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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Agora exibindo 1 - 9 de 9

Acesso aberto (Open Access)
Análise das proteínas relacionadas a formação de metástase em linhagens de adenocarcinoma gástrico
(Universidade Federal do Pará, 2014-03-11) VALENTE, Tárik Olívar de Nunes; CALCAGNO, Danielle Queiroz; http://lattes.cnpq.br/1326603355062154; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
Gastric cancer is a serious public health problem worldwide. The high incidence of advanced tumors with poor survival by metastasis, especially in the north, made us realize the comparative study of strains of metastatic gastric adenocarcinoma (AGP01) with gastric adenocarcinoma without metastasis (ACP02) by proteomic evaluation of cell motility that may be related to the formation of these metastasis. Proteomic study was conducted strains AGP01 and ACP02 through the technique of high performance liquid chromatography 2D Nanoultra (UPLC) together with nanoESI - (MSE mudpit) and functional analysis of differentially expressed proteins in the Ingenuity Pathways Analysis (IPA) software. We observed 19 proteins with increased expression in AGP01 lineage regarding ACP02, which are related to movement, organization and cell morphology, where we suggest that ACTB, ANXA1, LGALS1, IQGAP1, EZR, MSN, MYH9 and S100A11 proteins, according to our findings and supported by the research literature is associated with metastasis of gastric adenocarcinomas. Other proteins showed strong expression in our study, but its expression in the research literature is related to the dissemination routes only other tumors, such as breast (RAB5C), lung (PLS1 and CAP1), rectum (ACTN1) and GIST (SYNE2). Conflicting with our study, the expressions of CAPZA1, FLNA and FLNC protein, were observed in the literature as an inhibitor of tumor advancement, where the expression of MYL6, MYL6B and ACTN2 proteins first appear as being related to cell motility, invasion and metastasis in cancer.
Acesso aberto (Open Access)
Avaliação bacteriológica por cultivo e metagenômica de peixes pirarucu (Arapaima gigas) submetidos a diferentes procedimentos de salga
(Universidade Federal do Pará, 2017-12-01) SILVA, Flávia Thamires Barbosa da; ASSUMPÇÃO, Paulo Pimentel de; http://lattes.cnpq.br/7323606327039876; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
In the North region, gastric cancer (GC) ranks second of the most frequent types of tumors in men and fourth in women. For 2016, were estimated 690 new cases in the state of Pará, 260 cases in the capital. GC has a multifactorial etiology, resulting from the interaction of genetic (endogenous) and environmental (exogenous) factors. Epidemiological studies have shown a clear association between the excessive consumption of salt-preserved foods and the occurrence of GC, this is mainly due to the carcinogenic action of N-nitroses compounds resulting from the union of Nitrate reduction pathway (from salting) products and of organic compounds present in the stomach region. This reduction is performed by bacterial enzymes (nitrate reductase) that are present in contaminating species that can proliferate in this type of food. Such salt-preserved foods, such as pirarucu (among other fish), shrimp and charque, have been incorporated for many years into the food pattern of the state of Pará and other areas of the Amazon region. This reduction is performed by bacterial enzymes (nitrate reductase) present in contaminating species that can proliferate in this type of food. Salt-preserved foods, such as pirarucu (among other fish), shrimp and charque, have been incorporated for many years into the food pattern of the state of Pará and other areas of the Amazon region. During the salting process, the time and conditions of processing, storage and commercialization of the food are directly related to the quality of these products. For this reason, the importance of studies that evaluate alternative processing conditions, such as use of refrigeration, in order to mitigate the production of components harmful to human health. In the present study, we investigated the bacterial composition in different salting processes of these foods, through bacterial and metagenomic isolation. Samples of fresh pirarucu evidenced growth of E. coli, indicating microbial contamination of fecal origin, which was not noticed in the samples submitted to salting. From the metagenomic analyzes we can observe an abundance of the genus Staphylococcus in the samples of salted fish, especially in those kept exposed at room temperature. This genus contains species that cause toxinfections and have the enzyme nitrate reductase. The contamination of pirarucu by these bacterial species leads to the production of nitrite, which when consumed lead to the formation of carcinogens involved in the formation of mutations, which may trigger gastric neoplasms. Although refrigeration has diminished the bacterial quantitative, the bacteriostatic or bactericidal effect of the salting process was not sufficient to maintain the quality of the salted fish in levels suitable for consumption, therefore, the consumption of the fish can be harmful to the health of the population and be related with high GC rates in the population of Belém and the North region.
Acesso aberto (Open Access)
Avaliação da atividade antineoplásica dos fármacos metformina e mebendazol isolados e em associação em linhagem celular de câncer
(Universidade Federal do Pará, 2018) SILVA, Karla de Assis; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
Gastric cancer will account for 782,685 deaths worldwide in 2018, being the fifth most common cause of cancer in the world and a fourth in Brazil. For example, the diagnosis of pathognomonic cases, the diagnosis of gastric cancer occurs late in most cases. In addition, this is a series of patients with chemotherapy and radiotherapy, being a resection surgery that offers the greatest healing potential. Adenocarcinoma is the most common subtype of lung cancer, with incidence greater than 90%. The risk factors for the pathology are multiple and cover the genetic, environmental and food. The drugs metformin and mebendazole, now used in the processes of diabetes and parasitic infections, are presented as antineoplastic effects in studies of various types of cancer. For metformin, it is possible that anticancer mechanisms of action, among others, may be made viable by LKB1 / AMPK / mTOR. Mebendazole prevents the polymerization of tubulins, inhibiting the growth and invasiveness of cancer cells. Thus, the present study has as a preventive effect metformin and mebendazole, known for their anti-neoplastic antibodies and low toxicity, in isolation and in combination with AGP01 (prescribed from neoplastic cells present in the patient with gastric ascites fluid of the intestinal type). This study is in vitro: MTT cytotoxicity, viability / apoptosis and necrosis assessment, cell cycle analysis and migration assay. One metfomine had 6.2mM IC50 and the 300mM IC50 mebendazole given alone, when combined with a new level of new IC50 values of 1.8mM and 88nM, respectively. The cell migration was inhibited for the metformin from the time of 12h and mebendazole from the time of 24h, a combination of the drugs showed no change in the time of inhibition, but increased the reliability of the test. Mebendazole and metformin induced cell death by apoptosis and prevented cell cycle progression, increasing the percentage of cells in the G1 / G0 phase and decreasing the percentage of cells in the S phase and G2 / M phase. These data confirm, at least in the antineoplastic effects of these drugs.
Acesso aberto (Open Access)
Avaliação da expressão da proteína twist em amostras de carcinoma epidermóide bucal e sua correlação com aspectos clínico-patológicos
(Universidade Federal do Pará, 2014) ABREU, Michelle Carvalho; PONTES, Hélder Antônio Rebelo; http://lattes.cnpq.br/8076555757131891; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
Among the malignant neoplasms that occur in the mouth, 95% are represented by oral squamous cell carcinoma (oscc). in brazil, the estimates for the 2014, according to the inca point more than 15,290 new cases. these data show that the oscc represents a public health problem because of the morbidity away a large numbers of patients from de work, and weigh the cost of health care in the state, due the days of hospitalization and the treatment applied. the pathogenesis of the oscc is related to genetic factors as well as chemical agents, such as tobacco and alcohol, physical and biological agents considered carcinogenic. the transcription factor twist was recently appointed as an important regulator of emt during tumor progression and metastasis and has become an important diagnostic and prognostic marker for patients due to the fact its positive upregulation and methylation of the gene are being implicated in several cancers. although many studies provide important insights into understanding the biology of malignant tumors as well as genes involved in emt, twist mechanisms in tumorigenesis and epithelial-mesenchymal transition in oral squamous cell carcinoma remain to be elucidated. in this study we investigated the pattern of expression of twist protein by immunohistochemical technique in 59 oscc samples from patients from the national health system of the state of pará and evaluated the possible association of the results with clinical and pathologic features survival of patients.the results showed a statistically significant association between alcohol consumption and the most sites affected by the oscc, suggesting that ethanol may play a potentiating role of tobacco agents in sites that receive greater exposure of these substances. the expression of twist protein also showed a decrease in average survival of individuals. despite this decline have not shown statistical significance in our studies, we believe that it should be more widely studied, aiming at a better understanding of its role in oral squamous cell carcinoma. the positivity of protein labeling demonstrated relationship to smoking, where 87.8% of smoking patients showed positive staining for protein, corroborating the fact that smoking can modulate the expression of emt markers including twist. in summary, the results of this study show some intriguing correlations, which in our opinion deserve special attention in order to be clarified. as the intracellular localization of the protein observed in this study, is probably related to some oncogenic process is not described
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/6305099258051586
Gastric 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.
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/6305099258051586
In 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.
Acesso aberto (Open Access)
Estudo da expressão das proteínas Twist1, Kai1 e E-Caderina em amostras de câncer de pênis, de pacientes atendidos em um hospital de referência do estado do Pará
(Universidade Federal do Pará, 2015-11-10) BATISTA, Lecildo Lira; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
Penile neoplasms are a rare disease in developed nations and occur more in the development areas, which states as a major problem of public health by its mutilating features that may lead to social and psychological problems for the patient. The most important prognosis factor are the lymph node involvement and the presence of distance metastasis. Those patiens who have these features rarely survive for five years. By the other side, the prognosis is good at the initial phases and the cure is obtained in most of the cases. In the search for more reliable prognosis indicators, countless of gens and proteins associated with the penile carcinogenesis have been evaluated for a better understanding of the process, in order to achieve more accurate diagnosis methods to identify patients with aggressive disease, then submit them to a more efficient primarily treatment and a better survive rate. Some groups of epithelial and mesenchymal markers have been used to determinate the transition of mesenchymal epithelium in neoplasm tissues. Those groups include surface proteins like E-cadherin and cytoskeleton markers, as vimentin and β-catenin, and transcription factors, as Snail, Slug and Twist1. With this approach, we did a retrospective study which was analyzed 109 patients from Ophir Loyola Hospital, between January 2012 to November 2014. It was investigated the protein expression of Twist1, Kai1 and E-cadherin in penile tissues with benign and malign lesions to look for evidence of the immunoreactivity pattern and correlate that immunoreactivity pattern with the progression and invasion features of the penile neoplasms and other clinicopathological features of the studied tumor. In relation to E-cadherin, 48,6% of the patients had lower expression of this protein when compared to non-neoplasms tissues, this result showed statistical significance. But the association of the abnormal expression of E-cadherin with others clinicopathoogical factors was not found. The higher expression of Twist1 it was not associated with clinicopathological factors and the KAI1. There was statistical significance when we simultaneously compared the defective expression of E-cadherin and Kai1 and we obtained an inconclusive outcome about the association between them and there was not statistical significance among the analysis of the Twist1 e Kai1 proteins.
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/6305099258051586
Acute 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.
Acesso aberto (Open Access)
Papel do gene PIWIL1 como possível agente no processo de transição epitélio-mesenquimal no câncer gástrico
(Universidade Federal do Pará, 2019) PAIVA, Juliana Albuquerque Pinto; KHAYAT, André Salim; http://lattes.cnpq.br/6305099258051586
The PIWI-LIKE PROTEIN 1 (PIWIL1) gene has emerged as an attractive target for gastric cancer, as studies have shown that PIWIL1 protein is expressed at increased levels in cancer tissues, stem cells and germ cells, but it has been shown to be absent in normal somatic tissues. This means that it could be a potential target for therapy, since most non-cancer cells would not be affected by cytotoxic effects. Although relevant information on the possible role of PIWIL1 in the carcinogenesis of gastric cancer is provided by the current literature, the molecular mechanisms involved in this carcinogenic process remain unclear. Therefore, in order to investigate the molecular mechanisms by which PIWIL1 confers advantages to cancer cells, CRISPR/Cas9 technology was employed in order to perform the permanent knockout of PIWIL1 gene in the AGP01 gastric cancer cell line. After knockout, experiments were carried out to evaluate the effect of this molecular alteration on the migration and invasion capacity of the cell line, as well as on the expression of genes involved in these two cellular mechanisms. The results demonstrated that PIWIL1 gene knockout caused a significant decrease in the migration capacity of AGP01 after 24 hours, as well as a significant decrease in the cell invasion capacity. In addition, gene expression results revealed 26 genes (five overexpressed and 21 hypoexpressed - when comparing the cell lines before and after knockout) that encode proteins involved in invasion and migration cellular processes. According to the current literature, nine of these 26 genes (DOCK2, ZNF503, PDE4D, ABL1, ABL2, LPAR1, SMAD2, WASF3 and DACH1) are possibly related to the mechanisms used by PIWIL1 to promote carcinogenic effects related to migration and invasion, since their functions are consistent with the observed modification (being overexpressed or hypoexpressed after knockout). Taken together, these data reinforce the idea that PIWIL1 should play a crucial role in the gastric cancer signaling pathway, regulating several genes involved in the migration and invasion processes, so its use as a therapeutic target can generate promising results in the treatment of this type of cancer.

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