A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery.

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.

A visibilidade da enfermagem e suas implicações no cotidiano de trabalho

Ao rever a história da Enfermagem percebe-se que sua origem foi sustentada em bases empíricas e em práticas fundamentalmente místicas, constituindo-se como uma profissão caritativa e vocacional, reproduzindo alguns estereótipos ainda presentes no imaginário da população e dos demais profissionais da área da saúde. É possível que a trajetória da Enfermagem tenha corroborado para uma baixa visibilidade profissional e, que a Enfermagem ainda enfrente reflexos de sua gênese profissional. Assim, tem-se como objetivo geral: conhecer a percepção das enfermeiras acerca das possíveis implicações da visibilidade da Enfermagem no cotidiano de trabalho; e como objetivo específico: construir estratégias que podem promover o reconhecimento e a visibilidade da Enfermagem. A pesquisa foi desenvolvida através de uma abordagem qualitativa do tipo exploratória, com 30 enfermeiros atuantes no Hospital Universitário Dr. Miguel Riet Corrêa Jr. (HU-FURG), da Universidade Federal do Rio Grande (FURG). Para a coleta dos dados, utilizou-se a entrevista semiestruturada. O processo de análise compreendeu a análise textual discursiva, e os resultados foram apresentados em dois artigos intitulados: “Implicações da Visibilidade da Enfermagem no Exercício Profissional” e “Estratégias para Promover o Reconhecimento e Visibilidade da enfermagem”. Após as análises concluiu-se que a visibilidade da Enfermagem está relacionada à trajetória histórica da profissão, à falta de reconhecimento da Enfermagem como profissão que possui saberes científicos, à veiculação errônea da imagem da Enfermagem na mídia, à ausência da realização de marketing por parte do enfermeiro, aos posicionamentos inadequados perante a equipe e ainda, à sobrecarga de trabalho. Para garantir o reconhecimento e a visibilidade da enfermagem é preciso demonstrar conhecimentos de forma crítica-reflexiva no cotidiano de trabalho. Evidenciou-se que, para proporcionar a mudança desejada da imagem profissional é necessário que a própria enfermagem desenvolva estratégias para promover sua visibilidade e valorização, as quais são essenciais à consolidação da profissão.

The Political and Social Dynamics of Poverty, Poor Relief and Health Care in Early-Modern Portugal

By the end of the fifteenth century most European countries had witnessed a profound reformation of their poor relief and health care policies. As this book demonstrates, Portugal was among them and actively participated in such reforms. Providing the first English language monograph on this topic, Laurinda Abreu examines the Portuguese experience and places it within the broader European context. She shows that, in line with much that was happening throughout the rest of Europe, Portugal had not only set up a systematic reform of the hospitals but had also developed new formal arrangements for charitable and welfare provision that responded to the changing socioeconomic framework, the nature of poverty and the concerns of political powers. The defining element of the Portuguese experience was the dominant role played by a new lay confraternity, the confraternity of the Misericórdia, created under the auspices of King D. Manuel I in 1498. By the time of the king's death in 1521 there were more than 70 Misericórdias in Portugal and its empire, and by 1640, more than 300. All of them were run according to a unified set of rules and principles with identical social objectives. Based upon a wealth of primary source documentation, this book reveals how the sixteenth-century Portuguese crown succeeded in implementing a national poor relief and health care structure, with the support of the Papacy and local elites, and funded principally through pious donations. This process strengthened the authority of the royal government at a time which coincided with the emergence of the early modern state. In so doing, the book establishes poor relief and public health alongside military, diplomatic and administrative authorities, as the pillars of centralisation of royal power.

Exploration of portuguese-bengal cultural heritage throught museological studies

The Portuguese came to Bengal in the early 16th century for trading. Between 1575 and 1600, they established many colonies on the banks of river Ganga, like Chinsura, Hooghly (Porto Pequeno), Satagaon, Gopalpur and Bandel, covering the eastern part of India. During their stay, Portuguese built many churches, schools and charitable institutions. Churches of Augustinians and Jesuits became popular tourist destinations until today. Although by the 18th century, the Portuguese presence had almost disappeared from Bengal with the emergence of British imperialism, the 500 years old (approx.) Portuguese culture is still living in modern Bengal, in the form of tangible and intangible heritage. Traces of the Portuguese impact could be seen in Bengali language, literature, folk-tales, folksongs, cuisines, agriculture, religion, cinema and trade. Some of these are included in the academic curriculum of history at school, college and university levels. In this context, research has been undertaken in the past and is still ongoing in several universities. However, heritage studies under a museological point of view have not yet been initiated at the university level. Though Goa, Panaji, Calicut, Chennai and Nagapattanam were the Portuguese centers for long periods and research has been conducted there along with the establishment of some museums,

New ethnicities online: reflexive racialisation and the internet

In this article we analyse the emergence of Internet activity addressing the experiences of young people in two British communities: South Asian and Chinese.We focus on two web sites: www.barficulture.com and www.britishbornchinese.org.uk, drawing on interviews with site editors, content analysis of the discussion forums, and E-mail exchanges with site users. Our analysis of these two web sites shows how collective identities still matter, being redefined rather than erased by online interaction. We understand the site content through the notion of reflexive racialisation. We use this term to modify the stress given to individualisation in accounts of reflexive modernisation. In addition we question the allocation of racialised meaning from above implied by the concept of racialisation. Internet discussion forums can act as witnesses to social inequalities and through sharing experiences of racism and marginalisation, an oppositional social perspective may develop. The online exchanges have had offline consequences: social gatherings, charitable donations and campaigns against adverse media representations. These web sites have begun to change the terms of engagement between these ethnic groups and the wider society,and they have considerable potential to develop new forms of social action.

Desarrollo de la Medicina Social en la escuela de medicina de la Universidad de Cuenca

ANTECEDENTES: La Escuela de Medicina es una de las primeras de la Universidad de Cuenca en ser fundadas, no obstante el desarrollo de la Medicina Social ha sido paulatino cobrando impulso desde la década de los sesenta. Es un tema poco investigado y reportado. La enseñanza de la Medicina Social se relaciona con los cambios surgidos en la práctica de la Medicina con la ciudad y la llegada de profesores formados en el extranjero que enseñaban Higiene y Salud Pública. La Medicina Social parte desde una Medicina caritativa cuyo objetivo era el buen morir de las personas y no se centraba en su curación; para luego desarrollarse la privatización de los servicios de salud, también se produce la intervención del estado y los municipios en el área médica y social, posteriormente existe la desaparición de la Medicina Caritativa realizada por religiosas y médicos de la facultad, para surgir en una tendencia hacia un Sistema de Salud basado en el concepto de la salud como mercancía Posteriormente existe un enfoque principal en la Medicina que abarca la prevención, promoción y el desarrollo de la Atención Primaria en Salud.

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.