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

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

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

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

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

To understand the function of cortical circuits it is necessary to classify their underlying cellular diversity. Traditional attempts based on comparing anatomical or physiological features of neurons and glia, while productive, have not resulted in a unified taxonomy of neural cell types. The recent development of single-cell transcriptomics has enabled, for the first time, systematic high-throughput profiling of large numbers of cortical cells and the generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data have revealed the existence of clear clusters, many of which correspond to cell types defined by traditional criteria, and which are conserved across cortical areas and species. To capitalize on these innovations and advance the field, we, the Copenhagen Convention Group, propose the community adopts a transcriptome-based taxonomy of the cell types in the adult mammalian neocortex. This core classification should be ontological, hierarchical and use a standardized nomenclature. It should be configured to flexibly incorporate new data from multiple approaches, developmental stages and a growing number of species, enabling improvement and revision of the classification. This community-based strategy could serve as a common foundation for future detailed analysis and reverse engineering of cortical circuits and serve as an example for cell type classification in other parts of the nervous system and other organs