DNA vaccines against ErbB2+ Carcinomas: From mice to humans.

DNA vaccination exploits a relatively simple and flexible technique to generate an immune response against microbial and tumor-associated antigens (TAAs). Its effectiveness is enhanced by the application of an electrical shock in the area of plasmid injection (electroporation). In our studies we exploited a sophisticated electroporation device approved for clinical use (Cliniporator, IGEA, Carpi, Italy). As the target antigen is an additional factor that dramatically modulates the efficacy of a vaccine, we selected ErbB2 receptor as a target since it is an ideal oncoantigen. It is overexpressed on the cell membrane by several carcinomas for which it plays an essential role in driving their progression. Most oncoantigens are self-tolerated molecules. To circumvent immune tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human ErbB2 proteins. Their immunogenicity was compared in wild type mice naturally tolerant for mouse ErbB2, and in transgenic mice that are also tolerant for rat or human ErbB2. In several of these mice, RHuT and HuRT elicited a stronger anti-tumor response than plasmids coding for fully human or fully rat ErbB2. The ability of heterologous moiety to blunt immune tolerance could be exploited to elicit a significant immune response in patients. A clinical trial to delay the recurrence of ErbB2+ carcinomas of the oral cavity, oropharynx and hypopharynx is awaiting the approval of the Italian authorities

Diagnosing Misattribution of Commitments: A Normative and Pragmatic Model of for Assessing Straw Man

This paper builds a nine-step method for determining whether a straw man fallacy has been committed in a given case or not, by starting with some relatively easy textbook cases and moving to more realistic and harder cases. The paper shows how the type of argument associated with the fallacy can be proved to be a fallacy in a normative argumentation model, and then moves on to the practical task of building a hands-on method for applying the model to real examples of argumentation. Insights from linguistic pragmatics are used to distinguish the different pragmatic processes involved in reconstructing what is said and what is meant by an utterance, and to differentiate strong and weak commitments. In particular, the process of interpretation is analyzed in terms of an abductive pattern of reasoning, based on co-textual and contextual information, and assessable through the instruments of argumentation theory

Reporting and Interpreting Intentions in Defamation Law

The interpretation and the indirect reporting of a speaker’s communicative intentions lie at the crossroad between pragmatics, argumentation theory, and forensic linguistics. Since the leading case Masson v. New Yorker Magazine, Inc., in the United States the legal problem of determining the truth of a quotation is essentially equated with the correctness of its indirect reporting, i.e. the representation of the speaker’s intentions. For this reason, indirect reports are treated as interpretations of what the speaker intends to communicate. Theoretical considerations, aimed at establishing the pragmatic meaning of an utterance and differentiating between presumptive and non-presumptive interpretation, are thus interwoven with the practical legal need of distinguishing a correct indirect report from an indirect one or a misquotation. An incorrect report or a misquotation has the dialectical effect of attributing to the misquoted party commitments that he never held, which the latter needs to rebut. This shifting of the burden of persuasion can be increased by using strategically the conflict between the presumptive interpretation of an utterance and the non-presumptive one, i.e. the different types of pragmatic ambiguity. When an interpreter is confronted with an utterance taken out of its dialogical context, his interpretative process is not guided by the actual context or intention, but rather the most frequent or prototypical dialogical setting or the most typical individual purpose that it could have served to achieve. This presumptive reconstruction can be used to provide a prima facie case that the other party needs to reject. The stronger the interpretative presumptions a speaker needs to rebut, the more effective the misquotation strategy. The conflict between the systematic and the presumptive process of interpretation can be represented as an argumentative mechanism of reconstruction of the individual intention, which allows one to assess the reasonableness of the interpretative reasoning

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

Prenatal tobacco smoke exposure increases hospitalizations for bronchiolitis in infants

BACKGROUND: Tobacco smoke exposure (TSE) is a worldwide health problem and it is considered a risk factor for pregnant women's and children's health, particularly for respiratory morbidity during the first year of life. Few significant birth cohort studies on the effect of prenatal TSE via passive and active maternal smoking on the development of severe bronchiolitis in early childhood have been carried out worldwide. METHODS: From November 2009 to December 2012, newborns born at ≥ 33 weeks of gestational age (wGA) were recruited in a longitudinal multi-center cohort study in Italy to investigate the effects of prenatal and postnatal TSE, among other risk factors, on bronchiolitis hospitalization and/or death during the first year of life. RESULTS: Two thousand two hundred ten newborns enrolled at birth were followed-up during their first year of life. Of these, 120 (5.4%) were hospitalized for bronchiolitis. No enrolled infants died during the study period. Prenatal passive TSE and maternal active smoking of more than 15 cigarettes/daily are associated to a significant increase of the risk of offspring children hospitalization for bronchiolitis, with an adjHR of 3.5 (CI 1.5-8.1) and of 1.7 (CI 1.1-2.6) respectively. CONCLUSIONS: These results confirm the detrimental effects of passive TSE and active heavy smoke during pregnancy for infants' respiratory health, since the exposure significantly increases the risk of hospitalization for bronchiolitis in the first year of lif

The communicative functions of metaphors between explanation and persuasion

In the literature, the pragmatic dimension of metaphors has been clearly acknowledged. Metaphors are regarded as having different possible uses, and in particular, they are commonly viewed as instruments for pursuing persuasion. However, an analysis of the specific conversational purposes that they can be aimed at achieving in a dialogue and their adequacy thereto is still missing. In this paper, we will address this issue focusing on the distinction between the explanatory and persuasive goal. The difference between explanation and persuasion is often blurred and controversial from a theoretical point of view. Building on the analysis of explanation in different theories and fields of study, we show how it can be conceived as characterized by a cognitive and a pragmatic dimension, where the transference of understanding is used pragmatically for different dialogical goals. This theoretical proposal will be applied to examples drawn from the medical context, to show how a pragmatic approach to explanation can account for the complexity of the cases that can be found in actual dialogical contexts

Towards an approach for analysing external representations created during sensemaking using generative grammar

During sensemaking, users often create external representations to help them make sense of what they know, and what they need to know. In doing so, they necessarily adopt or construct some form of representational language using the tools at hand. By describing such languages implicit in representations we believe that we are better able to describe and differentiate what users do and better able to describe and differentiate interfaces that might support them. Drawing on approaches to the analysis of language, and in particular, Mann and Thompson’s Rhetorical Structure Theory, we analyse the representations that users create to expose their underlying ‘visual grammar’. We do this in the context of a user study involving evidential reasoning. Participants were asked to address an adapted version of IEEE VAST 2011 mini challenge 3 (interpret a potential terrorist plot implicit in a set of news reports). We show how our approach enables the unpacking of the heterogeneous and embedded nature of user-generated representations and allows us to show how visual grammars evolve and become more complex over time in response to evolving sensemaking needs