BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments

Back to the past: the individual and its role in creativity in organisations

O objetivo deste texto é realçar o papel do indivíduo na criatividade nas organizações. Esse papel tem sido estranhamente remetido para um plano secundário, à medida que as modernas visões da criatividade a definem, sobretudo, com relação ao contexto em que ocorre. De fato, na perspectiva atual, a criatividade não pode ser entendida sem se considerarem os contextos funcional, relacional e organizacional nos quais está inserido o trabalhador. Tais são as considerações da maior parte dos autores que escreve sobre o tópico, como sejam Amabile (1996), Csikszentmihalyi (1996), ou, mais recentemente, Glăveanu (2010a, 2010b). Essa corrente dominante, com origem no interacionismo psico-social, tem ainda influenciado o desenvolvimento teórico de outros conceitos em psicologia, sociologia, e, na sequência, nas ciências sociais e humanas, e na gestão. Essa supremacia no que concerne a criatividade, tem conduzido os autores a olvidar o papel do indivíduo no processo e no resultado criativos, chegando a retirar-lhe a responsabilidade e o protagonismo pela geração e produção de ideias. Desse modo, no presente texto, recuperam-se os argumentos em favor da centralidade da pessoa na criatividade, defendendo-se que esta tem uma existência isolada de influências externas, e que, como tal, devem relembrar-se as bases individuais da criatividadeThe goal of the current text is to highlight the role of the individual in creativity in organisations. This role has been strangely disregarded in recent years, as modern accounts of creativity have been emphasising the idea that creativity is only defined in context. This main stream argues that creativity is a process that essentially occurs within a functional, relational, and organisational context in which workers are inserted. Key authors defending such a position include the likes of Amabile (1996), Csikszentmihalyi (1996), and, more recently, Glăveanu (2010a, 2010b). This is a vision rooted in the psychosocial interactionist perspective, which has also had a considerable impact in other areas in psychology, sociology, management and other social and human sciences. This supremacy, with regards to creativity, has led many to forget the role of the individual person in the creative process and output, removing their responsibility and protagonism for generating and producing ideas. Hence, the current text intends to bring back to discussion the individual bases of creativity, that people can have an existence isolated from external influences, further defending that the concept can and should be defined out of context, rather than in contextinfo:eu-repo/semantics/publishedVersio

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

The Transformation from Traditional Nonprofit Organizations to Social Enterprises: An Institutional Entrepreneurship Perspective

The development of commercial revenue streams allows traditional nonprofit organizations to increase financial certainty in response to the reduction of traditional funding sources and increased competition. In order to capture commercial revenue-generating opportunities, traditional nonprofit organizations need to deliberately transform themselves into social enterprises. Through the theoretical lens of institutional entrepreneurship, we explore the institutional work that supports this transformation by analyzing field interviews with 64 institutional entrepreneurs from UK-based social enterprises. We find that the route to incorporate commercial processes and convert traditional nonprofit organizations into social enterprises requires six distinct kinds of institutional work at three different domains; these are—“engaging commercial revenue strategies”, “creating a professionalized organizational form”, and “legitimating a socio-commercial business model”. In elaborating on social entrepreneurship research and practice, we offer a comprehensive framework delineating the key practices contributing to the transformation from traditional nonprofit organizations to social enterprises. This extends our understanding of the ex-ante strategy of incorporating commercial processes within social organizations. Furthermore, the identification of these practices also offers an important tool for scholars in this field to examine the connection (or disconnection) of each practice with different ethical concerns of social entrepreneurship in greater depth.British Academ

The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways