JULIANA MACHADO RUGOLO
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- Circulating Plasma miRNA and Clinical/Hemodynamic Characteristics Provide Additional Predictive Information About Acute Pulmonary Thromboembolism, Chronic Thromboembolic Pulmonary Hypertension and Idiopathic Pulmonary Hypertension(2021) FABRO, Alexandre Todorovic; MACHADO-RUGOLO, Juliana; BALDAVIRA, Camila Machado; PRIETO, Tabatha Gutierrez; FARHAT, Cecilia; MANGONE, Flavia Regina Rotea; BATAH, Sabrina Setembre; CRUVINEL, Heloisa Resende; ALDA, Maiara Almeida; MONTEIRO, Jhonatas Sirino; PADUA, Adriana Inacio; MORAIS, Sirlei Siani; OLIVEIRA, Rogerio Antonio de; SANTOS, Marcel Koenigkam; BADDINI-MARTINEZ, Jose Antonio; SETUBAL, Joao Carlos; RAINHO, Claudia Aparecida; YOO, Hugo Hyung Bok; SILVA, Pedro Leme; NAGAI, Maria Aparecida; CAPELOZZI, Vera LuizaIdiopathic pulmonary artery hypertension (IPAH), chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (APTE) are life-threatening cardiopulmonary diseases without specific surgical or medical treatment. Although APTE, CTEPH and IPAH are different pulmonary vascular diseases in terms of clinical presentation, prevalence, pathophysiology and prognosis, the identification of their circulating microRNA (miRNAs) might help in recognizing differences in their outcome evolution and clinical forms. The aim of this study was to describe the APTE, CTEPH, and IPAH-associated miRNAs and to predict their target genes. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. The miRNAs were detected using RT-PCR. Finally, we incorporated plasma circulating miRNAs in baseline and clinical characteristics of the patients to detect differences between APTE and CTEPH in time of evolution, and differences between CTEPH and IPAH in diseases form. We found five top circulating plasma miRNAs in common with APTE, CTEPH and IPAH assembled in one conglomerate. Among them, miR-let-7i-5p expression was upregulated in APTE and IPAH, while miRNA-320a was upregulated in CTEP and IPAH. The network construction for target genes showed 11 genes regulated by let-7i-5p and 20 genes regulated by miR-320a, all of them regulators of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell, and pulmonary artery smooth muscle cells. AR (androgen receptor), a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in pathways in cancer, whereas PRKCA (Protein Kinase C Alpha), also a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in KEGG pathways, such as pathways in cancer, glioma, and PI3K-Akt signaling pathway. We inferred that CTEPH might be the consequence of abnormal remodeling in APTE, while unbalance between the hyperproliferative and apoptosis-resistant phenotype of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell and pulmonary artery smooth muscle cells in pulmonary artery confer differences in IPAH and CTEPH diseases form. We concluded that the incorporation of plasma circulating let-7i-5p and miRNA-320a in baseline and clinical characteristics of the patients reinforces differences between APTE and CTEPH in outcome evolution, as well as differences between CTEPH and IPAH in diseases form.
- The Fibrosis-Targeted Collagen/Integrins Gene Profile Predicts Risk of Metastasis in Pulmonary Neuroendocrine Neoplasms(2021) PRIETO, Tabatha Gutierrez; MACHADO-RUGOLO, Juliana; BALDAVIRA, Camila Machado; VELOSA, Ana Paula Pereira; TEODORO, Walcy Rosolia; SABE, Alexandre Muxfeldt Ab; CAPELOZZI, Vera LuizaRecently, collagen/integrin genes have shown promise as predictors of metastasis mainly in non-small cell lung cancer and breast cancer. However, it is unknown if these gene expression profiling differ in metastatic potential of pulmonary neuroendocrine neoplasms (PNENs). In this study, we sought to identify differentially expressed collagen/integrin genes in PNENs in order to understand the molecular mechanisms underlying the development of stroma-associated fibrosis for invasion and metastasis. We compared collagen/integrin gene expression profiling between PNE tumors (PNETs) and PNE carcinomas (PNECs) using a two-stage design. First, we used PCR Array System for 84 ECM-related genes, and among them, we found COL1A2, COL3A1, COL5A2, ITGA5, ITGAV, and ITGB1 functionally involved in the formation of the stroma-associated fibrosis among PNENs histological subtypes. Second, we examined the clinical association between the six collagen/integrin genes in tumor tissues from 24 patients with surgically excised PNENs. However, the pathological exam of their resected tissues demonstrated that 10 developed lymph node metastasis and 7 distant metastasis. We demonstrated and validated up regulation of the six fibrogenic genes in PNECs and down regulation in PNETs that were significantly associated with metastasis-free and overall survival (P<0.05). Our study implicates up regulation of fibrogenic genes as a critical molecular event leading to lymph node and distant metastasis in PNENs.
- Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications(2022) BALANCIN, Marcelo Luiz; BALDAVIRA, Camila Machado; PRIETO, Tabatha Gutierrez; MACHADO-RUGOLO, Juliana; FARHAT, Cecilia; ASSATO, Aline Kawassaki; VELOSA, Ana Paula Pereira; TEODORO, Walcy Rosolia; AB'SABER, Alexandre Muxfeldt; TAKAGAKI, Teresa Yae; CAPELOZZI, Vera LuizaBackgroundMalignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression. MethodsIn a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome. ResultsEpithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm(2)) for epithelioid MM. ConclusionDifferential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.