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

Tumor suppressor pathways shape EGFR-driven lung tumor progression and response to treatment.

In vivo modeling combined with CRISPR/Cas9-mediated somatic genome editing has contributed to elucidating the functional importance of specific genetic alterations in human tumors. Our recent work uncovered tumor suppressor pathways that affect EGFR-driven lung tumor growth and sensitivity to tyrosine kinase inhibitors and reflect the mutational landscape and treatment outcomes in the human disease

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

A community-based transcriptomics classification and nomenclature of neocortical cell types

© 2020, The Author(s). To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body

Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab

Publisher Correction: A community-based transcriptomics classification and nomenclature of neocortical cell types (Nature Neuroscience, (2020), 23, 12, (1456-1468), 10.1038/s41593-020-0685-8)

© 2020, The Author(s). In the version of this article initially published, author Thomas V. Wuttke’s affiliation was shown incorrectly. Dr. Wuttke is affiliated with University of Tübingen, Tübingen, Germany. The error has been corrected in the PDF and HTML versions of this article

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