Juliana Meola - Academia.edu (original) (raw)

Papers by Juliana Meola

Genética na Escola, May 20, 2009

Cancer Detection and Prevention, 2009

Background: Prostate cancer consists of multifactorial and multifocal events, generating differen... more Background: Prostate cancer consists of multifactorial and multifocal events, generating differential gene expression in tumor cells. Methods: The molecular profile of 14 gene expression was analyzed through cDNA array in blood samples of patients with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). Results: Messenger RNA from patient's blood showed significant differences between PCa and BPH groups only for the NOS3 gene, with an occurrence chance for PCa 5.8-fold higher than BPH disease. Conclusion: The NOS3 gene expression in the patient's blood may be used as a putative biomarker for prostate cancer.

Fertility and Sterility, 2008

Objective: To develop a web-based system to store, recover, compare, and associate information ob... more Objective: To develop a web-based system to store, recover, compare, and associate information obtained using high-throughput molecular genetic techniques regarding differentially expressed genes in patients with endometriosis. Methods: A web-based tool was developed using the Java programming and XHTML markup languages. Professionals and researchers in the field contributed to the database by uploading research data from scientific articles in which screening techniques had been performed to determine differential gene expression in women with and without endometriosis. Results: a web-based system with the main functionalities of article registration and gene searching was developed. These functions allow the user to identify coincidences between the results reported in the registered articles regarding differential gene expression. Conclusion: The developed tool allows for the collection of principal data regarding dysregulated gene expression in endometriosis and highlights candidate genes for future studies to better understand the etiopathogenesis of this disease.

Journal of health informatics, Oct 19, 2015

Revista Brasileira de Ginecologia e Obstetrícia, Oct 1, 2020

Scientific Reports, Mar 8, 2021

It has been suggested that menstrual blood-derived mesenchymal stem/stromal cells (MenMSCs) are a... more It has been suggested that menstrual blood-derived mesenchymal stem/stromal cells (MenMSCs) are associated with the etiopathogenesis of endometriosis and considerable effort has been invested in searching for target genes and deciphering associated molecular pathways. However, reference gene stability for proper reproducible normalization in the analyses of the expression data validation is still unexplored in this experimental context. Therefore, in this exploratory study, we used stringent case and control selection criteria and collected menstrual blood from women with a laparoscopic diagnosis of advanced endometriosis and from fertile women without endometriosis. We tested for the first time the stability of 32 candidate reference genes to achieve increased accuracy and reliable results in the quantification of gene expression and direct future experiments using reverse transcription-quantitative PCR (RT-qPCR) in MenMSCs for endometriosis studies. Using the RefFinder web tool, we recommend the EIF2B1 and POP4 reference genes for the normalization of RT-qPCR data in study designs similar to ours. Furthermore, we suggest avoiding the commonly used GAPDH and ACTB reference genes as they are unstable. This high-visibility study is capable of directing different experimental designs as MenMSCs are derived from a minimally invasive tissue source with multifunctional roles in regenerative medicine. Endometriosis is a benign estrogen-dependent gynecologic disease characterized by endometrium-like tissue outside of the uterine cavity. It is estimated that over 176 million women are affected by this condition globally, with women of reproductive age being more frequently affected 1,2. The most widely accepted explanation for the etiology of endometriosis is Sampson's theory, which considers the retrograde menstrual flow of endometrial tissue to the peritoneal cavity through the uterine tubes 3. Although this theory is plausible, it does not explain all the nuances of the disease. Recently, it has been found that the endometrium, endometrial lesions and menstrual flow present cells with progenitor potential [known as endometrial mesenchymal stem/stromal cells (eMSCs) when obtained from the endometrium and lesions, and menstrual blood-derived stem/stromal cells (MenMSCs) when derived from menstrual flow] that might be directly related to the genesis of the disease 4. In parallel with the discovery of these cells, high-throughput methodologies have rapidly developed, enabling great advances in the understanding of numerous diseases. One of these advances concerns the gene expression analysis of the eutopic and ectopic endometrium, which has supported the identification of pathways and molecular processes involved in the physiopathology of endometriosis 5-7. Although these methods are reliable, they have some constraints. One critical issue is the validation of identified genes. The gold standard method for this validation is reverse transcription-quantitative PCR (RT-qPCR) 8. RT-qPCR is a robust, reproducible, highly sensitive, and specific method with rapid detection that is capable of identifying targets in low-concentration samples 9,10. However, the reliability of gene expression measurements is strongly affected by technical factors, such as template quality, efficiency of complementary DNA (cDNA) synthesis, primer performance, and data normalization 11,12. The latter, when inappropriately performed, compromises the conclusions of studies 13,14. There are many options for normalizing the quantification of gene expression, such

Scientific Reports, Jan 15, 2020

Eutopic endometrium appears to be crucial for endometriosis development. Despite of the evident i... more Eutopic endometrium appears to be crucial for endometriosis development. Despite of the evident importance, data regarding the cellular microenvironment remain unclear. Our objective was to explore the tissue microenvironment heterogeneity, transcripts, and pathways that are enriched in all phases of the menstrual cycle by analysing publicly deposited data derived from whole transcriptome microarrays of eutopic endometria of women with and without endometriosis. A meta-analysis of the transcriptome microarrays was performed using raw data available from a public database. Eligibility criteria included eutopic endometrium samples from women with endometriosis and healthy controls without any pathological condition reported the presence of an adequately reported normal menstrual phase, and samples containing both glandular and stromal components. Raw data were processed using a robust multiarray average method to provide background correction, normalisation, and summarisation. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Cellular tissue heterogeneity was inferred using the xCell package. Differentially expressed genes were identified based on a 5% adjusted p value and a 2.0-fold change. Pathways were identified by functional enrichment based on the Molecular Signatures Database, a p value of < 5%, and an FDR q value of ≤ 25%. Genes that were more frequently found in pathways were identified using leading edge analysis. In a manner independent of cycle phase, the subpopulations of activated dendritic cells, CD4 T effector memory phenotype cells, eosinophils, macrophages M1, and natural killer T cells (NKT) were all higher in stage I-II endometriosis compared to those in healthy controls. The subpopulations of M2 macrophages and natural killer T cells were elevated in eutopic endometriums from women with stage III-IV endometriosis, and smooth muscle cells were always more prevalent in healthy eutopic endometriums. Among the differently expressed genes, FOS, FOSB, JUNB, and EGR1 were the most frequently mapped within the interaction networks, and this was independent of stage and cycle phase. The enriched pathways were directly related to immune surveillance, stem cell self-renewal, and epithelial mesenchymal transition. PI3K AKT mTOR, TGF signalling, and interferon alpha/gamma responses were enriched exclusively in stage III-IV endometriosis. The cellular microenvironments and immune cell profiles were different between eutopic endometriums from women with stage I-II and stage III-IV endometriosis, and these differences were independent of the hormonal milieu. Specifically, a pro-inflammatory profile was predominant in stage I-II endometriosis, and M1-M2 polarization into eutopic endometrium may be crucial for the progression of the disease. The higher prevalence of NKT cells in eutopic endometriums from women with endometriosis that

Annals of Translational Medicine, Oct 1, 2020

Rosa-e-Silva et al. Central sensitization and endometriosis

Revista Brasileira de Ginecologia e Obstetrícia, Nov 1, 2018

Objective To characterize the patterns of cell differentiation, proliferation, and tissue invasio... more Objective To characterize the patterns of cell differentiation, proliferation, and tissue invasion in eutopic and ectopic endometrium of rabbits with induced endometriotic lesions via a well-known experimental model, 4 and 8 weeks after the endometrial implantation procedure. Methods Twenty-nine female New Zealand rabbits underwent laparotomy for endometriosis induction through the resection of one uterine horn, isolation of the endometrium, and fixation of tissue segment to the pelvic peritoneum. Two groups of animals (one with 14 animals, and the other with15) were sacrificed 4 and 8 weeks after endometriosis induction. The lesion was excised along with the opposite uterine horn for endometrial gland and stroma determination. Immunohistochemical reactions were performed in eutopic and ectopic endometrial tissues for analysis of the following markers: metalloprotease (MMP-9) and tissue inhibitor of metalloprotease (TIMP-2), which are involved in the invasive capacity of the endometrial tissue; and metallothionein (MT) and p63, which are involved in cell differentiation and proliferation. Results The intensity of the immunostaining for MMP9, TIMP-2, MT, and p63 was higher in ectopic endometria than in eutopic endometria. However, when the ectopic lesions were compared at 4 and 8 weeks, no significant difference was observed, with the exception of the marker p63, which was more evident after 8 weeks of evolution of the ectopic endometrial tissue. Conclusion Ectopic endometrial lesions seem to express greater power for cell differentiation and tissue invasion, compared with eutopic endometria, demonstrating a potentially invasive, progressive, and heterogeneous presentation of endometriosis.

Reproductive Sciences, Jun 15, 2020

Endometriosis is responsible for pain symptoms with great impact on the patient's quality of life... more Endometriosis is responsible for pain symptoms with great impact on the patient's quality of life. Several medication lines have been studied aiming at its definitive treatment. Among them, angiogenesis inhibitor factors may be effective given that angiogenesis has fundamental role in the establishment and growth of endometriotic lesions. In this study, we investigated the influence of bevacizumab, anti-factor drug of endothelial growth (anti-VEGF), used at two different dosages, in experimental endometriosis induced in rats. After the induction of endometriosis lesions in rats, they were divided in 3 groups: control group, no treatment, and two other groups were treated with different dosages of the same medication for 4 weeks. At the end of the treatment, endometriotic lesions were removed and evaluated regarding area of lesions, presence of endometrial tissue in microscopy, positivity for anti-VEGF antibody in immunohistochemistry, and gene expression of Pcna, Mmp9, Tp63, and Vegfa. Bevacizumab acted by reducing the area of lesions in the groups that received medication (p = 0.002) and reducing gene expression to Tp63 in lesions (p = 0.04). There was no significant result in other evaluations. We observed that there was significant reduction of the area of lesions among groups, suggesting that bevacizumab has a positive effect on disease control. The gene expression of Tp63 was significantly lower in the group that received high dose of the drug when compared with the other two groups; therefore, we concluded that bevacizumab acts by reducing cell proliferation and differentiation in lesions, constituting a real option for treating endometriosis.

Revista Brasileira de Ginecologia e Obstetrícia, May 24, 2016

Several authors have investigated the malignant transformation of endometriosis, which supports t... more Several authors have investigated the malignant transformation of endometriosis, which supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but there are few data about the pathways and molecular events related to this phenomenon. This review provides current data about deregulated genes that may function as key factors in the malignant transition of endometriotic lesions. In order to do so, we first searched for studies that have screened differential gene expression between endometriotic tissues and normal endometrial tissue of women without endometriosis, and found only two articles with 139 deregulated genes. Further, using the PubMed database, we crossed the symbol of each gene with the terms related to malignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444 were studies about gene expression associated with specific types of tumor. This revealed that more than 68% of the analyzed genes are also deregulated in cancer. We have also found genes functioning as tumor suppressors and an oncogene. In this study, we present a list of 95 informative genes in order to understand the genetic components that may be responsible for endometriosis' malignant transformation. However, future studies should be conducted to confirm these findings. Resumo Vários autores têm estudado transformações malignas em endometriose que suportam a hipótese de um estado pré-neoplásico das lesões endometrióticas; contudo, existem poucos dados sobre as vias e eventos moleculares relacionados a este fenômeno. Esta revisão fornece dados atuais sobre genes desregulados que possam funcionar como fatores-chave para a transição maligna das lesões endometrióticas. Assim, inicialmente, estudos de expressão gênica diferencial em larga escala

Fertility and Sterility, Sep 1, 2017

The mechanisms of endometriosis-related infertility still remain to be elucidated, although sever... more The mechanisms of endometriosis-related infertility still remain to be elucidated, although several studies propose a deleterious effect of this disease in oocyte quality. Capable of predicting oocyte quality, e202

Fertility and Sterility, Sep 1, 2017

of this disease in oocyte quality. Capable of predicting oocyte quality, cumulus cells (CCs) coul... more of this disease in oocyte quality. Capable of predicting oocyte quality, cumulus cells (CCs) could be used as indirect biomarkers. Thus, through an unprecedented study, we aimed to determine the differential transcript profile in CCs of infertile women with and without endometriosis in the initial stages (I/II) undergoing controlled ovarian stimulation (COS) for intracytoplasmic sperm injection (ICSI). DESIGN: Prospective case-control study. MATERIALS AND METHODS: This study was conducted between August of 2014 and February of 2016. CCs from controls (infertility related to male and/or tubal factor) and women with endometriosis I/II (EI/II) were collected after COS for ICSI. RNA next generation sequencing was performed in CCs by the Illumina platform HiSeq2500, High Output, pairend. Data normalization and differential expression analyses were performed using the R statistical environment and STAR package. Enrichment analysis was conducted in DAVID web toll using KEGG database. Based on previous studies that used global transcript profile methodology we established the study size, 9 patients per group, grouped in 3 pools/samples of 3 women each. RESULTS: The comparison between CCs from EI/II patients and controls revealed 59 altered genes. The enrichment analysis of these deregulated transcripts evidenced genes associated with oxidative phosphorylation, chemokine signaling pathway, nuclear factor-kappa B signaling pathway and hypoxia inducible factor-1 signaling pathway. CONCLUSIONS: CCs of infertile women with EI/II undergoing COS seem to be molecularly different from those of infertile women without endometriosis and carry essential molecular alterations linked with the acquisition of oocyte competence. These findings open new perspectives on the mechanisms of the impairment of natural fertility in women with EI/II.

Brazilian Journal of Medical and Biological Research, 2022

The objective of this study was to evaluate the immunohistochemical expression of Dicer, Drosha, ... more The objective of this study was to evaluate the immunohistochemical expression of Dicer, Drosha, and Exportin-5 in the eutopic and ectopic endometrium of women with adenomyosis. Twenty-two paired ectopic and eutopic endometrium from women with adenomyosis and 10 eutopic endometrium samples from control women undergoing hysterectomy were included in the study. Paraffin-embedded tissue blocks were cut and stained for immunohistochemistry. The percentage of epithelial cells positively marked was identified digitally after an automated slide scanning process. Mann-Whitney test or Wilcoxon signedrank test was performed for independent and paired groups, respectively. A lower expression of Drosha was observed in the eutopic endometrium of women with adenomyosis than in the eutopic endometrium of women without the disease (69.9 ± 3.4% vs 85.2±2.9%, respectively) (P=0.016; 95%CI: 3.4 to 27.4%). We also detected lower Drosha expression in the ectopic endometrium of women with adenomyosis than in the eutopic endometrium of the same women (59.6 ± 3.2% vs 69.9 ± 3.4%, respectively) (P=0.004; 95%CI: 2.3 to 16.7%). Additionally, we observed a correlation between Drosha expression in the ectopic and paired eutopic endometrium (P=0.034, rho=0.454). No significant difference in Dicer or Exportin expression was observed. Predominant pattern of cytoplasmic staining for the anti-Drosha antibody and both a nuclear and cytoplasmic pattern for the anti-Exportin antibody were observed. Drosha expression was significantly lower in the endometrium of women with adenomyosis compared to the eutopic endometrium of asymptomatic women without the disease. Furthermore, its expression was lower in the ectopic endometrium but correlated to the paired eutopic endometrium.

Reproductive Biomedicine Online, May 1, 2021

RESEARCH QUESTION Is the transcriptome of cumulus cells of infertile women with advanced endometr... more RESEARCH QUESTION Is the transcriptome of cumulus cells of infertile women with advanced endometriosis (EIII/IV), with and without endometrioma, altered? DESIGN In this prospective case-control study, next-generation RNA sequencing was used to compare the transcript profile of cumulus cells among infertile patients undergoing ovarian stimulation for intracytoplasmic sperm injection with EIII/IV, with (n = 9) and without endometrioma (n = 9), and controls (n = 9). An in-silico enrichment analysis was conducted to establish the possibly altered pathways in cumulus cells of patients with endometriosis. RESULTS Most of the differentially expressed genes (DEG) were found when cumulus cells from women with EIII/IV with endometrioma were compared with controls (DEG, n = 461). In women with EIII/IV without endometrioma, only 66 DEG were verified compared with controls. The enrichment analysis showed that some DEG in cumulus cells of endometriosis are involved in important pathways for the oocyte competence acquisition, such as oxidative phosphorylation, metabolism, mitochondrial function, acetylation and steroid biosynthesis. No DEG were found when cumulus cells from women with EIII/IV with and without endometrioma were compared. CONCLUSION RNA sequencing results suggest that cumulus cells of infertile women with EIII/IV have an altered transcriptome, regardless of endometrioma. The present findings offer a better understanding of the genes and molecular mechanisms that may be involved in endometriosis-related infertility, mostly in the oocyte competence acquisition process.

Scientific Reports, Apr 6, 2022

Endometriosis is a chronic inflammatory disorder that is highly associated with infertility. This... more Endometriosis is a chronic inflammatory disorder that is highly associated with infertility. This association seems to be related to oocyte impairment, mainly in the initial stages of endometriosis (minimal and mild), where no distortions or adhesions are present. Nonetheless, invasive oocyte analyses are not routinely feasible; thus, indirect assessment of oocyte quality is highly desirable, and, in this context, cumulus cells (CCs) may be more suitable targets of analysis. CCs are crucial in oocyte development and could be used as an index of oocyte quality. Therefore, this prospective casecontrol study aimed to shed light on the infertility mechanisms of endometriosis I/II by analyzing the CCs' mRNA transcription profile (women with endometriosis I/II, n = 9) compared to controls (women with tubal abnormalities or male factor, n = 9). The transcriptomic analyses of CCs from patients with minimal and mild endometriosis revealed 26 differentially expressed genes compared to the controls. The enrichment analysis evidenced some altered molecular processes: Cytokine-cytokine receptor interactions, Chemokine signaling, TNF signaling, NOD-like receptor signaling, NF-kappa B signaling, and inflammatory response. With the exception of CXCL12, all enriched genes were downregulated in CCs from patients with endometriosis. These findings provide a significant achievement in the field of reproductive biology, directing future studies to discover biomarkers of oocyte quality in endometriosis.

Journal of Reproductive Immunology, Jun 1, 2021

The aim of this study was to identify the key similarities between the eutopic endometrium of wom... more The aim of this study was to identify the key similarities between the eutopic endometrium of women with endometriosis and chlamydia-induced endometritis taking into account tissue microenvironment heterogeneity, transcript gene profile, and enriched pathways. A meta-analysis of whole transcriptome microarrays was performed using publicly available data, including samples containing both glandular and stromal endometrial components. Control samples were obtained from women without any reported pathological condition. Only samples obtained during the proliferative menstrual phase were included. Cellular tissue heterogeneity was predicted using a method that integrates gene set enrichment and deconvolution approaches. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Differentially expressed genes were identified using an adjusted p-value < 0.05 and fold change = 1.5. The protein-protein interaction network was built using the STRING database and interaction score over 400. The Molecular Signatures Database was used to analyse the functional enrichment analysis. Both conditions showed similarities in cell types in the microenvironment, particularly CD4+ and CD8+ Tem cells, NKT cells, Th2 cells, basophils, and eosinophils. With regards to the regulation of cellular senescence and DNA integrity/damage checkpoint, which are commonly enriched pathways, 21 genes were down-regulated and directly related to DNA repair. Compared to the endometriosis samples, some chlamydial endometritis samples presented a lack of enriched immune pathways. Our results suggest that both conditions show similar distributions of microenvironment cell types, the downregulation of genes involved in DNA repair and cell cycle control, and pathways involved in immune response evasion.

Genética na Escola, May 20, 2009

Cancer Detection and Prevention, 2009

Fertility and Sterility, 2008

Journal of health informatics, Oct 19, 2015

Revista Brasileira de Ginecologia e Obstetrícia, Oct 1, 2020

Scientific Reports, Mar 8, 2021

Scientific Reports, Jan 15, 2020

Annals of Translational Medicine, Oct 1, 2020

Rosa-e-Silva et al. Central sensitization and endometriosis

Revista Brasileira de Ginecologia e Obstetrícia, Nov 1, 2018

Reproductive Sciences, Jun 15, 2020

Revista Brasileira de Ginecologia e Obstetrícia, May 24, 2016

Fertility and Sterility, Sep 1, 2017

Brazilian Journal of Medical and Biological Research, 2022

Reproductive Biomedicine Online, May 1, 2021

Scientific Reports, Apr 6, 2022

Journal of Reproductive Immunology, Jun 1, 2021