Programa de Pós-Graduação em Oncologia e Ciências Médicas - PPGOCM/NPO
URI Permanente desta comunidadehttps://repositorio.ufpa.br/handle/2011/4631
O Programa de Pós-Graduação em Oncologia e Ciências Médicas (PPGOCM) integra o Núcleo de Pesquisas em Oncologia (NPO) da Universidade Federal do Pará (UFPA). Trata-se do único centro de referência em pesquisa e formação de recursos humanos stricto sensu na área de oncologia na região Norte do Brasil. Os outros centros se concentram nas cidades do Rio de Janeiro e São Paulo.
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Item Acesso aberto (Open Access) Análise da expressão de DNA metiltransferases e methyl - binding proteins na carcinogênese gástrica(Universidade Federal do Pará, 2018-11-28) SOUSA, Stefanie Braga Maia de; CALCAGNO, Danielle Queiroz; http://lattes.cnpq.br/1326603355062154Despite the worldwide decline in the incidence of gastric cancer in recent years, this type of cancer is the third with higher mortality. Modifications in the pattern of DNA methylation are common in different types of cancer, including gastric cancer. In addition, changes in the expression of proteins responsible for this epigenetic mechanism in tumors are associated with changes in DNA methylation patterns. Therefore, understanding the gene machinery of the DNA methylation during carcinogenesis is crucial for understanding the biological processes involved in tumor development. In the present study, the relative mRNA expression of the DNMT1, DNMT3A, DNMT3B, MeCP2 and MBD4 genes from 61 paired samples of gastric tumors and adjacent non-neoplastic gastric tissues and 30 gastric tissue samples from individuals without neoplasia. In the analysis between the different groups of samples, mRNA of DNMT1 gene was significantly more expressed in gastric tumor and non-neoplastic adjacent tissue when compared to gastric tissue of individual without neoplasia (p = 0.0196, p = 0.0466, respectively). In addition, we observed that DNMT3A mRNA was significantly more expressed in adjacent non-neoplastic gastric tissue compared to tumor tissue and non-neoplastic individuals (p = .0.0076, p = 0.0029, respectively). The analysis with clinicopathological data showed an association between DNMT3B mRNA expression with presence of lymph node metastasis (p = 0.034) and gastric tumor stage III-IV (p = 0.048). When performing the gene correlation, it was observed that MECP2 had a strong correlation between DNMT1 (0.666), DNMT3B (0.685) and MBD4 (0.790) genes, another correlation was found between DNMT3B and MBD4 (0.650). These results suggest that alterations in DNMT1 and DNMT3A gene mRNA expression may be present in the early stages of gastric carcinogenesis, DNMT3B can be used as a marker of prognosis.Item Acesso aberto (Open Access) Avaliação do potencial antineoplásico da idarrubicina associada ao mebendazol em linhagem de adenocarcinoma gástrico metástatico(Universidade Federal do Pará, 2018-10-30) OLIVEIRA, Marcelli Geisse Sousa de; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586Gastric cancer represents the fourth and fifth type of tumor with the highest incidence in Brazil, in men and women respectively. Current therapies directed to this type of cancer have an unsatisfactory success rate. Among the possible strategies is the use of specific inhibitors that assist in the interruption of tumor progression. Therefore, the present study evaluated the cytotoxic potential of idarubicin in combination with mebendazole (MBZ) in a metastatic gastric cancer cell line, AGP01. Idarubicin (IDA) capable of inducing DNA damage through intercalation between base pairs, breaking the DNA strand and interacting with the enzyme topoisomerase II and MBZ, in turn, acts through depolymerization of tubulin and subsequent disruption of microtubule function. In view of this, the study aimed to perform in vitro tests to evaluate the efficacy of these drugs alone and in combination in a cell line established from a sample of a patients with metastatic gastric cancer. The data revealed that both IDA and MBZ showed high cytotoxicity in the AGP01 (242nM and 300nM) cell line, with the highest cytotoxic activity being conferred on the association of the substances with the IC50 of 123,9nM for IDA and 153,5nM for the MBZ. In addition, both isolated and associated substances delayed the cell migration process 12 hours after treatment with IDA isolated at the concentration of 121nM when compared to the negative control (p<0.05), 12 hours after the treatment with isolated IDA at the concentration of 242nM when compared to the negative control (p<0.001), 12 hours after treatment in the 123,9nM concentration (IC50 of the IDA combination) and 153,5nM (IC50 of the combination MBZ) when compared to the negative control (p<0.05). In addition, both IDA and MBZ, isolated and in association induced apoptosis in the AGP01 cell line (p<0.001). In addition, it was found that both substances, both alone and in combination, were able to block the cell cycle, in the S phase for IDA and MBZ + IDA and in the G2/M phase for MBZ. It is worth mentioning that this is the first study that associates IDA with MBZ in cancer. In assessing the effects of substances, it is of the utmost importance to note that by combining the substances we find that the dose needed to produce the same effects as the isolated substances has been halved. The results generated by the present study demonstrate that both MBZ and IDA present a very promising anticancer potential for patients with advanced gastric cancer.Item Acesso aberto (Open Access) Efeitos do consumo de água de pH alcalino em pacientes com gastrite e correlação com marcadores epigenéticos relacionados com a inflamação(Universidade Federal do Pará, 2018-10-10) CHAVES, Juliana Ramos; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586In the carcinogenesis of gastric cancer, the stages usually manifest clinically as gastritis, gastric atrophy, ulcerations, intestinal metaplasia, dysplasia and finally, as malignant neoplasia. The association between gastric cancer and diet is already widely described in the literature and several studies have demonstrated the influence of food intake with preservatives and with high concentration of nitrates and salt, with the development of this neoplasia. Regarding water consumption, there’s no relevant evidences. The pH of most of the water sold in the metropolitan área of Belem does not match the standarts recommended by the govermnment Health department, being more acidic. Thus, the benefits of both healthy eating and alkaline water consumption are object of several discussions. Nowadays the other types of markers that can aid the detection of pre-neoplastic and neoplastic lesions will be hosted. Among them, find themselves as epigenetic proteins. Environmental factors such as diet, inflammation and infection have been excluded as contributors to epigenetic changes. Hence, the present work intends to provide evidence that only the water pH modification is able to lead the variations the expressions pattern of miRNAs, associated with a first stage of gastric carcinogenesis, a gastritis. For this it was applied the microRNAs miR-7, mir-155, mir-29c and mir-135b, in 28 patients porters of gastritis that were burned to digestive endoscopy alkaline PH. After collection, the RNA from the samples was extracted, and the complementary tape DNA (cDNA) was obtained. The cDNAs were submitted to qPCR amplification analysis for analysis of miRNA expression. They assessment were using the Biostat and Stata 11.0 programs, being statistically superior to values of p <0.05. Comparing the levels of expression and clinical evaluation of gastritis by EDA before and after alkaline water consumption, the results demonstrated that there was a increasing of the target microRNAs, of miR-7 (p = 0.09), miR155 (p = 0.13), miR-29c (p =0.21) and miR-135b(p=0.19). On the other hand, it was possible to observe a significant endoscopic improvement of the gastritis (p=0.024), demonstrating the clinical benefit of alkaline water intake.Item Acesso aberto (Open Access) Estudo da resposta terapêutica e prognóstico de pacientes com diagnóstico de leucemia linfóide aguda com fusões gênicas em um hospital de referência do Pará(Universidade Federal do Pará, 2017-07-31) PANTOJA, Laudreísa da Costa; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586Acute Lymphoblastic Leukemia (ALL) is the main neoplasia that affects children and adolescents, accounting for 25% of all types of cancer in the age group. It is a hematopoietic system neoplasia. and can be classified by several types of cell morphology, immunophenotyping, cytogenetic and molecular biology. Despite advances in treatment, up to a quarter of patients with ALL are still relapsed, and are associated with recurrent genetic conditions. In recent years, intensive efforts have been devoted to identifying the genetic factors that contribute to a leukemogenesis, influence a response to treatment and which are applied in the clinic as new prognostic tools and/or as new therapeutic targets. In this sense, this project aims to evaluate the therapeutic response and prognosis of patients with acute lymphoblastic leukemia carriers of the main genetic fusions that are believed to play an important role in the diagnosis, prognosis and targeting of therapeutic actions of ALL, such as a TCF3-PBX1, MLL-AF4, BCR-ABL, TEL-AML1 and SIL-TAL, in pediatric patients at a referral center in the State of Pará. Material and Methods: Bone marrow and peripheral blood samples were extracted from 55 patients from 0 to 18 years, with ALL, which were also submitted to data collection. Their samples were submitted to RT-PCR technique to investigate the main fusions found in leukemias. Results: Patients older than 10 years were more refractory to treatment than the other patients (p=0.017). The initial leukometry presented a mean of 92.235 leukocytes and 35.3% presented leukometry greater than 50.000, being a higher risk factor (p=0.000) and present other factors of poor prognosis as age group (p= 0.004) and Egil classification of ALL T (p= 0.001). The frequency of fusions was BCRABL-11%; MLL-AF4 = 3.6%; TEL-AML1 - 7.2%, E2A-PBX1 - 21.8% and SIL-TAL 5.4%. Patients with TEL-AML1 fusion were mostly HR (p=0.026, OR= 0.82 e IC= 0.68– 0.99), those with MLL-AF4 presented a relative risk for death of 1.33, and all died (p=0.019), those with SIL-TAL had an unfavorable age at diagnosis (greater than or equal to 10 years) (p=0.017) and initial leukometry greater than 50.000 (p=0.039). The refractoriness of the initial treatment was 9%, recurrence 18% and death 14.5%, not being significantly associated with gender, age, leukocyte count at diagnosis, cell line or presence of fusions in this limited number of patients, except for the MLL-AF4 fusion that presented a death chance ratio of 1.33 (p = 0.019) and all pacients died. Conclusion: The population studied has a worse prognosis even in those patients with favorable genetic characteristics such as TEL-AML1 fusion. The frequency of fusions in this research was high, and associated with other prognostic factors such as age greater than 10 years and initial hyperleukocytosis contributed to a worse prognosis and decrease of the therapeutic response and in addition, MLL-AF4 fusion in infants alone presented a high risk for death. The outcomes in children with ALL may be a reflection of health care conditions, socioeconomic status, and other associated genetic factors.Item Acesso aberto (Open Access) Expressão diferencial de genes regulados pelo MYC em linhagens de câncer gástrico(Universidade Federal do Pará, 2018) PESSOA, Carla Mariana Ferreira; BURBANO, Rommel Mario Rodriguéz; http://lattes.cnpq.br/4362051219348099MYC is an oncogene responsible for excessive cell growth in cancer, allowing the transcriptional activation of genes involved in cell cycle regulation, metabolism and apoptosis, and is generally overexpressed in Gastric Cancer (GC). Using siRNA and Next Generation Sequencing (NGS), we identified the Genes Differential Expression (DEGs) regulated by MYC in three Brazilian cell lines of GC represented by the diffuse, intestinal and metastatic histological subtypes, and later integrated these data with a computational gene enrichment with the GSEA (Gene Set Enrichment Analysis) tool. We identified a total of 5,471 DEGs with a high correlation (80%). The silencing of MYC by siRNA in diffuse and metastatic CG cell lines resulted in an increase in the number of DEGs with decreased expression, while in intestinal-type lineage they exhibited a greater amount of DEGs with an increased expression profile. From gene enrichment, using our sequenced samples compared to the hallmark gene sets, we found 11 significant sets of genes enriched mainly in the following categories of processes: proliferation, pathway, metabolic signaling and DNA damage. Subsequently, DEGs were enriched in the metabolic pathways of the KEGG (Kyoto Encyclopedia of Genes and Genomes) database, and 12 enriched pathways were found that added a variety of biological functions, and three of them were common to all three cell lines of GC: ubiquitin-mediated proteolysis, ribosomes, system and epithelial cell signaling in Helicobacter pylori infection. In this study, GC cell lines shared 14 genes regulated by MYC, but their gene expression profile was different for each histological subtype. Therefore, the results of the in silico analysis of this study revealed expression signatures related to MYC in GC. Thus, we present evidence that these CG cell lines, represented by distinct histological subtypes, have different expression profiles regulated by MYC, but share a common nucleus of genes with altered profiles. This is an important step towards understanding the role of MYC in gastric carcinogenesis, as well as an indication of probable new drug targets in stomach cancer.Item Acesso aberto (Open Access) Expressão imunofenotípica da PD-1 e PD-L1 em adenocarcinoma gástrico de pacientes atendidos no Hospital Universitário João de Barros Barreto(Universidade Federal do Pará, 2017-08-31) CANELAS, Érika Thaiane Couto; DEMACHKI, Samia; http://lattes.cnpq.br/7568391537270652Gastric cancer is the third leading cause of cancer-related death in both genders, and at an advanced stage the prognosis has been unfavorable. Human tumors are prone to escape from immunovigilance, and one of the axes involved in this scenario is PD-1, a receptor expressed on the surface of cells, and its PD-L1 linker, which have already been detected in samples from gastric adenocarcinoma. This study aimed to characterize the immunophenotypic expression of PD-1 and PD-L1 proteins in tissue adjacent to the tumor, primary gastric adenocarcinoma tissue, associated with clinicopathological and demographic findings from patients attending at University Hospital João de Barros Barreto since 2008 to 2016. We selected 92 samples from patients with gastric adenocarcinoma and 55 tissue samples adjacent to the tumor. Tissue microarrays (TMA) were constructed and automated immunostaining was performed (GX Ventana - Roche ®) for PD-1 and PD-L-1. The immunoreactivity for PD-L1 in tumor cells was observed in 8 cases (8.7%), all of them of intestinal histological type of Láuren and advanced staging, presenting, in the most, grade II of differentiation. Whereas cytoplasmic immunoreactivity for PD-1 in the lymphocyte of the intratumoral microenvironment (TIL) was observed in the cytoplasm and occurred in 64 cases (69.6%), being the majority of intestinal histological type of Láuren, advanced staging and grade II of differentiation. Intratumoral PD-1 positive lymphocytes were observed in a greater number of cases when evaluated intratumoral stroma, as compared to the tumor-associated PD-1 lymphocyte lymphocytes adjacent to the tumor. These data reinforce that patients with gastric adenocarcinoma who features the histopathological characteristics found in predominance for both markers analyzed, may be more likely to activate the PD-1 / PD-L1 pathway and are eligible candidates to use anti-PD-1 monoclonal antibody or anti- PD-L1.Item Acesso aberto (Open Access) Redução de MIR-218 no soro como biomarcador de pior prognóstico em entes com câncer gástrico(Universidade Federal do Pará, 2018-08-03) MARTINS, Nina Nayara Ferreira; CALCAGNO, Danielle Queiroz; http://lattes.cnpq.br/1326603355062154Recently, liquid biopsy has emerged as a promising tool for the identification of potential diagnosis, prognosis and/or predictive biomarkers in blood of patients with many different diseases, including cancer. MicroRNAs are among that potential biomarkers, and when deregulated, could contribute to the development of various types of cancer, such as gastric cancer. The literature demonstrates an association of miR-218 expression as a potential tumor suppressor associated with gastric cancer progression. However, only one previous study in Asiatic population evaluated the expression of circulating miR-218 in the serum of patients vs control. Therefore, the aim of this study was to evaluate the expression of miR-218 in the serum of patients with gastric cancer and its correlation with clinical-pathological characteristics. Samples were collected from 302 patients and 120 healthy subjects for analysis of mirR-218 expression by Real-Time Quantitative Polymerase Chain Reaction. The results demonstrated decreased expression of miR-218 in the serum of patients with gastric cancer in association with health subjects. In addition, the reduction of miR-218 expression was significantly associated with tumor invasion, presence of lymph node metastases, Lauren’s diffuse type, advanced stages of cancer, indicating worse prognosis. Therefore, corroborating with findings from the literature, theses results suggest the potential use of miR-218 in serum as a prognostic biomarker in gastric cancer patients.Item Acesso aberto (Open Access) Variabilidade do gene CYP2D6 em populações ameríndias(Universidade Federal do Pará, 2018-12-03) LEITÃO, Luciana Pereira Colares; SANTOS, Ney Pereira Carneiro dos; http://lattes.cnpq.br/1290427033107137The genetic cytochrome P450 superfamily is of significant relevance to the process of metabolizing drugs in the human liver. The CYP2D6 gene, one of the most studied genes due to its vast amount of genomic variations and the low influence of external non-genetic factors that affect the metabolization process of more than 20% of the drugs marketed. The molecular profile of the CYP2D6 gene influences several classes of drugs: antidepressants, antipsychotics, antiarrhythmics, opioid analgesics, anticancer agents among other drugs. However, these protocols are designed mainly for populations of European origin, not being properly employed in Brazilian populations, as are results from a complex process of miscegenation involving the contribution mainly from European, African and Amerindian. Pharmacogenomic studies in Amerindian populations are scarce. Thus, in the absence of consistent data, the establishment of public health policies aimed at the implementation of precision medicine in these populations, and in peoples mixed with these ethnic groups, is impaired. Genomic studies capable of analyzing the genetic heterogeneity of biomarkers associated with the metabolism process of several drugs in Amerindian and mixed populations are of great scientific impact. Based on this study evaluated the molecular profile 22 therapy important predictors of the CYP2D6 gene polymorphisms in individuals in American Indians Amazon samples from three tribes: the Asurini Trocará, Asurini Koatinemo and the Kayapo-Xikrin. The DNA was extracted from the peripheral blood of the individuals studied. Polymorphism genotypes were performed by Taqman® assays in OpenArray® on the QuantStudio ™ 12K Flex Real-Time PCR System. The statistical analyses was due in the programs Arlequin v. 3.5.2.2, SPSS v. 12.0 and the statistical package of R. In addition to this original work, a review was carried out to group CYP2D6 gene data in other Amerindian populations. From the results it was possible to observe that the normal extensive metabolism profile is the most frequent in the Amerindian population of the review and in the Brazilian Amazon Amerindian population. The profiles of clinical importance, slow and ultrafast, presented low frequency in the populations of the review and was not observed in the Amazonian population. These data may infer that the Amerindian population may have some protection from drug-related adverse effects and drug failure that are metabolized by CYP2D6.