ADHEMAR LONGATTO FILHO
Projetos de Pesquisa
Unidades Organizacionais
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
16 resultados
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article 1 Citação(ões) na Scopus Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the *NIS-LAMS** cohort(2012) SYRJANEN, K.; SHABALOVA, I.; SARIAN, L.; NAUD, P.; LONGATTO-FILHO, A.; DERCHAIN, S.; KOZACHENKO, V.; ZAKHARCHENKO, S.; ROTELI-MARTINS, C.; NEROVJNA, R.; KLJUKINA, L.; TATTI, S.; BRANOVSKAJA, M.; BRANCA, M.; GRUNJBERGA, V.; ERZEN, M.; JUSCHENKO, A.; HAMMES, L. Serpa; PODISTOV, J.; COSTA, S.; SYRJANEN, S.Background: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these compet ng events have not been previously assessed using competing-risks regression models. Objectives: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariaies associated with these competing events. Study Design and Methods: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). Results: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance of ASCUS+Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. Conclusions: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.- Characterization of PAR1 and FGFR1 expression in invasive breast carcinomas: Prognostic significance(2012) TIBURCIO, Marta; COSTA, Sandra M. A.; DUARTE, Maria De Fatima; SCHMITT, Fernando C.; LONGATTO FILHO, AdhemarBreast cancer is the most common cause of cancer mortality among women worldwide. Among the several factors associated with breast cancer development, angiogenesis plays an essential role and has currently emerged as a potential diagnostic, prognostic and therapeutic target. Protease-activated receptor 1 (PAR1) and fibroblast growth factor receptor 1 (FGFR1) have important activities in tumor angiogenesis and progression. The aim of this study was to investigate the prognostic significance of these two receptors, hypothesising significant correlations between receptor expression in tumor angiogenesis and clinicopathological parameters customarily used in breast cancer prognosis and prediction. Formalin-fixed and paraffin-embedded samples of ductal invasive breast carcinomas were used to analyze the expression of PAR1 and FGFR1, in the tumor cells as well as in the tumor stroma, and further determine intratumoral microvessel density (iMVD) to quantify intratumoral angiogenesis. Correlations between PAR1 and FGFR1 expression in tumor cells and stroma, iMVD and several clinicopathological parameters and molecular markers used in breast cancer diagnosis have been addressed. The correlation between PAR1 and FGFR1 suggests an association of the two receptors with a more aggressive breast cancer phenotype and, consequently, a potential role during tumor progression. The results reported in the present study also emphasize the importance of microenvironmental factors in tumor progression, while precluding the positive association between iMVD and breast cancer aggressiveness.
article 5 Citação(ões) na Scopus Covariates of high-risk human papillomavirus (HPV) infections are distinct for incident CIN1, CIN2 and CIN3 as disclosed by competing-risks regression models(2012) SYRJANEN, K.; SHABALOVA, I.; SARIAN, L.; NAUD, P.; LONGATTO-FILHO, A.; DERCHAIN, S.; KOZACHENKO, V.; ZAKHARCHENKO, S.; ROTELI-MARTINS, C.; NEROVJNA, R.; KLJUKINA, L.; TATTI, S.; BRANOVSKAJA, M.; BRANCA, M.; GRUNJBERGA, V.; ERZEN, M.; JUSCHENKO, A.; HAMMES, L. Serpa; PODISTOV, J.; COSTA, S.; SYRJANEN, S.Background: In addition to the oncogenic human papillomavirus (HPV), several cofactors are needed in cervical carcinogenesis, but whether the HPV covariates associated with incident i) CIN1 are different from those of incident ii) CIN2 and iii) CIN3 needs further assessment. Objectives: To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV covariates associated with incident CIN1, CIN2, and CIN3. Study Design and Methods: HPV covariates associated with progression to CIN1, CIN2 and CIN3 were analysed in the combined cohort of the NIS (n = 3,187) and LAMS study (n = 12,114), using competing-risks regression models (in panel data) for baseline HR-HPV-positive women (n = 1,105), who represent a sub-cohort of all 1,865 women prospectively followed-up in these two studies. Results: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2, and CIN3, respectively. Among these baseline HR-HPV-positive women, the risk profiles of incident GIN I, CIN2 and CIN3 were unique in that completely different HPV covariates were associated with progression to CIN1, CIN2 and CIN3, irrespective which categories (non-progression, CIN1, CIN2, CIN3 or all) were used as competing-risks events in univariate and multivariate models. Conclusions: These data confirm our previous analysis based on multinomial regression models implicating that distinct covariates of HR-HPV are associated with progression to CIN1, CIN2 and CIN3. This emphasises true biological differences between the three grades of GIN, which revisits the concept of combining CIN2 with CIN3 or with CIN1 in histological classification or used as a common end-point, e.g., in HPV vaccine trials.- Loss of RKIP expression during the carcinogenic evolution of endometrial cancer(2012) Martinho, Olga; Faloppa, Carlos Chaves; Neto, Cristovam Scapulatempo; Longatto-Filho, Adhemar; Baiocchi, Glauco; da Cunha, Isabela Werneck; Soares, Fernando Augusto; Tavares Guerreiro Fregnani, Jose Humberto; Reis, Rui ManuelAims Endometrial cancer is one of the most common cancers in women worldwide, but there is a lack of diagnostic markers for early detection of these tumours. The raf kinase inhibitory protein (RKIP) negatively regulates the Raf/MEK/ERK pathway, and the downregulation of RKIP is associated with tumour progression and metastasis in several human neoplasms. The aim of this study was to assess the expression levels of RKIP in endometrial cancer and determine whether this expression correlates with clinical outcome in these patients. Methods Tissue microarrays constructed using tissue samples from 209 endometrial adenocarcinomas, 49 endometrial polyps and 48 endometrial hyperplasias were analysed for RKIP expression by immunohistochemistry. Results The authors found that RKIP expression decreases significantly during malignant progression of endometrial cancer; it is highly expressed in non-neoplastic tissues (polyps 79.6%; hyperplasias 87.5%) and expressed at very low levels in endometrioid adenocarcinomas (29.7%). No correlations were observed between RKIP expression, clinicopathological data and survival. Conclusion This study demonstrated for the first time that RKIP expression is lost during the carcinogenic evolution of endometrial tumours and that the loss of RKIP expression is associated with a malignant phenotype. Functional studies are needed to address the biological role of RKIP downregulation in endometrial cancer.
- Detection of the Epstein-Barr virus in blood and bone marrow mononuclear cells of patients with aggressive B-cell non-Hodgkin's lymphoma is not associated with prognosis(2012) MARQUES, Herlander; CATARINO, Raquel; DOMINGUES, Nelson; BARROS, Eliane; PORTELA, Catarina; ALMEIDA, Maria Ines; COSTA, Sandra; REIS, Rui Manuel; MEDEIROS, Rui; LONGATTO-FILHO, AdhemarThe Epstein-Barr virus (EBV) is associated with a large spectrum of lymphoproliferative diseases. Traditional methods of EBV detection include the immunohistochemical identification of viral proteins and DNA probes to the viral genome in tumoral tissue. The present study explored the detection of the EBV genome, using the BALF5 gene, in the bone marrow or blood mononuclear cells of patients with diffuse large B-cell lymphomas (DLBCL) and related its presence to the clinical variables and risk factors. The results show that EBV detection in 21.5% of patients is not associated with age, gender, staging, B symptoms, international prognostic index scores or any analytical parameters, including lactate dehydrogenase (LDH) or beta-2 microglobulin (B2M). The majority of patients were treated with R-CHOP-like (rituximab. cyclophosphamide, doxorubicin, vincristine and prednisolone or an equivalent combination) and some with CHOP-like chemotherapy. Response rates [complete response (CR) + partial response (PR)] were not significantly different between EBV-negative and -positive cases, with 93.2 and 88.9%, respectively. The survival rate was also similar in the two groups, with 5-year overall survival (OS) rates of 64.3 and 76.7%, respectively. However, when analyzing the treatment groups separately there was a trend in EBV-positive patients for a worse prognosis in patients treated with CHOP-like regimens that was not identified in patients treated with R-CHOP-like regimens. We conclude that EBV detection in the bone marrow and blood mononuclear cells of DLBC patients has the same frequency of EBV detection on tumoral lymphoma tissue but is not associated with the risk factors, response rate and survival in patients treated mainly with immunochemotherapy plus rituximab. These results also suggest that the addition of rituximab to chemotherapy improves the prognosis associated with EBV detection in DLBCL.
- Role of monocarboxylate transporters in human cancers: state of the art(2012) PINHEIRO, Celine; LONGATTO-FILHO, Adhemar; AZEVEDO-SILVA, Joao; CASAL, Margarida; SCHMITT, Fernando C.; BALTAZAR, FatimaMonocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acid-resistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness.
conferenceObject Role of Monocarboxylate Transporters (MCTs) in the Regulation of the Metabolic Profile of Cervical Cancer Cells by Hypoxia(2012) PINHEIRO, C.; SANTOS, F.; MIRANDA-GONCALVES, V.; BOCCARDO, E.; LEPIQUE, A. P.; LONGATTO-FILHO, A.; VILLA, L. L.; BALTAZAR, F.Background: Due to the high growth rates of some tumors, cells are exposed to hypoxia, leading to a metabolic switch from oxidative phosphorylation to glycolysis. High glycolytic rates, in turn, lead to production of important amounts of lactate, which are exported to the extracellular milieu, contributing to the acidic microenvironment. Low oxygen concentrations lead to stabilization of hypoxia-inducible factor 1 alpha (HIF-1a), which regulates the expression of several glycolytic markers, as well as pH regulators. Thus, monocarboxylate transporters (MCTs) by mediating the co-transport of lactate with a proton, allow the maintenance of the glycolytic phenotype and intracellular pH, contributing to the tumour acidic microenvironment. However, MCT regulation by hypoxia is not fully understood, being sometimes controversial such as the case of MCT1. Aims: We aimed to characterize the expression of MCT1 and MCT4 and other glycolytic markers, as well as lactate transport activity under hypoxia conditions. The sensitivity of uterine cervix tumour cells to the MCT1 inhibitor CHC (a-cyano-4-hydroxycinnamic acid) was compared between normoxic and hypoxic conditions. Material and Methods: Hypoxia was induced by incubation of human cervical cancer cell lines in a hypoxic chamber (<1% O2). Expression of MCT1, MCT4, CD147, GLUT-1, CAIX and LDH was evaluated by immunocytochemistry and Western blot. Glycolytic metabolism was assessed through quantification of glucose consumption and lactate production. The effect of CHC on cell biomass was performed through the Sulforhodamine B assay. Results and Discussion: In general, the expression of the glycolytic metabolic markers GLUT-1, CAIX and LDH increased with hypoxia, which was accompanied by an increase in MCT1 expression in C33 cells and increased plasma membrane expression of MCT1 of SiHa cells. However, the expected increase in MCT4 expression was not observed. Interestingly, the expression of the MCT1/4 chaperone CD147 decreased in C33 and SiHa cells, pointing to the possible association with a different chaperone. Consistent with the increase in MCT1 expression, the sensitivity to CHC decreased in hypoxic conditions. Conclusion: We showed that hypoxia upregulates the expression of MCT1 in cervical cancer cells, rather than MCT4, and decreased the sensitivity to the MCT1 inhibitor CHC. These findings provide evidence for MCT regulation by hypoxia in cervical cancer and for the role of MCT1 in glycolytic metabolism. Acknowledgements: Part of this work was supported by FAPESP-São Paulo Research Foundation: 2008/03232−1 and the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of 'Programa Operacional Temático Factores de Competitividade' (COMPETE) of ‘Quadro Comunitário de Apoio III’ and co-financed by Fundo Comunitário Europeu FEDER.- HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical Carcinogenesis(2012) CARDEAL, Laura Beatriz da Silva; BOCCARDO, Enrique; TERMINI, Lara; RABACHINI, Tatiana; ANDREOLI, Maria Antonieta; LORETO, Celso di; LONGATTO FILHO, Adhemar; VILLA, Luisa Lina; MARIA-ENGLER, Silvya StuchiCervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/ RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.
- Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs)(2012) OLIVEIRA, Antnio Talvane Torres de; PINHEIRO, Celine; LONGATTO-FILHO, Adhemar; BRITO, Maria Jose; MARTINHO, Olga; MATOS, Delcio; CARVALHO, Andre Lopes; VAZQUEZ, Vinicius Lima; SILVA, Thiago Buosi; SCAPULATEMPO, Cristovam; SAAD, Sarhan Sydney; REIS, Rui Manuel; BALTAZAR, FatimaMonocarboxylate transporters (MCTs) have been described to play an important role in cancer, but to date there are no reports on the significance of MCT expression in gastrointestinal stromal tumors (GISTs). The aim of the present work was to assess the value of MCT expression, as well as co-expression with the MCT chaperone CD147 in GISTs and evaluate their clinical-pathological significance. We analyzed the immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 in a series of 64 GISTs molecularly characterized for KIT, PDGFRA and BRAF mutations. MCT1, MCT2 and MCT4 were highly expressed in GISTs. CD147 expression was associated with mutated KIT (p = 0.039), as well as a progressive increase in Fletcher's Risk of Malignancy (p = 0.020). Importantly, co-expression of MCT1 with CD147 was associated with low patient's overall survival (p = 0.037). These findings suggest that co-expression of MCT1 with its chaperone CD147 is involved in GISTs aggressiveness, pointing to a contribution of cancer cell metabolic adaptations in GIST development and/or progression.
- CD147 immunohistochemistry discriminates between reactive mesothelial cells and malignant mesothelioma(2012) PINHEIRO, Celine; LONGATTO-FILHO, Adhemar; SOARES, Tony R.; PEREIRA, Helena; BEDROSSIAN, Carlos; MICHAEL, Claire; SCHMITT, Fernando C.; BALTAZAR, FatimaMalignant mesothelioma (MM) is a rare form of cancer. Its histopathological diagnosis is very difficult, as it exhibits a number of different appearances that can be misinterpreted as metastatic invasion or atypical hyperplasia. Thus, there is an urgent need to identify adequate markers to distinguish between benign and malignant cells, allowing the implementation of appropriate therapies and, possibly, specific directed therapies. MM, like other tumors, show an increase in glucose uptake, due to high rates of glycolysis, inducing an intracellular overload of acids. In this context, monocarboxylate transporters (MCTs) emerge as important players, by mediating the transmembranar co-transport of lactate with a proton, thereby, regulating pH and allowing continuous glycolysis. Importantly, proper MCT expression and activity depend on its co-expression with a chaperone, CD147, which is associated with poor prognosis in cancer. Twenty-two samples including reactive mesothelial cells, MM, and atypical mesothelial hyperplasias were evaluated for immunoexpression of MCT1, MCT4, and CD147. Expression of these proteins was compared with GLUT1 as a new promising marker for MM. Although MCT isoforms were not differentially expressed in the two types of cytological specimens, CD147, as GLUT1, was almost exclusively expressed in MM. Both MCT1 and MCT4 are not able to discriminate between mesothelial reactive cells and mesothelial malignant cells, while CD147 was able to distinguish these two proliferations. If confirmed, besides being a good marker for identification of MM, CD147 may also be a target for therapeutical strategies in this rare type of tumor. Diagn. Cytopathol. 2012;40:478483. (c) 2012 Wiley Periodicals, Inc.