MARIA APARECIDA NAGAI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
15 resultados
Resultados de Busca
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conferenceObject Immune Profiling Data and Mutational Status Improves Prediction of Risk of Death in Non-Small Cell Lung Carcinoma(2019) PARRA, E.; JANG, M.; MACHADO-RUGOLO, J.; FARHAT, C.; NAGAI, M.; TAKAGAKI, T.; TERRA, R.; FABRO, A.; CAPELOZZI, V.conferenceObject Immune Checkpoint Profiling Related to Epithelial-to-Mesenchymal Genes Alterations Predict the Risk of Death in Lung Cancer(2020) RUGOLO, J. M.; PARRA, E.; BATAH, S. S.; FABRO, A. T.; NAGAI, M. A.; CAPELOZZI, V. L.- Usefulness of complementary next-generation sequencing and quantitative immunohistochemistry panels for predicting brain metastases and selecting treatment outcomes of non-small cell lung cancer(2019) MACHADO-RUGOLO, Juliana; FABRO, Alexandre Todorovic; ASCHERI, Daniel; FARHAT, Cecilia; AB'SABER, Alexandre Muxfeldt; SA, Vanessa Karen de; NAGAI, Maria Aparecida; TAKAGAKI, Teresa; TERRA, Ricardo; PARRA, Edwin Roger; CAPELOZZI, Vera LuizaTo demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed, paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma, and large cell carcinoma were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors. In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of p53 and a higher PD-LI protein H-score were detected in patients who underwent surgical treatment followed by chemotherapy as compared with those who underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEBI. The combination of protein overexpression according to IHC and mutation according to NGS was rare (ie, represented by a very low percentage of concordant cases), except for p53 and vascular endothelial growth factor. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include squamous cell carcinoma and even large cell carcinoma, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features seemed to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCDILG2, or ZEBI complemented with PD-L1 or p53 protein lower expression that only underwent surgical treatment who develop brain metastases may have the worst prognosis.
conferenceObject Molecular features of breast cancer involved in classification and prognosis of a multi-country Latin American cohort: The US-LACRN-MPBCS breast cancer cohort.(2021) LLERA, Andrea S.; ABDELHAY, Eliana; PODHAJCER, Osvaldo; ARTAGAVEYTIA, Nora; DANERI-NAVARRO, Adrian; MULLER, Bettina; CONTRERAS, Carlos Velazquez; ROCHA, Dario; SENDOYA, Juan Martin; BINATO, Renata; FERNANDEZ, Elmer; ALCOBA, Elsa; ALONSO, Isabel; BRAVO, Alicia I.; CAMEJO, Natalia; CARRARO, Dirce; CASTRO, Monica; CASTRO-CERVANTES, Juan M.; CATALDI, Sandra; CAYOTA, Alfonso; CERDA, Mauricio; CROCAMO, Susanne; DELGADILLO-CISTERNA, Raul; DELGADO, Lucia; ARREOLA, Alicia del Toro; BREITENBACH, Marisa Dreyer; FERNANDEZ, Jorge; FERNANDEZ, Wanda; FRANCO-TOPETE, Ramon A.; GAETE, Fancy; GOMEZ, Jorge; GREIF, Gonzalo; GUERRERO, Marisol; HENDERSON, Marianne Marianne; MORAN-MENDOZA, Andres de J.; NAGAI, Maria Aparecida; OCEGUERA-VILLANUEVA, Antonio; QUINTERO-RAMOS, Antonio; REIS, Rui; RETAMALES, Javier; RODRIGUEZ, Robinson; ROSALES, Cristina; SALAS-GONZALEZ, Efrain; SEGOVIA, Laura; SILVA-GARCIA, Araceli; VEDHAM, Vidya; ZAGAME, Livia- Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells(2013) PEREIRA, Michelly C.; BESSA-GARCIA, Simone A. De; BURIKHANOV, Ravshan; PAVANELLI, Ana Carolina; ANTUNES, Lourival; RANGNEKAR, Vivek M.; NAGAI, Maria A.Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.
- Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women(2022) ALMEIDA, Liz Maria de; CORTES, Sandra; VILENSKY, Marta; VALENZUELA, Olivia; CORTES-SANABRIA, Laura; SOUZA, Mirian de; BARBEITO, Rafael Alonso; ABDELHAY, Eliana; ARTAGAVEYTIA, Nora; DANERI-NAVARRO, Adrian; LLERA, Andrea S.; MULLER, Bettina; PODHAJCER, Osvaldo L.; VELAZQUEZ, Carlos; ALCOBA, Elsa; ALONSO, Isabel; I, Alicia Bravo; CAMEJO, Natalia; CARRARO, Dirce Maria; CASTRO, Monica; CATALDI, Sandra; CAYOTA, Alfonso; CERDA, Mauricio; COLOMBO, Alicia; CROCAMO, Susanne; TORO-ARREOLA, Alicia Del; DELGADILLO-CRISTERNA, Raul; DELGADO, Lucia; BREITENBACH, Marisa Dreyer; FERNANDEZ, Elmer; FERNANDEZ, Jorge; FERNANDEZ, Wanda; FRANCO-TOPETE, Ramon A.; GAETE, Fancy; GOMEZ, Jorge; GONZALEZ-RAMIREZ, Leivy P.; GUERRERO, Marisol; GUTIERREZ-RUBIO, Susan A.; JALFIN, Beatriz; LOPEZ-VAZQUEZ, Alejandra; LORIA, Dora; MIGUEZ, Silvia; MORAN-MENDOZA, Andres de J.; MORGAN-VILLELA, Gilberto; MUSSETTI, Carina; NAGAI, Maria Aparecida; OCEGUERA-VILLANUEVA, Antonio; REIS, Rui M.; RETAMALES, Javier; RODRIGUEZ, Robinson; ROSALES, Cristina; SALAS-GONZALEZ, Efrain; SEGOVIA, Laura; SENDOYA, Juan M.; SILVA-GARCIA, Aida A.; VINA, Stella; ZAGAME, Livia; JONES, Beth; SZKLO, MoysesMolecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status not less than or equal to 1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (>= 60 years) (1.84) compared with younger (<= 40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.
- The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma(2023) LABERIANO-FERNANDEZ, Caddie; BALDAVIRA, Camila Machado; MACHADO-RUGOLO, Juliana; TAMEGNON, Auriole; PANDURENGAN, Renganayaki Krishna; AB'SABER, Alexandre Muxfeldt; BALANCIN, Marcelo Luiz; TAKAGAKI, Teresa Yae; NAGAI, Maria Aparecida; CAPELOZZI, Vera Luiza; PARRA, Edwin RogerSimple Summary Identifying biomarkers to guide immunotherapy regimens remains an unmet clinical need in malignant pleural mesothelioma. A potential source of such markers is tumor-associated macrophages (TAMs), which contribute to the immunosuppressive microenvironment of mesothelioma. By examining distinct subsets of pleural macrophages to identify their gene signatures and protein expression, we found that TAMs preferentially contribute to M2a and M2b phenotypes, and M2a, M2b, and M2c more specifically contributed to immune tolerance. CD206, ARG1, CD274, CD163, and MRP8-14 are potential therapeutic targets in this disease.Abstract Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
- Cocaine use disorder effects on blood oxytocin levels and OXTR DNA methylation(2023) SOUZA, Manasses Soares; SANVICENTE-VIEIRA, Breno; ZAPARTE, Aline; BAPTISTA, Talita; NAGAI, Maria Aparecida; MANGONE, Flavia Rotea; PAVANELLI, Ana Carolina; VIOLA, Thiago Wendt; GRASSI-OLIVEIRA, RodrigoSubstance use disorders have been associated with alterations in the oxytocinergic system, but few studies have investigated both the peptide and epigenetic mechanisms potentially implicated in the regulation of oxytocin receptor. In this study, we compared plasma oxytocin and blood DNA methylation in the OXTR gene between people with and without cocaine use disorder (CUD). We measured the oxytocin levels of 51 people with CUD during acute abstinence and of 30 healthy controls using an enzyme immunoassay. The levels of DNA methylation in four CpG sites at exon III of the OXTR gene were evaluated in a subsample using pyrosequencing. The Addiction Severity Index was used to assess clinical characteristics. We found higher oxytocin levels in men with CUD (56.5 pg/mL; 95% CI: 48.2-64.7) than in control men (33.6 pg/mL; 95% CI: 20.7-46.5), while no differences between women with and without CUD were detected. With a moderate effect size, the interaction effect between group and sex remained significant when controlling for height, weight and age data. A positive correlation in the CUD sample was found between oxytocin levels and days of psychological suffering prior to treatment enrollment. No group differences were observed regarding DNA methylation data. This suggests that CUD is associated with higher peripheral oxytocin levels in men during acute abstinence. This finding may be considered in future studies that aim at using exogenous oxytocin as a potential treatment for cocaine addiction.
- Interrelated but Not Time-Aligned Response in Myogenic Regulatory Factors Demethylation and mRNA Expression after Divergent Exercise Bouts(2023) TELLES, Guilherme Defante; LIBARDI, Cleiton Augusto; CONCEICAO, Miguel Soares; VECHIN, Felipe Cassaro; LIXANDRAO, Manoel Emilio; MANGONE, Flavia Regina Rotea; PAVANELLI, Ana Carolina; NAGAI, Maria Aparecida; CAMERA, Donny Michael; HAWLEY, John A.; UGRINOWITSCH, CarlosIntroductionDNA methylation regulates exercise-induced changes in the skeletal muscle transcriptome. However, the specificity and the time course responses in the myogenic regulatory factors DNA methylation and mRNA expression after divergent exercise modes are unknown.PurposeThis study aimed to compare the time course changes in DNA methylation and mRNA expression for selected myogenic regulatory factors (MYOD1, MYF5, and MYF6) immediately after, 4 h after, and 8 h after a single bout of resistance exercise (RE), high-intensity interval exercise (HIIE), and concurrent exercise (CE).MethodsNine healthy but untrained males (age, 23.9 +/- 2.8 yr; body mass, 70.1 +/- 14.9 kg; peak oxygen uptake [V?O-2peak], 41.4 +/- 5.2 mL center dot kg(-1)center dot min(-1); mean +/- SD) performed a counterbalanced, randomized order of RE (4 x 8-12 repetition maximum), HIIE (12 x 1 min sprints at V?O-2peak running velocity), and CE (RE followed by HIIE). Skeletal muscle biopsies (vastus lateralis) were taken before (REST) immediately (0 h), 4 h, and 8 h after each exercise bout.ResultsCompared with REST, MYOD1, MYF5, and MYF6, mean methylation across all CpGs analyzed was reduced after 4 and 8 h in response to all exercise protocols (P < 0.05). Reduced levels of MYOD1 methylation were observed after HIIE and CE compared with RE (P < 0.05). Compared with REST, all exercise bouts increased mRNA expression over time (MYOD1 at 4 and 8 h, and MYF6 at 4 h; P < 0.05). MYF5 mRNA expression was lower after 4 h compared with 0 h and higher at 8 h compared with 4 h (P < 0.05).ConclusionsWe observed an interrelated but not time-aligned response between the exercise-induced changes in myogenic regulatory factors demethylation and mRNA expression after divergent exercise modes. Despite divergent contractile stimuli, changes in DNA methylation and mRNA expression in skeletal muscle were largely confined to the late (4-8 h) recovery period and similar between the different exercise challenges.
conferenceObject Clinical Relevant Oncogenic Drivers in Advanced Adenocarcinoma Discloses New Therapeutic Targets in Negative EGFR/ALK/KRAS Patients(2017) MACHADO, Juliana; ASCHERI, Daniel; LEAO, Patricia; MILSONI, Priscila; OLIVEIRA, Rogerio; PARRA, Edwin; SA, Vanessa; FARHAT, Cecilia; RAINHO, Claudia; AB'SABER, Alexandre; NAGAI, Maria; TAKAGAKI, Teresa; FABRO, Alexandre; CAPELOZZI, Vera