PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53.

PRIMA-1 is a chemical compound identified as a growth suppressor of tumor cells expressing mutant p53. We previously found that in the MDA-MB-231 cell line expressing high level of the mutant p53-R280K protein, PRIMA-1 induced p53 ubiquitination and degradation associated to cell death. In this study, we investigated the ability of PRIMA-1 to induce autophagy in cancer cells. In MDA-MB-231 and HCT116 cells, expressing mutant or wild type p53, respectively, autophagy occurred following exposure to PRIMA-1, as shown by acridine orange staining, anti-LC3 immunofluorescence and immunoblots, as well as by electron microscopy. Autophagy was triggered also in the derivative cell lines knocked-down for p53, although to a different extent than in the parental cells expressing mutant or wild type p53. In particular, while wild type p53 limited PRIMA-1 induced autophagy, mutant p53 conversely promoted autophagy, thus sustaining cell viability following PRIMA-1 treatment. Therefore, the autophagic potential of PRIMA-1, besides being cell context dependent, could be modulated in a different way by the presence of wild type or mutant p53. Furthermore, since both cell lines lacking p53 were more sensitive to the cytotoxic effect of PRIMA-1 than the parental ones, our findings suggest that a deregulated autophagy may favor cell death induced by this drug

06N-P63\u3b1 and TA-P63\u3b1 exhibit intrinsic differences in transactivation specificities that depend on distinct features of DNA target sites.

TP63 is a member of the TP53 gene family that encodes for up to ten different TA and 06N isoforms through alternative promoter usage and alternative splicing. Besides being a master regulator of gene expression for squamous epithelial proliferation, differentiation and maintenance, P63, through differential expression of its isoforms, plays important roles in tumorigenesis. All P63 isoforms share an immunoglobulin-like folded DNA binding domain responsible for binding to sequence-specific response elements (REs), whose overall consensus sequence is similar to that of the canonical p53 RE. Using a defined assay in yeast, where P63 isoforms and RE sequences are the only variables, and gene expression assays in human cell lines, we demonstrated that human TA- and 06N-P63\u3b1 proteins exhibited differences in transactivation specificity not observed with the corresponding P73 or P53 protein isoforms. These differences 1) were dependent on specific features of the RE sequence, 2) could be related to intrinsic differences in their oligomeric state and cooperative DNA binding, and 3) appeared to be conserved in evolution. Since genotoxic stress can change relative ratio of TA- and 06N-P63\u3b1 protein levels, the different transactivation specificity of each P63 isoform could potentially influence cellular responses to specific stresses

Il sistema cooperativo-paritetico nell'AIMIT e alleanza terapeutica: studio preliminare sulla validità dei costrutti

La nascita dell' AIMIT (2008, in stampa) come strumento di analisi della motivazione interpersonale nei trascritti, apre nuove possi- bilità nell'analisi di aspetti connessi allo studio dei determinanti della qualità della relazione terapeutica. In questo lavoro preli- minare, viene proposto un affiancamento dei concetti di Sistema Motivazionale lnterpersonale (SMI) Cooperativo- Paritetico, così come descritto nel manuale AIMIT e di Alleanza Terapeutiea

Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo.

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601

Disability Management

none1noSummary Diversity management manifests in a set of transversal business practices – under the “umbrella” of the corporate social responsibility policies – that affect the corporate culture, the strategy, the financial and control management system, the operational activities, as well as the system of relations with the stakeholders and the company reporting (Angeloni 2013; D’Amato 2009; Metallo et al. 2009; Migliaccio 2016). The growing attention paid by policy makers, businesses, and institutions to diversity management is attributable to the increased complexity of society, characterized by a multiplicity of social, cultural, and individual subjectivities tied to gender, age, ethnic origins, disability, sexual orientation, personality characteristics, cognitive styles, level of education, background, etc. In such a context disability management is conceived as a proactive strategy aimed at identifying and solving the factors that prevent people with any type of disability from accessing work (Geisen and Harder 2011). While diversity management consists in practices that an organization implements to create an inclusive climate and an organizational culture (Oberfield 2014), aimed to allow workers attitudes and capabilities flourish and ensure growth and success of their personal and professional paths, disability management is not only limited to a process or to a set of procedures (O’Brien 2013; Sabharwal 2014), but it represents a professional activity which considers all the relational aspects (personal contacts and interactions) that contribute to the success of disability management. Currently disability strategies are often implemented as a reaction to the problems of a single person or an organization, while empirical studies suggest to consider such problems in advance through appropriate policies and procedures for overcoming and preventing them (Geisen and Harder 2011). Namely, workplace disability management concerns all cases of disability from personal and congenital disabilities tothose acquired during the working period (ranging from accidents to chronic-degenerative diseases). In this sense, disability management is conceived as a proactive strategy oriented to identify and remove all the factors that prevent people, with any type of disability, from accessing to developing a professional path (Bruyére and Filiberto 2013; Rahim et al. 2017). This conception differs from a more restrictive one according to which disability management coincides with the return to work, of disable people who are already working.https://link.springer.com/referencework/10.1007/978-3-030-02006-4 Book Springer Series: CSR, Sustainabiliy, Ethics & Governance. ISSN 2196-7075 ISSN 2196 – 7083 (electronic) E227181 Bibliographic information • DOIhttps://doi.org/10.1007/978-3-030-02006-4 • Copyright Information Springer Nature Switzerland AG 2020 • Publisher NameSpringer, Cham • Online ISBN 978-3-030-02006-4 • eBook PackagesBusiness and ManagementReference Module Humanities and Social SciencesrestrictedDel Baldo, MaraDel Baldo, Mar

Brain-Computer Interfaces and the Protection of the Fundamental Rights of the Vulnerable Persons

The contribution deals with the legal aspects of the brain-computer interfaces (BCI) and, in particular, of those used for the assisted and augmented communication of subjects not able to express themselves with eye-controlled devices. The chapter outlines the constitutional rights involved in the use of BCI, the European discipline applicable to their manufacture and, taking into consideration an Italian case-law, which seems to be extensible to other legal families, wonders the possible legal regime of the personal will expressed through those BCI so to protect vulnerable persons from abuse