Advancing Inclusive Research: Establishing Collaborative Strategies to Improve Diversity in Clinical Trials.

Well-characterized disparities in clinical research have disproportionately affected patients of color, particularly in underserved communities. To tackle these barriers, Genentech formed the External Council for Advancing Inclusive Research, a 14-person committee dedicated to developing strategies to increase clinical research participation. To help improve the recruitment and retention of patients of color, this article chronicles our efforts to tangibly address the clinical research barriers at the system, study, and patient levels over the last four years. These efforts are one of the initial steps to fully realize the promise of personalized health care and provide increased patient benefit at less cost to society. Instead of simply acknowledging the problem, here we illuminate the collaborative and multilevel strategies that have been effective in delivering meaningful progress for patients.

Conceptualising centres of excellence: a scoping review of global evidence.

OBJECTIVE: Globally, interest in excellence has grown exponentially, with public and private institutions shifting their attention from meeting targets to achieving excellence. Centres of Excellence (CoEs) are standing at the forefront of healthcare, research and innovations responding to the world's most complex problems. However, their potential is hindered by conceptual ambiguity. We conducted a global synthesis of the evidence to conceptualise CoEs. DESIGN: Scoping review, following Arksey and O'Malley's framework and methodological enhancement by Levac et al and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. DATA SOURCES: PubMed, Scopus, CINAHL, Google Scholar and the Google engine until 1 January 2021. ELIGIBILITY: Articles that describe CoE as the main theme. RESULTS: The search resulted in 52 161 potential publications, with 78 articles met the eligibility criteria. The 78 articles were from 33 countries, of which 35 were from the USA, 3 each from Nigeria, South Africa, Spain and India, and 2 each from Ethiopia, Canada, Russia, Colombia, Sweden, Greece and Peru. The rest 17 were from various countries. The articles involved six thematic areas-healthcare, education, research, industry, information technology and general concepts on CoE. The analysis documented success stories of using the brand 'CoE'-an influential brand to stimulate best practices. We identified 12 essential foundations of CoE-specialised expertise; infrastructure; innovation; high-impact research; quality service; accreditation or standards; leadership; organisational structure; strategy; collaboration and partnership; sustainable funding or financial mechanisms; and entrepreneurship. CONCLUSIONS: CoEs have significant scientific, political, economic and social impacts. However, there are inconsistent use and self-designation of the brand without approval by an independent, external process of evaluation and with high ambiguity between 'CoEs' and the ordinary 'institutions' or 'centres'. A comprehensive framework is needed to guide and inspire an institution as a CoE and to help government and funding institutions shape and oversee CoEs.

Understanding the key processes of excellence as a prerequisite to establishing academic centres of excellence in Africa.

BACKGROUND: Africa's economic transformation relies on a radical transformation of its higher education institutions. The establishment of regional higher education Centres of Excellence (CoE) across Africa through a World Bank support aims to stimulate the needed transformation in education and research. However, excellence is a vague, and often indiscriminately used concept in academic circles. More importantly, the manner in which aspiring institutions can achieve academic excellence is described inadequately. The main objective of this paper is to describe the core processes of excellence as a prerequisite to establishing academic CoE in Africa. METHODS: The paper relies on our collaborative discussions and real-world insight into the pursuit of academic excellence, a narrative review using Pubmed search for a contextual understanding of CoEs in Africa supplemented by a Google search for definitions of CoEs in academic contexts. RESULTS: We identified three key, synergistic processes of excellence central to institutionalizing academic CoEs: participatory leadership, knowledge management, and inter-disciplinary collaboration. (1) Participatory leadership encourages innovations to originate from the different parts of the organization, and facilitates ownership as well as a culture of excellence. (2) Centers of Excellence are future-oriented in that they are constantly seeking to achieve best practices, informed by the most up-to-date and cutting-edge research and information available. As such, the process by which centres facilitate the flow of knowledge within and outside the organization, or knowledge management, is critical to their success. (3) Such centres also rely on expertise from different disciplines and 'engaged' scholarship. This multidisciplinarity leads to improved research productivity and enhances the production of problem-solving innovations. CONCLUSION: Participatory leadership, knowledge management, and inter-disciplinary collaborations are prerequisites to establishing academic CoEs in Africa. Future studies need to extend our findings to understand the processes key to productivity, competitiveness, institutionalization, and sustainability of academic CoEs in Africa.

Using an immortalized cell line to study the HPV life cycle in organotypic "raft" cultures.

The papillomavirus life cycle is tied to the differentiation of the stratified squamous epithelium that this virus infects. The ability to study the papillomavirus life cycle is facilitated by organotypic culturing techniques that allow one to closely recapitulate this terminal differentiation process in the laboratory. Current techniques allow for the establishment of recombinant wild-type or mutant human papillomavirus (HPV) genomes in transfected early-passage human foreskin keratinocytes (HFKs). These cells can then be used in organotypic culture to investigate the role of individual viral genes in different aspects of the viral life cycle. When using early-passage HFKs, there is a need for the transfected HPV genome to extend the life span of the cells in order to have sufficient cell generations in which to carry out organotypic culturing. The recent isolation of a spontaneously immortalized HFK cell line that supports the complete HPV life cycle has further allowed investigators to study wild-type or mutant papillomaviral genomes that do not confer immortalization. In this chapter, we describe the methodologies that permit the study of the HPV life cycle in this HFK cell line.

Interactions with pocket proteins contribute to the role of human papillomavirus type 16 E7 in the papillomavirus life cycle.

Human papillomaviruses (HPVs), most commonly the HPV16 genotype, are the principle etiological determinant for cervical cancer, a common cancer worldwide resulting in over 200,000 deaths annually. The oncogenic properties of HPVs are attributable in part to the virally encoded protein E7, best known for its ability to bind to and induce the degradation of the retinoblastoma tumor suppressor, pRb, and related "pocket proteins" p107 and p130. Previously, we defined a role for E7 in the productive stage of the HPV16 life cycle, which takes place in stratified squamous epithelia. HPV perturbs the normal processes of cell growth and differentiation of stratified squamous epithelia. HPVs reprogram cells to support continued DNA synthesis and inhibit their differentiation in the suprabasal compartment of the epithelia, where cells normally have withdrawn from the cell cycle and initiated a well-defined pattern of terminal differentiation. These virus-induced perturbations, which contribute to the production of progeny HPVs, are dependent on E7. In this study, we define the mechanism of action by which E7 contributes to the productive stage of the HPV16 life cycle. We found that the ability of HPV16 to reprogram suprabasal cells to support DNA synthesis correlates with E7's ability to bind pocket proteins but not its ability to induce their degradation. In contrast, the ability of HPV16 to perturb differentiation correlated with both E7's binding to and degradation of pocket proteins. These data indicate that different hallmarks of the productive stage of the HPV16 life cycle rely upon different sets of requirements for E7.

Avian sarcoma and leukosis virus cytopathic effect in the absence of TVB death domain signaling.

The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptor-related receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signaling-deficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAIL-signaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.

R-Ras promotes focal adhesion formation through focal adhesion kinase and p130(Cas) by a novel mechanism that differs from integrins.

R-Ras regulates integrin function, but its effects on integrin signaling pathways have not been well described. We demonstrate that activation of R-Ras promoted focal adhesion formation and altered localization of the alpha2beta1 integrin from cell-cell to cell-matrix adhesions in breast epithelial cells. Constitutively activated R-Ras(38V) dramatically enhanced focal adhesion kinase (FAK) and p130(Cas) phosphorylation upon collagen stimulation or clustering of the alpha2beta1 integrin, even in the absence of increased ligand binding. Signaling events downstream of R-Ras differed from integrins and K-Ras, since pharmacological inhibition of Src or disruption of actin inhibited integrin-mediated FAK and p130(Cas) phosphorylation, focal adhesion formation, and migration in control and K-Ras(12V)-expressing cells but had minimal effect in cells expressing R-Ras(38V). Therefore, signaling from R-Ras to FAK and p130(Cas) has a component that is Src independent and not through classic integrin signaling pathways and a component that is Src dependent. R-Ras effector domain mutants and pharmacological inhibition suggest a partial role for phosphatidylinositol 3-kinase (PI3K), but not Raf, in R-Ras signaling to FAK and p130(Cas). However, PI3K cannot account for the Src-independent pathway, since simultaneous inhibition of both PI3K and Src did not completely block effects of R-Ras on FAK phosphorylation. Our results suggest that R-Ras promotes focal adhesion formation by signaling to FAK and p130(Cas) through a novel mechanism that differs from but synergizes with the alpha2beta1 integrin.