RESUMO
Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that is highly expressed in papillary thyroid carcinoma (PTC). The HLA-G gene presents several functional polymorphisms distributed across the coding and regulatory regions (5'URR: 5' upstream regulatory region and 3'UTR: 3' untranslated region) and some of them may impact HLA-G expression and human malignancy. To understand the contribution of the HLA-G genetic background in PTC, we studied the HLA-G gene variability in PTC patients in association with tumor morbidity, HLA-G tissue expression, and plasma soluble (sHLA-G) levels. We evaluated 185 PTC patients and 154 healthy controls. Polymorphic sites defining coding, regulatory and extended haplotypes were characterized by sequencing analyses. HLA-G tissue expression and plasma soluble HLA-G levels were evaluated by immunohistochemistry and ELISA, respectively. Compared to the controls, the G0104a(5'URR)G*01:04:04(coding)UTR-03(3'UTR) extended haplotype was underrepresented in the PTC patients, while G0104a(5'URR)G*01:04:01(coding)UTR-03(3'UTR) was less frequent in patients with metastatic and multifocal tumors. Decreased HLA-G tissue expression and undetectable plasma sHLA-G were associated with the G010102a(5'URR)G*01:01:02:01(coding)UTR-02(3'UTR) extended haplotype. We concluded that the HLA-G variability was associated with PTC development and morbidity, as well as the magnitude of the encoded protein expression at local and systemic levels.
Assuntos
Antígenos HLA-G , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Antígenos HLA-G/genética , Regiões 3' não Traduzidas , Morbidade , Neoplasias da Glândula Tireoide/genética , Proteínas de Ligação ao GTPRESUMO
As BRAF, TERT, HLA-G, and microRNAs have been individually associated with papillary thyroid carcinoma (PTC), we aimed to evaluate the individual and collaborative role of these markers in PTC in the same patient cohort. HLA-G and BRAF tumor expression was evaluated by immunohistochemistry. Using molecular methods, BRAFV600E and TERT promoter mutations were evaluated in thyroid fine needle aspirates. MicroRNA tumor profiling was investigated using massively parallel sequencing. We observed strong HLA-G (67.96%) while BRAF (62.43%) staining was observed in PTC specimens. BRAF overexpression was associated with poor response to therapy. The BRAFV600E (52.9%) and TERTC228T (13%) mutations were associated with extrathyroidal extension, advanced-age, and advanced-stage cancer. The TERT rs2853669 CC+TC genotypes (38%) were overrepresented in metastatic tumors. Nine modulated microRNAs targeting the BRAF, TERT, and/or HLA-G genes were observed in PTC and involved with cancer-related signaling pathways. The markers were individually associated with PTC features, emphasizing the synergistic effect of BRAFV600E and TERTC228T; however, their collaborative role on PTC outcome was not fully demonstrated. The differentially expressed miRNAs targeting the BRAF and/or HLA-G genes may explain their increased expression in the tumor milieu.
Assuntos
Carcinoma Papilar , MicroRNAs , Telomerase , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Antígenos HLA-G/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Regiões Promotoras Genéticas , Telomerase/genética , Telomerase/metabolismo , Mutação , MicroRNAs/genéticaRESUMO
A Aprendizagem Baseada em Problemas (ABP), introduzida no ensino de Ciências da Saúde na McMaster University, Canadá, em 1969, é uma proposta pedagógica que consiste no ensino centrado no estudante e baseado na solução de problemas, reais ou simulados. Os alunos, para solucionar esse problema,recorrem aos conhecimentos prévios, discutem, estudam, adquirem e integram os novos conhecimentos.Essa integração, aliada à aplicação prática, facilita a retenção do conhecimento. Portanto, a ABP valoriza, além do conteúdo a ser aprendido, a forma como ocorre o aprendizado, reforçando o papel ativo do aluno neste processo, permitindo que ele aprenda como aprender. A ABP oferece diversas vantagens, como o desenvolvimento da autonomia, a interdisciplinaridade, a indissociabilidade entre teoria e prática,o desenvolvimento do raciocínio crítico e de habilidades de comunicação, e a educação permanente. Porém, para a sua utilização são necessários investimentos em recursos humanos e materiais, além de um programa de capacitação de professores e alunos bem estruturado, que devem sempre ser considerados antes de sua implementação.
The Problem-Based Learning (PBL), introduced at McMaster University School of Medicine, Canada, in 1969, is a student-centered pedagogical approach based on critical thinking and problem solving. In order to solve a problem, students use their prior knowledge, discuss, study, acquire and integrate new information. This learning integration, combined with a practical application, facilitates knowledge retention.Therefore, students become actively involved in the learning process and improve the capacity of learn how to learn. PBL has several advantages, such as, it stimulates the development of autonomy on learning; interdisciplinary; integration of knowledge and practice; development of teamwork, critical thinking and communication skills; and continuing education. However, to be able to implement PBL on curriculum, its necessary investments in human and material resources, including a well-structured training program for teachers and students.