Identification of novel targets for breast cancer by exploring gene switches on a genome scale

<p>Abstract</p> <p>Background</p> <p>An important feature that emerges from analyzing gene regulatory networks is the "switch-like behavior" or "bistability", a dynamic feature of a particular gene to preferentially toggle between two steady-states. The state of gene switches plays pivotal roles in cell fate decision, but identifying switches has been difficult. Therefore a challenge confronting the field is to be able to systematically identify gene switches.</p> <p>Results</p> <p>We propose a top-down mining approach to exploring gene switches on a genome-scale level. Theoretical analysis, proof-of-concept examples, and experimental studies demonstrate the ability of our mining approach to identify bistable genes by sampling across a variety of different conditions. Applying the approach to human breast cancer data identified genes that show bimodality within the cancer samples, such as estrogen receptor (ER) and ERBB2, as well as genes that show bimodality between cancer and non-cancer samples, where tumor-associated calcium signal transducer 2 (TACSTD2) is uncovered. We further suggest a likely transcription factor that regulates TACSTD2.</p> <p>Conclusions</p> <p>Our mining approach demonstrates that one can capitalize on genome-wide expression profiling to capture dynamic properties of a complex network. To the best of our knowledge, this is the first attempt in applying mining approaches to explore gene switches on a genome-scale, and the identification of TACSTD2 demonstrates that single cell-level bistability can be predicted from microarray data. Experimental confirmation of the computational results suggest TACSTD2 could be a potential biomarker and attractive candidate for drug therapy against both ER+ and ER- subtypes of breast cancer, including the triple negative subtype.</p

Análise das políticas públicas: uma proposta metodológica para o estudo no campo da prevenção em Aids Public policies assessment: a methodological proposal for the study in the field of Aids prevention

As políticas públicas são respostas do poder público para problemáticas sociais. Elas são estratégias de grande relevância para o enfrentamento da Aids e desenvolvimento de ações de prevenção da infecção do HIV, pois institucionalizam no setor público de saúde ações sistemáticas para esse fim. Elas se estruturam numa rede de determinantes que delineiam os caminhos a serem trilhados pelo gestor público. Nesse contexto, entram em jogo diversos atores, com diferentes interesses e poder de barganha político-econômica, negociação de concepções de mundo, estratégias de ação e campos de luta por direitos e deveres sociais. É uma disputa de saberes e interesses travada no campo político, permeada por aspectos sócio-culturais e econômicos. Neste sentido, o presente trabalho objetiva uma discussão conceitual sobre esse tema, desenvolvendo a concepção teórica sobre a análise de políticas, enquanto uma metodologia de estudo, compreendendo as categorias: atores, conteúdo, contexto e processo, onde, nessa última, se delimitam especificamente os processos de construção de agenda, formulação e implementação de uma política. Esse quadro teórico é desenvolvido centrando a temática da prevenção da Aids, contextualizada no cenário brasileiro, a partir da qual são elencados alguns entraves das políticas propostas, articulando-as às considerações de especialistas que buscam reorientar as intervenções públicas de prevenção à Aids.<br>Public policies are the response of public power to social issues. They are very relevant strategies to face AIDS and the development of prevention measures concerning HIV infection, for they institutionalize systematic actions in the public health sector with this purpose. They are structured in a network of directives that establish the routes to be followed by public officials. Within this context, different actors are part of the game, with different interests and social and political bargaining powers, world concepts negotiation, actions strategies within the field of social rights and duties. It's a struggle of knowledge and interests in the political ground permeated by social, cultural and economic aspects. Therefore, this paper engages in a concept discussion of the theme, developing a theoretical concept of policies assessment from the viewpoint of a methodological study comprising the following: actors, content, context and process, process circumscribing specific agenda designing processes, policy formulation and implementation. This theoretical scenario is developed focusing on the theme of AIDS prevention, the context being the Brazilian environment from which some of the constraints of policies proposals are listed and linked to specialists'considerations pursuing a reorientation of public interventions concerning AIDS prevention

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease