The role of functional polymorphisms in immune response genes as biomarkers of BCG Immunotherapy outcome in bladder cancer: Establishment of a predictive profile in a Southern Europe population

OBJECTIVE: To evaluate the predictive value of genetic polymorphisms in the context of BCG immunotherapy outcome and create a predictive profile that may allow discriminating the risk of recurrence. MATERIAL AND METHODS: In a dataset of 204 patients treated with BCG, we evaluate 42 genetic polymorphisms in 38 genes involved in the BCG mechanism of action, using Sequenom MassARRAY technology. Stepwise multivariate Cox Regression was used for data mining. RESULTS: In agreement with previous studies we observed that gender, age, tumor multiplicity and treatment scheme were associated with BCG failure. Using stepwise multivariate Cox Regression analysis we propose the first predictive profile of BCG immunotherapy outcome and a risk score based on polymorphisms in immune system molecules (SNPs in TNFA-1031T/C (rs1799964), IL2RA rs2104286 T/C, IL17A-197G/A (rs2275913), IL17RA-809A/G (rs4819554), IL18R1 rs3771171 T/C, ICAM1 K469E (rs5498), FASL-844T/C (rs763110) and TRAILR1-397T/G (rs79037040) in association with clinicopathological variables. This risk score allows the categorization of patients into risk groups: patients within the Low Risk group have a 90% chance of successful treatment, whereas patients in the High Risk group present 75% chance of recurrence after BCG treatment. CONCLUSION: We have established the first predictive score of BCG immunotherapy outcome combining clinicopathological characteristics and a panel of genetic polymorphisms. Further studies using an independent cohort are warranted. Moreover, the inclusion of other biomarkers may help to improve the proposed model.

Predictive Biomarkers of Bacillus Calmette-Gu´erin Immunotherapy Response in Bladder Cancer: Where AreWe Now?

The most effective therapeutic option for managing nonmuscle invasive bladder cancer (NMIBC), over the last 30 years, consists of intravesical instillations with the attenuated strain Bacillus Calmette-Gu´erin (the BCG vaccine). This has been performed as an adjuvant therapeutic to transurethral resection of bladder tumour (TURBT) and mostly directed towards patients with highgrade tumours, T1 tumours, and in situ carcinomas. However, from 20% to 40% of the patients do not respond and frequently present tumour progression. Since BCG effectiveness is unpredictable, it is important to find consistent biomarkers that can aid either in the prediction of the outcome and/or side effects development. Accordingly, we conducted a systematic critical review to identify themost preeminent predictive molecular markers associated with BCG response. To the best of our knowledge, this is the first review exclusively focusing on predictive biomarkers for BCG treatment outcome. Using a specific query, 1324 abstracts were gathered, then inclusion/exclusion criteria were applied, and finally 87 manuscripts were included. Several molecules, including CD68 and genetic polymorphisms, have been identified as promising surrogate biomarkers. Combinatory analysis of the candidate predictive markers is a crucial step to create a predictive profile of treatment response.

Innovations in technology: a friendly math project and the learning analytics “challenge”

Currently the world around us "reboots" every minute and “staying at the forefront” seems to be a very arduous task. The continuous and “speeded” progress of society requires, from all the actors, a dynamic and efficient attitude both in terms progress monitoring and moving adaptation. With regard to education, no matter how updated we are in relation to the contents, the didactic strategies and technological resources, we are inevitably compelled to adapt to new paradigms and rethink the traditional teaching methods. It is in this context that the contribution of e-learning platforms arises. Here teachers and students have at their disposal new ways to enhance the teaching and learning process, and these platforms are seen, at the present time, as significant virtual teaching and learning supporting environments. This paper presents a Project and attempts to illustrate the potential that new technologies present as a “backing” tool in different stages of teaching and learning at different levels and areas of knowledge, particularly in Mathematics. We intend to promote a constructive discussion moment, exposing our actual perception - that the use of the Learning Management System Moodle, by Higher Education teachers, as supplementary teaching-learning environment for virtual classroom sessions can contribute for greater efficiency and effectiveness of teaching practice and to improve student achievement. Regarding the Learning analytics experience we will present a few results obtained with some assessment Learning Analytics tools, where we profoundly felt that the assessment of students’ performance in online learning environments is a challenging and demanding task.

Implementação da técnica Silver In Situ Hibridization para avaliação do status do gene EGFR em doentes com CPNPC

Avaliação do estado do gene Epidermal Growth Factor Receptor (EGFR), por Silver In Situ Hibridization (SISH), tem-se destacado como biomarcador preditivo na resposta à terapêutica. O principal objectivo foi optimizar a etapa de recuperação por calor da metodologia automatizada SISH Dual-Colour, em carcinomas pulmonares fixados em formol durante 24 e 72 horas. A optimização levou a um aumento da preservação do contorno nuclear e da intensidade e contraste dos sinais para os dois tempos de fixação, permitindo avaliar o estado do EGFR em 83,3% dos casos em estudo. A SISH Dual-Colour é uma alternativa para avaliar o estado do EGFR.

FASL polymorphism is associated with response to bacillus Calmette-Guérin immunotherapy in bladder cancer

Objective Deregulation of FAS/FASL system may lead to immune escape and influence bacillus Calmette-Guérin (BCG) immunotherapy outcome, which is currently the gold standard adjuvant treatment for high-risk non–muscle invasive bladder tumors. Among other events, functional promoter polymorphisms of FAS and FASL genes may alter their transcriptional activity. Therefore, we aim to evaluate the role of FAS and FASL polymorphisms in the context of BCG therapy, envisaging the validation of these biomarkers to predict response. Patients and methods DNA extracted from peripheral blood from 125 patients with bladder cancer treated with BCG therapy was analyzed by Polymerase Chain Reaction—Restriction Fragment Length Polymorphism for FAS-670 A/G and FASL-844 T/C polymorphisms. FASL mRNA expression was analyzed by real-time Polymerase Chain Reaction. Results Carriers of FASL-844 CC genotype present a decreased recurrence-free survival after BCG treatment when compared with FASL-844 T allele carriers (mean 71.5 vs. 97.8 months, P = 0.030) and have an increased risk of BCG treatment failure (Hazard Ratio = 1.922; 95% Confidence Interval: [1.064–3.471]; P = 0.030). Multivariate analysis shows that FASL-844 T/C and therapeutics scheme are independent predictive markers of recurrence after treatment. The evaluation of FASL gene mRNA levels demonstrated that patients carrying FASL-844 CC genotype had higher FASL expression in bladder tumors (P = 0.0027). Higher FASL levels were also associated with an increased risk of recurrence after BCG treatment (Hazard Ratio = 2.833; 95% Confidence Interval: [1.012–7.929]; P = 0.047). FAS-670 A/G polymorphism analysis did not reveal any association with BCG therapy outcome. Conclusions Our results suggest that analysis of FASL-844 T/C, but not FAS-670 A/G polymorphisms, may be used as a predictive marker of response to BCG immunotherapy.

Response of high-risk of recurrence/progression bladder tumours expressing sialyl-Tn and sialyl-6-T to BCG immunotherapy

High risk of recurrence/progression bladder tumours is treated with Bacillus Calmette-Guérin (BCG) immunotherapy after complete resection of the tumour. Approximately 75% of these tumours express the uncommon carbohydrate antigen sialyl-Tn (Tn), a surrogate biomarker of tumour aggressiveness. Such changes in the glycosylation of cell-surface proteins influence tumour microenvironment and immune responses that may modulate treatment outcome and the course of disease. The aim of this work is to determine the efficiency of BCG immunotherapy against tumours expressing sTn and sTn-related antigen sialyl-6-T (s6T). METHODS: In a retrospective design, 94 tumours from patients treated with BCG were screened for sTn and s6T expression. In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn. RESULTS: From the 94 cases evaluated, 36 had recurrence after BCG treatment (38.3%). Treatment outcome was influenced by age over 65 years (HR=2.668; (1.344-5.254); P=0.005), maintenance schedule (HR=0.480; (0.246-0.936); P=0.031) and multifocality (HR=2.065; (1.033-4.126); P=0.040). sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148-0.594); P=0.001). In vitro studies demonstrated higher adhesion and internalisation of the bacillus to cells expressing sTn, promoting cell death. CONCLUSION: s6T is described for the first time in bladder tumours. Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours. Furthermore, sTn and s6T expression are independent predictive markers of BCG treatment response and may be useful in the identification of patients who could benefit more from this immunotherapy.

Liderança autêntica e saúde organizacional: um estudo de caso num hospital

O conceito de Liderança tem sido amplamente estudado por diversos autores, sendo já considerado pela literatura como um tema clássico evolutivo. A investigação que aqui se apresenta pretende compreender a mais recente abordagem a esse conceito - a Liderança Autêntica, no contexto específico de um CH público em Portugal. Além disso, é seu propósito perceber se uma Liderança Autêntica é preditora de um Clima Organizacional Autentizótico e se ambos os construtos explicam a Satisfação - com o trabalho em geral e com a supervisão - e a Saúde Mental dos trabalhadores. Procura, ainda, mediante análises exploratórias, estudar a influência de algumas variáveis demográficas e profissionais na Liderança Autêntica, no Clima Organizacional Autentizótico, na Satisfação e na Saúde. Participaram neste estudo de caso 278 trabalhadores, de diferentes grupos profissionais e vínculos contratuais, tendo os resultados obtidos apontado para uma indubitável relação preditiva entre a Liderança Autêntica e a Satisfação com a Supervisão, a Satisfação com o Trabalho em Geral e a Saúde Mental. A Liderança Autêntica é igualmente uma preditora significativa do Clima Organizacional Autentizótico. Este último afigura-se, para a amostra, como explicativo de maior Satisfação e Saúde Mental dos trabalhadores. No que respeita ao estudo das variáveis demográficas (sexo, idade, estado civil e habilitações literárias) e profissionais (vínculo contratual, grupo profissional, nível da organização, antiguidade e sexo do superior hierárquico) em função das variáveis em estudo (Liderança Autêntica, Clima Organizacional Autentizótico, Satisfação e Saúde), concluiu-se que as mulheres evidenciam níveis inferiores de Saúde Mental, comparativamente aos homens. Os homens denotam menor perceção de Liderança Autêntica que as mulheres. Os “mais escolarizados” evidenciam menor Saúde Mental e maior perceção de Liderança Autêntica que os “menos escolarizados”. O grupo “técnico de saúde” está mais satisfeito com o trabalho em geral mas evidencia menor Saúde Mental que o grupo “técnico operacional”. Os trabalhadores cuja chefia é do sexo feminino demonstram níveis inferiores de Saúde Mental. Por fim, comparadas as perceções de Liderança Autêntica entre chefias e trabalhadores não chefias, inferimos que são os primeiros a perceber os líderes como mais autênticos. O estudo apresenta as suas conclusões e aponta estratégias de intervenção em termos da Gestão e Desenvolvimento e Recursos Humanos para o CH em investigação.

Building a microscope for the data center

Managing the physical and compute infrastructure of a large data center is an embodiment of a Cyber-Physical System (CPS). The physical parameters of the data center (such as power, temperature, pressure, humidity) are tightly coupled with computations, even more so in upcoming data centers, where the location of workloads can vary substantially due, for example, to workloads being moved in a cloud infrastructure hosted in the data center. In this paper, we describe a data collection and distribution architecture that enables gathering physical parameters of a large data center at a very high temporal and spatial resolutionof the sensor measurements. We think this is an important characteristic to enable more accurate heat-flow models of the data center andwith them, _and opportunities to optimize energy consumption. Havinga high resolution picture of the data center conditions, also enables minimizing local hotspots, perform more accurate predictive maintenance (pending failures in cooling and other infrastructure equipment can be more promptly detected) and more accurate billing. We detail this architecture and define the structure of the underlying messaging system that is used to collect and distribute the data. Finally, we show the results of a preliminary study of a typical data center radio environment.

Boas práticas de igualdade de género e sua relação nos domínios da satisfação laboral e clima organizacional

A Igualdade entre Homens e Mulheres e a não discriminação constituem princípios fundamentais da Constituição da Republica Portuguesa e do Tratado que institui a União Europeia – Tratado de Lisboa. A desigualdade entre Homens e Mulheres constitui uma violação dos direitos fundamentais, e impõe um pesado custo à economia na medida em que se desaproveitam talentos em função do género. A promoção de uma efetiva igualdade entre Homens e Mulheres constitui um dever fundamental do Estado. A promoção da participação ativa de Homens e Mulheres na vida política, ao nível da administração central, regional e local, é também um forte indicador da qualidade da democracia de um estado. Tomando por base a temática da Igualdade de Género, o Roteiro para a Igualdade entre Homens e Mulheres (2006-2010), o pacto Europeu para a Igualdade entre os Sexos (2006), a Estratégia para a Igualdade entre Homens e Mulheres 2010-2015 que elencam ações consideradas prioritárias – igualdade na independência económica; igualdade na remuneração por trabalho igual e por trabalho de igual valor; igualdade na tomada de decisões; promoção da dignidade e a integridade, pôr fim à violência de género; e questões horizontais – papéis desempenhados por Homens e Mulheres, legislação, governação e instrumentos no domínio da igualdade entre Homens e Mulheres, o objeto deste estudo centra-se na atividade do Estado Português, mais concretamente ao nível local. Procurou-se enquadrar esta temática na Gestão dos Recursos Humanos, na busca de um conhecimento mais aprofundado sobre a implementação de Boas Práticas de Igualdade de Género e a sua relação nos domínios da Satisfação Laboral assim como no Clima Organizacional. O presente estudo expõe uma abordagem quantitativa, de carácter descritivo, exploratório, correlacional e preditivo. O tratamento estatístico realizou-se com recurso ao programa IBM SPSS Statistics, versão 21. Os resultados encontrados apontam para uma associação positiva entre a existência de boas práticas de igualdade de género e a satisfação laboral dos trabalhadores, assim como do clima organizacional. São apresentadas pistas para a intervenção no domínio da função da gestão e desenvolvimento dos recursos humanos.