Navegando por Palavras-chave "p53"

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    Abnormal expression of MDM2 in prostate carcinoma
    (Lippincott Williams & Wilkins, 2001-05-01) Leite, Katia Ramos Moreira [UNIFESP]; Franco, Marcello Fabiano de [UNIFESP]; Srougi, Miguel [UNIFESP]; Nesrallah, Luciano J.; Nesrallah, Adriano; Bevilacqua, Ruy G.; Darini, Elaine; Carvalho, Claudia M.; Meirelles, Maria Ines; Santana, Isaque; Camara-Lopes, L. H.; Hosp Sirio Libanes; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)
    Mutation of p53 is rare in localized prostate carcinoma the oncoprotein MDM2, whose gene has a response element for p53, promotes the degradation of p53 protein and inhibits its transcriptional activation of genes related to cell cycle arrest and apoptosis, constituting a negative feedback control. We studied p53 and MDM2 expression by immunohistochemistry and looked for mutations in p53 exons 5 to 8 by polymerase chain reaction-single strand conformational polymorphism in 118 patients submitted to radical prostatectomy for localized prostate cancer. in 28 cases, we studied cell proliferation by immunohistochemistry, using antibody for Ki-67, and apoptosis by the deoxynucleotidyl transferase mediated dUTP biotin nick end labeling technique. Although no p53 mutations were found, p53 protein was detected in 31.4% of the cases, and these cases had higher Gleason scores (P = .03) and more advanced tumor stages (P = .02). MDM2 was overexpressed in 40.7% of the cases, and these: cases had greater tumor volumes (P = .001). Tumors that were positive for both p53 and MDM2 were larger (P = .003) and of more advanced stage (P = .03). Within the 28-case subset, the proliferative index was higher among MDM2-positive tumors (P = .046), and the apoptotic index was lower among p53-positive tumors (P = .01). We conclude that, although p53 mutation is a rare event in prostate carcinogenesis, the detection of p53 protein by immunohistochemistry is common and is associated with decreased apoptosis and increased histologic grade and tumor stage. We also conclude that the overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. Finally, we propose that the MDM2-positive/53-positive phenotype identifies prostate cancers with aggressive behavior.
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    Adrenocorticotropin-producing pituitary carcinoma with expression of c-erbB-2 and high PCNA index: A comparative study with pituitary adenomas and normal pituitary tissues
    (Humana Press Inc, 1998-03-01) Nose-Alberti, V; Mesquita, MIS; Martin, L. C.; Kayath, M. J.; Universidade Federal de São Paulo (UNIFESP)
    Pituitary carcinomas are very rare neoplasms with a poor prognosis. We report a case of Cushing's disease resulting from a pituitary carcinoma in a ZZ-yr-old female, who died of massive hepatic failure. At autopsy, there was invasion of the parasellar structures and vasculature by the tumor, which stained positively only for ACTH. There were two metastatic nodules in the liver, which also stained positively for ACTH. When compared to other cases of Cushing's disease (n = 52), other pituitary adenomas (n = 292), and normal pituitary tissues (n = 21), the pituitary carcinoma was the only one with c-erbB-2 membrane staining in both the sellar-located tissue and liver metastasis. C-erbB-2 staining was present in the cytoplasm of a variable number of cells in 40% of the invasive adenomas (n = 103), while only 1.2% of the noninvasive tumors (n = 241) expressed this protein (p < 0.001). No particular immunohistological type preferentially expressed this protein. in normal pituitary tissues, 10% of the cells expressed cytoplasmic c-erbB-2. A higher index of proliferating cell nuclear antigen (PCNA) in the primary tumor and liver metastasis (10%) was also found compared to other ACTH-secreting adenomas (invasive, 3.4 +/- 1.9% vs 1.7 +/- 1.5% in noninvasive) and other pituitary tumors (invasive, 2.9 +/- 1.5% vs 1.5 +/- 1.3% in noninvasive). the PCNA index was significantly higher in invasive tumors than in noninvasive adenomas (p = 0.004). PCNA staining was negative in normal pituitary tissues. Staining for p53, pRB and p(21ras) was negative in the carcinoma and liver metastasis. We suggest that the c-erbB-2 membrane pattern and a higher PCNA index may indicate a worse prognosis in adenohypophyseal neoplasia.
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    Análise do tempo de sobrevida de doentes com adenocarcinoma colorretal esporádico pela utilização de um painel de biomarcadores de carcinogênese constituído por vegf, egfr, ki-67, p53 e bcl-2
    (Universidade Federal de São Paulo (UNIFESP), 2014-12-17) Luderer, Loreley Andrade [UNIFESP]; Matos, Delcio Matos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Objective: To evaluate the prognostic power of survival of a carcinogenesis biomarkers panel formed by p53, VEGF, Bcl-2, Ki-67, and EGFR in subjects with sporadic colorectal adenocarcinoma subjected to radical surgical treatment. Methods: 114 post-surgical subjects with colorectal adenocarcinoma were studied and followed for 3 to 5 years at Fundação Pio XII – Hospital de Câncer de Barretos. The study was conducted in paraffin-embedded tumor tissue whose slides were stained using the hematoxylin-eosin technique. The tissue microarray slides, as well as the immunohistochemical staining, were examined by two pathologists, blinded to the evaluations. The statistical analyses were conducted using mean, median, minimum, maximum, and number of valid observations for the descriptive analysis of the numeric variable, global survival. The comparison of the expression of EGFR, VEGF, Ki-67, p53, and Bcl-2 biomarkers was conducted through the Chi-square test or, when required, Fisher’s exact test. The Cox regression model was used for global survival analysis with a panel of markers and for uni and multivariate global survival analyses. Results: Isolated expression correlation results of the markers with the variables: age, differentiation degree, venous invasion, perineural invasion, TNM (I+II) x (III+IV), and survival showed statistically significant differences in the EGFR expression with venous invasion, TNM classification, and global survival; the expression of the VEGF marker has showed significant correlation with the perineural invasion; the Ki-67 marker, with age, venous invasion, and TNM; expression of p53 was significantly related with age, venous invasion, TNM, and global survival; the Bcl-2 marker did not show significant correlation with any of the variables analyzed. The survival analysis, using the markers panel, has significantly showed lesser time of survival in surgical species with 60% or more overexpression. Conclusion: Overexpression of the selected tumor markers panel is related with lesser time of survival in those suffering from sporadic colorectal adenocarcinoma subjected to radical surgical treatment.
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    Analysis of p53 expression and proliferative assessment using PCNA in localized prostate carcinoma
    (Associação Brasileira de Divulgação Científica, 1999-03-01) Leite, Kátia Ramos Moreira [UNIFESP]; Srougi, Miguel [UNIFESP]; Nesrallah, Luciano João [UNIFESP]; Camara-Lopes, Luiz H [UNIFESP]; Hospital Sírio Libanês; Universidade Federal de São Paulo (UNIFESP)
    The surgical specimens from 51 men submitted to radical prostatectomy for localized prostate cancer were examined by immunohistochemistry using proliferation cell nuclear antigen (PCNA) monoclonal antibody to evaluate the proliferative index (PI). The relationship between PI, biological variables and p53 protein expression was evaluated by immunohistochemistry. PI was low in invasive localized prostate carcinoma (mean, 12.4%) and the incidence of PCNA-positive cells was significantly higher in tumors with p53 expression (P = 0.0226). There was no statistical difference in PCNA values when biological parameters such as Gleason score, tumor volume, extraprostatic involvement, seminal vesicle infiltration or lymph node metastasis were considered. We conclude that proliferative activity is usually low in prostate carcinoma but is correlated with p53 immune staining, indicating that p53 is important in cell cycle control in this neoplasm.
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    Apoptosis, PCNA and p53 in hepatocellular carcinoma
    (H G E Update Medical Publishing S A, 2002-07-01) Paiva, C.; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Lanzoni, Valeria Pereira [UNIFESP]; Forones, Nora Manoukian [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Background/Aims: The regulation of cell number is present in normal tissues but is lost in malignant neoplasms. The real :meaning of these alterations is not well known. Apoptosis is the programmed cell death. p53, a tumor supressor gene, has an important function in DNA repair and in regulation of apoptosis. Mutations of p53 were described in malignant tumors and can be the cause of the alterations of this balance. Proliferating cell nuclear antigen is an auxiliary protein present during G1-late phase and S phase.The aim of this study was to compare cell proliferation, apoptosis and expression of p53 in hepatocellular carcinoma.Methodology: Fifteen patients with hepatocellular carcinoma were included. Ten patients were men. The mean age of the patients was 55.53 years old. Cirrhosis was positive in nine patients, 5 were HBsAg positive and none were anti-HCV positive. The mean level of AST and ALT were respectively, 62.79 and 50.64. Formalin-fixed and paraffin-embedded tissues from these patients were examined retrospectively. Apoptosis were measured by counting the number of apoptotic bodies in 500 tumoral cells. The expression of p53 oncogene and the PCNA were determined by immunohistochemical method, using avidin-biotin method (DAKO). The p53 were considered positive when the number of positive nuclei was more than 5% of the tumoral cells. The proliferative activity was determined by proliferating cell nuclear antigen labeling index.Results: The proliferating cell nuclear antigen-labeling index ranged from 0.48 and 0.95 (mean: 0.82). The p53 was positive in five patients. The number of apoptotic bodies counted ranged from 0 to 15 (mean: 4.20). There were no differences among p53 and the mean levels of proliferating cell nuclear antigen labeling index or p53 and the number of apoptotic bodies.Conclusions: A high index of proliferation has been shown in the patients studied. Positivity of p53 was seen in less than a half of the patients (35.71%). The index of apoptotic bodies observed was very low. Our results suggest that high-grade proliferation is not associated with increase of apoptosis in hepatocellular carcinoma.
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    Ascorbic acid prevents acute myocardial infarction induced by isoproterenol in rats: role of inducible nitric oxide synthase production
    (Springer, 2009-04-01) Ribeiro, Daniel Araki [UNIFESP]; Buttros, Juliana Beatriz [UNIFESP]; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Bergamaschi, Cassia Toledo [UNIFESP]; Campos, Ruy Ribeiro [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    The goal of this study was to investigate whether sub-chronic anti-oxidant treatment with ascorbic acid (Vit C) is able to protect the heart against myocardial infarction. the effects of Vit C treatment on the histopatological changes and immunohistochemistry for p53, COX-2 and iNOS were evaluated in rats submitted to acute myocardial infarction induced by isoproterenol (ISO). Male Wistar rats (n = 32) were divided into four groups: group 1, control; group 2, ISO treated; group 3, Vit C treated; group 4, ISO + Vit C treated. An amount of 150 mg/kg of isoproterenol was administered for two consecutive days. the rats were treated with Vit C once a day (150 mg/kg, orally) for seven consecutive days. in the day 5 and 6 the rats from group ISO + Vit C were submitted to acute administration of ISO third minutes after Vit C treatment. the results pointed out that treatment with Vit C showed mild degenerative changes of myocardial tissue in ISO group. Also, the antioxidant was able to decrease the iNOS expression in rats treated with Vit C. Taken together, our results suggest that chronic Vit C administration was able to prevent the myocardial infarction induced by ISO as a result of iNOS downregulation. Certainly, this finding offers new insights into the mechanisms underlying the relation between oxidative stress and cardiac mortality after myocardial infarction.
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    Avaliação da proliferação celular e apoptose em células da mucosa bucal de ratos expostos ao decanoato de nandrolona
    (Universidade Federal de São Paulo, 2012-12-03) Pozzi, Renan [UNIFESP]; Ribeiro, Daniel Araki [UNIFESP]; http://lattes.cnpq.br/9969803499258672; http://lattes.cnpq.br/0724678991395028; Universidade Federal de São Paulo (UNIFESP)
    Objetivo: Verificar a interferência do decanoato de nandrolona em proteínas regulatórias relacionadas à proliferação celular, apoptose e COX-2 em células da mucosa bucal de ratos Wistar. Metodologia: Um total de 40 ratos foi distribuído em quatro grupos. Dois grupos experimentais foram tratados com decanoato de nandrolona, na dose de 5mg/kg, via subcutânea, três vezes por semana em dois períodos experimentais: 15 e 30 dias (G3 e G4, respectivamente). Os demais grupos (G1 e G2), receberam somente solução salina a 0,9% via subcutânea, três vezes por semana. Após os períodos experimentais, os animais foram submetidos à eutanásia e as línguas coletadas para análise morfológica e de marcadores relacionados à proliferação, apoptose e inflamação (ki67, p53 e COX-2) por meio da técnica de imunoistoquímica. Resultados: Na análise histopatológica, não foram observadas modificações morfológicas no tecido lingual em todos os grupos avaliados. Entretanto, um aumento significativo na imunoexpressão das proteínas ki-67, p53 e COX-2 foi detectado nos grupos tratados com decanoato de nandrolona em 15 e 30 dias quando comparados aos seus respectivos controles. Além disso, houve correlação tempo-resposta para a proteína ki-67, a qual se evidenciou aumento significativo. Encontrou-se também correlação positiva entre a imunoexpressão das proteínas p53 e COX-2 nos dois momentos experimentais avaliados. Conclusão: Nossos resultados sugerem que o decanoato de nandrolona foi capaz de alterar a expressão de proteínas relacionadas ao ciclo celular, bem como induzir a imunoexpressão de COX-2 em células da língua de ratos Wistar. Foi confirmada a correlação positiva de tempo-resposta para a proteína ki-67 e entre a imunoexpressão das proteínas COX-2 e p53.
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    Cell-Cycle Analysis and Apoptosis-associated Proteins in Cervical Lesions of Brazilian Women
    (Int Inst Anticancer Research, 2014-06-01) Dobo, Cristine [UNIFESP]; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Lima, Flavio de Oliveira [UNIFESP]; Gomes, Thiago Simao [UNIFESP]; Stavale, Joao Norberto [UNIFESP]; Arias, Vitor [UNIFESP]; Ribeiro, Daniel Araki [UNIFESP]; Focchi, Gustavo Rubino de Azevedo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Aim: The aim of the present study was to detect the relative expressions of p53, p21(Waf1/Cip1), p27(Kip1) Bcl-2 and cleaved caspase-3 in cervical lesion samples from Brazilian women by immunohistochemistry. Materials and Methods: A total of 230 cervical biopsies in paraffin-embedded blocks were studied: 43 were invasive squamous cell carcinomas (SCC), 52 carcinomas in situ/cervical intraepithelial neoplasias III (CIN III), 54 cervical intraepithelial neoplasias II (CIN II), 51 cervical intraepithelial neoplasias I (CIN I) and 30 non-neoplastic lesions (NN) with benign cellular changes. Results: Significant differences were observed in the p53 expression between the different groups: NN and CIN I (p=0.010); NN and CIN II (p<0.00001); CIN II and CIN III (p=0.02); CIN II and CIS (p=0.0220); CIN II and CEC (p=0.010). Regarding p21(WAF1/Cip1), significant differences were observed between NN and CEC (p=0.001); CIN I and CEC (p=0.001); CIN II and CIN III (p=0,001); CIN II and CIS (p=0.0004) and CIN II and CEC (p<0.0001). For p27(Kip1), significant differences were observed between NN and GIN I (p<0.00001); NN and CIN II (p<0.00001); NN and CIS (p=0.038); CIN I and CIN III (p=0.001); CIN I and CIS (p=0.009); CIN I and CEC (p=0.0001); CIN II and CIN III (p=0.000.3); CIN II and CIS (p=0.002); CIN II and CEC (p< 0.00001). Bcl-2 and caspase-3 did not show remarkable differences between groups. Conclusion: p53, p21(WAF1/CIP1), p27(KIP1) appear to be involved in the course of carcinogenesis. Rare expression of Bcl-2 and cleaved caspase-3 suggests that these proteins probably do not participate in cervical apoptosis.
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    Clinical significance of c-myc and p53 expression in head and neck squamous cell carcinomas
    (Elsevier B.V., 2004-01-01) Waitzberg, AFL; Nonogaki, S.; Nishimoto, L. N.; Kowalski, L. P.; Miguel, R. E.; Brentani, R. R.; Brentani, M. M.; Universidade Federal de São Paulo (UNIFESP); Inst Adolfo Lutz Registro; Hosp Canc AC Camargo; Inst Ludwig Pesquisa Canc
    c-myc and p53 genes were frequently deregulated in head and neck squamous cell carcinoma (HNSCC). To determine if the concomitant expression of the two oncogenes might have prognostic value, the survival and free disease time of 140 consecutive HNSCC patients followed up for a median time of 29.9 months was analyzed in the light of p53 and c-myc expression assessed by immumohistochemistry. Positive c-myc and p53 staining was detected respectively in 35.7 and 50.7% of the tumors. Double positivity emerged in 16.4% of the cases. Overall-survival of patients was not associated with the immunoreactivity of p53 or c-myc considered separately or grouped in subsets. Considering only the advanced stages, the concomitant expression of both oncogenes in tumors was associated with worse disease-free survival (P = 0.004) suggesting a role for p53 and c-myc genes in progression of this HNSCC subset. Clinical parameters (presence of lymph nodes, histologic grade and tumor width) remained important indicators of overall survival (OS). (C) 2004 International Society for Preventive Oncology. Published by Elsevier B.V. All rights reserved.
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    Comparative study of the expression of cellular cycle proteins in cervical intraepithelial lesions
    (Elsevier B.V., 2006-01-01) Queiroz, Conceicao; Silva, Tania Correia; Alves, Venancio A. F. [UNIFESP]; Villa, Luisa L.; Costa, Maria Cecilia; Travassos, Ana Gabriela; Araujo, Jose Bouzas; Studart, Eduardo; Cheto, Tatiana; Freitas, Luiz Antonio R. de; Universidade Federal da Bahia (UFBA); Fiocruz MS; Ludwig Inst Canc Res; Universidade Federal de São Paulo (UNIFESP)
    Interaction of human papilloma virus oncoproteins E6 and E7 with cell cycle proteins leads to disturbances of the cell cycle mechanism and subsequent alteration in the expression of some proteins, such as p16(INK4a), cyclin DI, p53 and KI67. in this study, we compared alterations in the expression of these proteins during several stages of intra-epitelial cervical carcinogenesis. Accordingly, an immunohistochemical study was performed on 50 cervical biopsies, including negative cases and intraepithelial neoplasias. the expression patterns of these markers were correlated with the histopathological diagnosis and infection with HPV. the p16(INK4a), followed by Ki67, showed better correlation with cancer progression than p53 and cyclin DI, which recommends their use in the evaluation of cervical carcinogenesis. These monoclonal antibodies can be applied to cervical biopsy specimens to identify lesions transformed by oncogenic HPV, separating CIN 1 (p16(INK4a) positive) and identifying high-grade lesions by an increase in the cellular proliferation index (Ki67). in this way, we propose immunomarkers that can be applied in clinical practice to separate patients who need a conservative therapeutic approach from those who require a more aggressive treatment. (c) 2006 Elsevier GmbH. All rights reserved.
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    Correlation of c-erbB-2 oncogene and p53 tumor suppressor gene with malignant transformation of hydatidiform mole
    (Blackwell Publishing, 2006-06-01) Sun, Sue Yazaki [UNIFESP]; Daher, Silvia [UNIFESP]; Ishigai, Marcia Marcelino de Souza [UNIFESP]; Alves, MTS; Mantovani, T. M.; Mattar, Rosiane [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Considering the roles of c-erB-2 and p53 oncoproteins in tumor progression, we aimed to evaluate their expression in hydatidiform moles, and the possible predictive value of this immunoexpression in postmolar follow-up.Group I comprised 35 patients with progression to gestational trophoblastic tumor, and group II included 32 patients with progression to spontaneous remission. Immunohistochemical tests were performed by streptavidin-peroxidase method. c-erbB-2 immunoexpression was evaluated according to quantitative and semiquantitative criteria; p53 according to percentage of cells with stained nuclei. Data were analyzed by Student t-test, Mann-Whitney test, ROC curve and logistic regression analysis.c-erbB-2 and p-53 expressions were significantly increased in group I. Quantitative and semiquantitative analysis of c-erb-2 showed that its expression may be associated with mole hydatidiform progression to gestational trophoblastic tumor. Taking into account cells with complete membranous delineation we proposed a cut-off value of 10.8%. Similarly, considering the percentage of cells presenting nuclei marked by p53 we suggested a cut-off value of 40.1% for the prediction of malignant transformation of mole hydatidiform.c-erbB-2 and p53 immunoexpression in hydatidiform mole are usually increased with malignant transformation. in addition to beta-fraction of human chorionic gonadotropin, they could possibly help the establishment of a therapeutic protocol.
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    Efeito da ciclosporina a na expressão da sirtuína 1 e no estresse oxidativo/nitrosativo em células mesangiais imortalizadas de camundongos
    (Universidade Federal de São Paulo, 2024-10-29) Torres Júnior, José Rodrigues [UNIFESP]; Higa, Elisa Mieko Suemitsu [UNIFESP]; http://lattes.cnpq.br/8578252701813423; http://lattes.cnpq.br/4504363291561933
    Introdução: A ciclosporina A (CsA) é uma droga imunossupressora desempenha um papel crucial no campo do transplante de órgãos, reduzindo as taxas de rejeição e melhorando a sobrevivência dos pacientes submetidos a transplantes de órgãos e enxertos. Apesar de ser um importante agente na imunossupressão em transplantes renais, seu uso está associado a efeitos colaterais, incluindo nefrotoxicidade. A fisiopatologia da lesão renal causada pela CsA ainda não foi totalmente elucidada. Evidências indicam que a CsA induz estresse oxidativo (EO) e nitrosativo (EN), contribuindo para danos estruturais e funcionais nos rins. A sirtuina 1 (SIRT1), uma enzima pertencente à família Sir2 parte do grupo das histonas desacetilases (HDACs), é conhecida como um regulador da morte/sobrevivência celular e pela resposta ao EO. A SIRT1 promove a expressão da superóxido dismutase (SOD) e catalase (CAT) aumentando a resistência ao EO, e a desacetilação promovida pela SIRT também pode estar envolvida na melhora da sobrevida celular ao inibir a apoptose relacionada ao gene Trp53 induzida pela CsA. Objetivo: Estudar o efeito da CsA na expressão da SIRT1 e sua correlação com fatores epigenéticos e o EO/EN, em células mesangiais imortalizadas de camundongos (CMiC). Métodos: As CMiC foram alocadas nos grupos: controle e CsA (20 µg/mL), na presença ou ausência de 25 µM de resveratrol (RSV), um agonista de SIRT1. Avaliamos a viabilidade e proliferação celular, o óxido nítrico (NO) e espécies reativas de oxigênio (ROS). Analisamos as proteínas SIRT1, HDAC e SOD, CAT, nitrotirosina, caspase-3 e calpaína por imunocitoquímica. Os resultados foram descritos como média ± erro padrão, com significância estatística para p < 0,05. Resultados: Nos grupos tratados com CsA houve uma diminuição da viabilidade celular, assim como aumento de ROS, indicando EO. Também evidenciamos a regulação positiva da expressão de SIRT1, HDAC1 e CAT, indicando possível mecanismo compensatório provocado pelo estresse induzido pela CsA, sugerindo que a SIRT1 e HDAC1 podem inibir a apoptose por p53. Os níveis elevados de CAT nos grupos tratados com CsA podem ser indicativos de uma possível ativação desta enzima pela SIRT1. Os grupos tratados com RSV demonstraram aumento da viabilidade celular, porém, observamos redução na expressão SOD1 e elevação dos níveis de nitrotirosina e calpaína, sugerindo possível EN na dose utilizada. Conclusão: A CsA induz o EO em CMICs, diminuindo a viabilidade celular e aumentando a expressão da SIRT1 como mecanismo compensatório.
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    Efeito da via de TLR4 na resposta ao tratamento quimioterápico em células tumorais de cabeça e pescoço
    (Universidade Federal de São Paulo, 2023-06-26) Cruz, Kayo Alexandre Souza da [UNIFESP]; Morale, Mirian Galliote [UNIFESP]; Araújo, Natália Meneses; http://lattes.cnpq.br/3053586308787599; http://lattes.cnpq.br/6470564394319683; http://lattes.cnpq.br/9224780743352543
    O Toll Like Receptor 4 (TLR4), receptor do sistema imune inato, possui um papel ambíguo quando ativado em neoplasias, sendo capaz de induzir a proliferação celular, ou ainda atuar inibindo o tumor, dependendo de fatores como tipo celular ou mutações como exemplo na proteína p53. A p53 é conhecida por controlar o ciclo celular e induzir à apoptose em resposta a danos no DNA, e é mutada grande parte dos tumores de cabeça e pescoço. Nesse tipo específico de tumores há diferentes fatores responsáveis por desencadear o processo tumorigênico, entre eles o HPV. O objetivo do trabalho é analisar o efeito da ativação e inibição da via de TLR4 nas respostas ao tratamento quimioterápico em linhagens celulares de tumores de cabeça e pescoço apresentando diferentes status de HPV e alterações na proteína p53. Foram utilizadas 3 linhagens celulares provenientes de tumores escamosos de cabeça e pescoço, sendo elas: SCC078, apresentando mutação em p53 e sem genoma de HPV; SCC143, sem mutações em p53 e sem genoma de HPV; e SCC154, sem alterações em p53 e apresentando genoma de HPV16. As análises incluíram ensaios de proliferação celular, análises de expressão gênica por RT-q-PCR e análise de produção de espécies reativas a oxigênio por citometria de fluxo. Os resultados mostraram um aumento do número de células nas amostras estimuladas com LPS, assim como uma redução do número de células no tratamento com TAK242. Já as análises de expressão gênica evidenciaram um aumento na produção de IL-6 na combinação da TAK com cisplatina na SCC154, e um aumento de SOD2 no tratamento de TAK com cisplatina na SCC78. Os ensaios de espécies reativas de oxigênios (ROS) apresentaram resultados inconsistentes, o que não permitiu uma conclusão sobre o efeito dos tramentos na produção de ROS nas 3 linhagens. No entanto, mostramos que a modulação da atividade do TLR4 impacta na proliferação celular além de alterar a expressão gênicas nas linhagens de cabeça e pescoço, sendo assim um potencial alvo terapêutico nesse tipo tumoral.
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    Expression Profiling of Cell Cycle Regulatory Proteins in Oropharyngeal Carcinomas Using Tissue Microarrays
    (Int Inst Anticancer Research, 2010-05-01) Ribeiro, Daniel Araki [UNIFESP]; Nascimento, Fábio Dupart [UNIFESP]; Fracalossi, Ana Carolina Cuzzuol [UNIFESP]; Gomes, Thiago Simao [UNIFESP]; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Franco, Marcello Fabiano de [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Aim: The aim of this study was to investigate the expressions of cell cycle regulatory proteins such as p53, p16, p21, and Rb in squamous cell carcinoma of the oropharynx and their relation to histological differentiation, staging of disease, and prognosis. Patients and Methods: Paraffin blocks from 21 primary tumors were obtained from archives of the Department of Pathology, Paulista Medical School, Federal University of Sao Paulo, UNIFESP/EPM. Immunohistochemistry was used to detect the expression of p53, p16, p21, and Rb by means of tissue microarrays. Results: Expression of p53, p21, p16 and Rb was not correlated with the stage of disease, histopathological grading or recurrence in squamous cell carcinoma of the oropharynx. Conclusion: Taken together, our results suggest that p53, p16, p21 and Rb are not reliable biomarkers for prognosis of the tumor severity or recurrence in squamous cell carcinoma of the oropharynx as depicted by tissue microarrays and immunohistochemistry.
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    Gemistocytes in astrocytomas: Are they a significant prognostic factor?
    (Springer, 2006-10-01) Martins, Dely C.; Malheiros, Suzana M.; Santiago, Lucila H.; Stavale, Joao N.; Universidade Federal de São Paulo (UNIFESP)
    Our aim was to retrospectively evaluate the influence of gemistocytic astrocytes, cellular proliferation indices, immunoexpression of proteins p53 and bcl-2 in the clinical outcome of 39 patients with WHO grade II and III astrocytomas with the presence of gemistocytes. the mean proportion of gemistocytes was 18.7% and the mean proliferative index was 3.3%. Immunoexpression of p53 was detected in 29 cases (74.4%) and all cases (100%) were positive for bcl-2. the median overall survival was 97.2 months and the progression-free survival was 43.1 months. Estimated 1-, 5- and 10-year overall survival rates were 94.3%, 69.5% and 46.4%; 1-, 5- and 10-year progression-free survival rates were 91.1%, 26.1% and 13.1%. Out of 24 who presented clinical and neuroimaging worsening, characterized as tumor progression or recurrence, 16 had histological confirmation and were also analyzed. We could not detect significant differences when comparing all the indices between WHO grade II and III and also between the first and second biopsies. We also could not detect significant differences in progression-free and overall survival when analyzing the gemistocyte index and the immunohistochemical labeling indices p53, bcl-2 and MIB-1, as well as patients' age (median value, up to 34 vs. over 34 years) and histological grade (II or III). Our finding confirms recent reports that question the role of gemistocytes as a prognostic factor in diffuse astrocytomas. the significance and role of gemistocytes in astrocytomas has yet to be defined and warrants further study.
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    GerbB-2 expression is a better predictor for survival than galectin-3 or p53 in early-stage breast cancer
    (Professor D A Spandidos, 2007-07-01) Logullo, Angela Flavia [UNIFESP]; Lopes, Andréa Braga de Godoy; Nonogaki, Suely; Soares, Fernando Augusto; Mourão Netto, Mario; Nishimoto, Inês Nobuko; Brentani, Maria Mitzi [UNIFESP]; Universidade de São Paulo (USP); Hosp Canc; Inst Adolfo Lutz Registro; Universidade Federal de São Paulo (UNIFESP)
    The definition of high risk patients with early stage breast cancer is still controversial. We evaluated the ability of galectin-3, c-erbB-2 and p53 immunohistochemical expression to predict recurrence and survival in a homogeneous set of 92 patients with T1N0M0 ductal carcinoma with a long-term follow-up. In normal breast tissue, the epithelial and fibroblast components were positive for galectin-3 mostly showing nuclear and cytoplasmic reactivity. At the tumor epithelial component, galectin-3 expression was found in 46.7% of the samples with a predominant cytoplasmic staining. Similar results were presented by concurrent in situ lesions. Tumor stromal fibroblasts maintained positivity in 70 out of 92 cases (76%). We found expression of p53 in only 16 cases (17.4%), and c-erbB-2 in 17 (18.48%). A marginal association was found between co-expression of p53 and galectin-3 (p=0.055) and a significant correlation between p53 accumulation and c-erbB-2 expression (p=0.009). There was no significant association between (galectin-3 protein expression with disease-free survival or overall survival. C-erbB2 and p53 expression correlated with recurrence (p=0.002, p=0.02; respectively). Diminished overall survival at 10 years was associated with c-erbB-2 (p=0.010), but marginally with p53 expression (p=0.076). Epithelial galectin-3 expression cannot be considered a prognostic factor for patients with T1N0M0 breast cancer, p53 seems to be of minor relevance and c-erbB-2 expression was the best discriminator and may be a marker for aggressive clinical behavior in patients with early stage breast cancer.
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    Grape juice concentrate modulates p16 expression in high fat diet-induced liver steatosis in Wistar rats
    (Informa Healthcare, 2012-04-01) Ferreira, Andressa Orlandeli [UNIFESP]; Boiago Golluecke, Andrea Pittelli; Noguti, Juliana [UNIFESP]; Pereira da Silva, Victor Hugo [UNIFESP]; Hojo Yamamura, Elsa Tiemi; Ribeiro, Daniel Araki [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Univ Catolica Santos
    Purpose: the goal of this study was to investigate whether subchronic treatment with grape juice concentrate is able to protect the liver from high fat diet injury in rats. the effects of grape juice concentrate treatment on histopathological changes, and immunohistochemistry for p53, p16 and p21 were evaluated.Methods: Male Wistar rats (n = 18) were distributed into three groups: group 1: negative control; group 2: cholesterol at 1% (w/w) in their diet, treated during 5 weeks; and group 3: cholesterol at 1% in their chow during 5 weeks, and grape juice concentrate at 222 mg per day in their drinking-water in the last week only.Results: the results pointed out that treatment with grape juice concentrate did not show remarkable differences regarding liver tissue in the cholesterol-exposed group when compared to group 2. However, grape juice concentrate was able to modulate p16 immunoexpression when compared to high fat diet group. p53 and p21 did not show any significant statistical differences among groups.Conclusion: Taken together, our results suggest that subchronic grape juice concentrate administration was able to modulate cell cycle control by downregulation of p16 immunoexpression in high fat diet-induced liver steatosis in rats.
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    Imunoexpressão dos biomarcadores ts, cox-2, egfr, msh6, mlh1 no adenocarcinoma colorretal e sua correlação com o grau de diferenciação tumoral e os fatores prognósticos
    (Universidade Federal de São Paulo (UNIFESP), 2013-09-25) Batista, Wilson Roberto [UNIFESP]; Matos, Delcio Matos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Objective: To study the immunoexpression of biomarkers TS, p53, COX2, EGFR, MSH6, MLH1 in patients with colorectal carcinoma, correlating with the degree of tumor differentiation and clinical prognostic factors patolólogicos. Methods: We analyzed tissues fixed in formalin and embedded in paraffin blocks of tumors from 107 patients, for immunohistochemistry by the streptavidin-biotin method using the technique of matrix arrangement of tissue samples (tissue-microarray). In the evaluation of positive markers was used categorical scores that determined the cutoff value in the percentage of stained tumor cells. Tissue expression of the proteins were correlated with the variables of degree of cell differentiation, staging, disease-free, recurrence, survival and specific mortality. We employed the Fisher exact test (Agresti, 1990) to study the association between tumor grade and TS, Cox-2, EGFR, MSH1, MSH6 and p53, and tumor staging correlated with TS, Cox-2, EGFR, MSH1, MSH6 and p53. Estimation of Kaplan-Meier (Collett, 2003), Log-rank test (Collett, 2003) and adjusting the Cox regression model (Cox, 1972) to investigate the behavior of the overall survival of patients (months) according to TS, COX-2, EGFR, MSH6, MLH1 and p53 and disease-free interval of subjects (months), according to TS, COX-2, EGFR, MSH6, MLH1 and p53. Results: The degree of tumor differentiation of individuals is not associated with TS (p = 0.138), COX-2 (p = 0.428), EGFR (p = 0.103), MSH6 (p = 0.876), MLH1 (p = 0.792) and p53 (p = 0.884). The staging is not associated with TS (p = 0.817), COX-2 (p = 0.842), EGFR (p = 0.344), MSH6 (p = 0.923) and p53 (p = 0.666). The same behavior was not observed for MLH1 (p = 0.021) in which the group of patients with stage III or IV is a higher percentage of MLH1 negative (27.4%) than in the group of patients with stage 0, I, or II (2.2%). The survival time of individuals is not related to TS (p = 0.480), COX-2 (p = 0.998), EGFR (p = 0.600), MSH6 (p = 0.318), MLH1 (p = 0.798) and p53 (p = 0.695). The disease-free interval of subjects is not related to TS (p = 0.356), COX-2 (p = 0.885), EGFR (p = 0.786), MSH6 (p = 0.178), MLH1 (p = 0.691) and p53 (p = 0.441). Conclusion: There was no correlation of the association between the degree of tumor differentiation, staging, survival time and disease-free interval with markers TS, p53, COX2, EGFR, MSH6. In advanced cases of RCC with stage III and IV, there was a higher percentage of MLH1 negative.
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    Índice de astrócitos gemistocíticos e imuno-expressão da proteína p53 em astrocitomas, grau II e III OMS
    (Academia Brasileira de Neurologia - ABNEURO, 2001-12-01) Martins, Dely Cristina [UNIFESP]; Stávale, João Norberto [UNIFESP]; Malheiros, Suzana Maria Fleury [UNIFESP]; Santiago, Lucila Heloisa Simardi [UNIFESP]; Roman, Leonor Cristina Manoja [UNIFESP]; Aguiar, Kátia Cilene Carozzi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Twenty-two patients with astrocytomas, grade II or III WHO, were studied from 1990 to 1998. In all cases, histopathology showed that the astrocytomas had a gemistocytic component. The aims of this study were to establish the fraction of gemistocytic astrocytes, to investigate p53 protein immunoexpression and to evaluate correlations between these two parameters with the tumour outcome. Tumor cells were quantified at high-power magnification (x400). At least 1000 neoplastic cells (small neoplastic astrocytes plus gemistocytes) were counted in each specimen. The percentage of gemistocytes was defined as the gemistocytic index. Nuclear expression of p53 protein was evaluated in neoplastic astrocytes and gemistocytes. Both the frequency (7/22) as well the p53 immunoexpression indices in gemistocytes, regardless of the grade of the astrocytomas, were inferior from those reported in the literature. No correlation was found between the gemistocytic indices and the p53 immunoexpression.
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    Inhibition of cytoplasmic p53 differentially modulates Ca2+ signaling and cellular viability in young and aged striata
    (Elsevier B.V., 2014-10-01) Ureshino, Rodrigo Portes [UNIFESP]; Hsu, Yi-Te; Garcez-do-Carmo, Lucia [UNIFESP]; Yokomizo, Cesar Henrique; Nantes, Iseli Lourenco; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Med Univ S Carolina; Fed Univ ABC
    The p53 protein, a transcription factor with many gene targets, can also trigger apoptosis in the cytoplasm. the disruption of cell homeostasis, such as Ca2+ signaling and mitochondrial respiration, contributes to the loss of viability and ultimately leads to cell death. However, the link between Ca2+ signaling and p53 signaling remains unclear. During aging, there are alterations in cell physiology that are commonly associated with a reduced adaptive stress response, thus increasing cell vulnerability. in this work, we examined the effects of a cytoplasmic p53 inhibitor (pifithrin mu) in the striatum of young and aged rats by evaluating Ca2+ signaling, mitochondrial respiration, apoptotic protein expression, and tissue viability. Our results showed that pifithrin mu differentially modulated cytoplasmic and mitochondrial Ca2+ in young and aged rats. Cytoplasmic p53 inhibition appeared to reduce the mitochondrial respiration rate in both groups. in addition, p53 phosphorylation and Bax protein levels were elevated upon cytoplasmic p53 inhibition and could contribute to the reduction of tissue viability. Following glutamate challenge, pifithrin mu improved cell viability in aged tissue, reduced reactive oxygen species (ROS) generation, and reduced mitochondrial membrane potential (Delta Psi m). Taken together, these results indicate that cytoplasmic p53 may have a special role in cell viability by influencing cellular Ca2+ homeostasis and respiration and may produce differential effects in the striatum of young and aged rats. (C) 2014 Elsevier Inc. All rights reserved.