Browsing by Author "Tavares, Ana"
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- FASL polymorphism is associated with response to bacillus Calmette-Guérin immunotherapy in bladder cancerPublication . Lima, Luís; Ferreira, José Alexandre; Tavares, Ana; Oliveira, Daniela; Morais, António; Videira, Paula; Medeiros, Rui; Santos, LúcioObjective 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.
- Intérprete que souPublication . Barbosa, Susana; Macedo, Vera; Silva, Joana; Branco, Susana; Tavares, Ana
- P53 and Cancer-Associated Sialylated Glycans Are Surrogate Markers of Cancerization of the Bladder Associated with Schistosoma haematobium InfectionPublication . Santos, Júlio; Fernandes, Elisabete; Ferreira, José Alexandre; Lima, Luís; Tavares, Ana; Peixoto, Andreia; Parreira, Beatriz; Costa, José Manuel Correira da; Brindley, Paul J; Lopes, Carlos; Santos, LúcioBACKGROUND: Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers. METHODOLOGY/PRINCIPAL FINDINGS: Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67>17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium. CONCLUSION/SIGNIFICANCE: This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests.
- Portugal's special education law: implementing the International Classification of Functioning, Disability and Health in policy and practicePublication . Sanches-Ferreira, Manuela; Simeonsson, Rune J; Silveira-Maia, Mónica; Alves, Sílvia; Tavares, Ana; Pinheiro, SaraThe International Classification of Functioning, Disability and Health (ICF) was introduced in Portuguese education law as the compulsory system to guide eligibility policy and practice in special education. This paper describes the implementation of the ICF and its utility in the assessment process and eligibility determination of students for special education.
- Projecto da Avaliação Externa da Implementação do Decreto-Lei n.º 3/2008Publication . Sanches-Ferreira, Manuela; Simeonsson, Rune; Silveira Maia, Mónica; Pinheiro, Sara; Tavares, Ana; Alves, Silvia
- Projecto da Avaliação Externa da Implementação do Decreto-Lei n.º 3/2008Publication . Simeonsson, Rune J.; Sanches-Ferreira, Manuela; Silveira-Maia, Mónica; Pinheiro, Sara; Tavares, Ana; Alves, SílviaO Decreto-Lei n.º 3/2008 introduz mudanças substantivas no modo de entender e responder aos alunos com deficiência e incapacidade, propondo mais um passo na direcção de um pensamento e de uma pragmática inclusiva. Um elemento central deste articulado foi a substituição da necessidade de um diagnóstico médico ou psicológico na elegibilidade de alunos para a Educação Especial, pela descrição de um perfil de funcionalidade baseado numa avaliação biopsicossocial mediada pela utilização da Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF). Este projecto teve como objectivo a avaliação da implementação do Decreto-Lei n.º 3/2008, incidindo sobre quatro grandes questões: (1) utilização da CIF como referencial na descrição da funcionalidade dos alunos elegíveis e não elegíveis; (2) procedimentos de referenciação, de avaliação especializada e de elaboração do relatório técnico-pedagógico; (3) medidas educativas seleccionadas para os alunos elegíveis e não elegíveis; (4) recursos e apoios disponibilizados pela escola (disposições finais).
- Response of high-risk of recurrence/progression bladder tumours expressing sialyl-Tn and sialyl-6-T to BCG immunotherapyPublication . Lima, Luís; Severino, Paulo; Silva, Mariana; Miranda, Andreia; Tavares, Ana; Pereira, Sofia; Fernandes, Elisabete; Cruz, Ricardo; Amaro, Teresina; Reis, Celso; Dall'Olio, Fabio; Amado, Francisco; Videira, Paula; Santos, Lúcio; Ferreira, José AlexandreHigh 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.
- The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failurePublication . Lima, Luís; Oliveira, Daniela; Tavares, Ana; Amaro, Teresina; Cruz, Ricardo; Ferreira, José Alexandre; Santos, LúcioOBJECTIVE: Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome. PATIENTS AND METHODS: The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68+ and CD163+ macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression. RESULTS: Patients in whom BCG failed had high stroma-predominant CD163+ macrophage counts (high stroma but low tumor CD163+ macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163+ macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163+ in the tumor presented high expression of HIF-1α in tumor nests. CONCLUSIONS: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163+ macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.
- 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 populationPublication . Lima, Luís; Oliveira, Daniela; Ferreira, José Alexandre; Tavares, Ana; Cruz, Ricardo; Medeiros, Rui; Santos, LúcioOBJECTIVE: 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.
- Virtual reality and associated technologies in disability research and interventionPublication . Lopes-dos-Santos, Pedro; Silveira-Maia, Mónica; Tavares, Ana; Santos, Miguel Augusto; Sanches-Ferreira, ManuelaThis paper concerns the application of virtual reality and associated technologies (VRAT) in the disability research and intervention field. By reviewing a 144 studies presented at the International Conference Series on Disability, Virtual Reality and Associated Technologies (1996-2006), our analytic work examine the underlying conceptual frameworks of disability and methodological rationales used in selected papers. In the last 15 years, there was a paradigmatic shift from the medical to the biopsychosocial model of disability. Yet, our analyses indicate that such shift is not clearly reflected in the way VRAT have been addressing disability issues. The present manuscript offers recommendations regarding definition of goals, methodological procedures, and assessment rationales in order to stimulate discussions on how the use of VRAT can be improved in the field of disability research and practice