such displacing devices are called monsters. This thesis has recently faced various empirical challenges (e.g., Schlenker 2003; Anand and Nevins 200

Compositionality in Truth Conditional Pragmatics

In the past decade various linguists and philosophers (e.g. Pagin, Pelletier, Recanati, Westerståhl, Lasersohn) have proposed a weakening of the standard interpretation of compositionality for propositional content. Their move is motivated by the desire to accommodate radical forms of context sensitivity within a systematic account of natural languages. In this paper I argue against weakening compositionality in the way proposed by them. I argue that weak compositionality fails to provide some of the expected benefits of compositionality. First, weak compositionality fails to provide systematic meaning-rules which can handle forms of context-sensitivity that are not amenable to explanation in terms of a fixed and limited set of contextual parameters. Secondly, I argue that weak-compositionality fails to play any role in explaining speakers’ ability to calculate the semantic values of complex expressions. I conclude that weak compositionality is not a viable alternative to standard interpretations of compositionality, and that it doesn’t offer an acceptable way to accommodate radical forms of context-sensitivity within a systematic account of natural languages. Given the central role that weak-compositionality plays in recent approaches to natural language (e.g. in truth-conditional pragmatics) this also casts doubt on the viability of these projects

Unity through truth

Renewed worries about the unity of the proposition have been taken as a crucial stumbling block for any traditional conception of propositions. These worries are often framed in terms of how entities independent of mind and language can have truth conditions: why is the proposition that Desdemona loves Cassio true if and only if she loves him? I argue that the best understanding of these worries shows that they should be solved by our theory of truth and not our theory of content. Specifically, I propose a version of the redundancy theory according to which ‘it is true that Desdemona loves Cassio’ expresses the same proposition as ‘Desdemona loves Cassio’. Surprisingly, this variant of the redundancy theory treats ‘is true’ as an ordinary predicate of the language, thereby defusing many standard criticisms of the redundancy theory

Against the identification of assertoric content with compositional value

This essay investigates whether the things we say are identical to the things our sentences mean. It is argued that these theoretical notions should be distinguished, since assertoric content does not respect the compositionality principle. As a paradigmatic example, Kaplan's formal language LD is shown to exemplify a failure of compositionality. It is demonstrated that by respecting the theoretical distinction between the objects of assertion and compositional values certain conflicts between compositionality and contextualism are avoided. This includes the conflict between eternalism and the semantics of tense, the embedding problems for contextualism about epistemic modals and taste claims, and the conflict between direct reference and the semantics of bound pronouns (and monstrous operators). After presenting the theoretical picture which distinguishes assertoric content from compositional semantic value, some objections to the picture are addressed. In so doing, the objection from King (Philos Perspect 17(1):195-246, 2003) stemming from apparent complications with the interaction of temporal expressions and attitude reports is assessed and shown to be non-threatening