Characteristics associated with Lactobacillus-depleted vaginal microbiota in women with different sexual behavior Mariana Alice de Oliveira Ignacio, Camila Marconi, Lucas Tadeu Bidinotto, Eduardo Balsanelli, Rafael Belleti, Márcia Guimarães da Silva, Marli Teresinha Cassamassimo Duarte Scientific Reports, 2026 The aim of this study was to compare the vaginal microbiome of women with different sexual behaviors and to examine characteristics associated with Lactobacillus-deprived community state type IV. In this prospective study performed in a community-based population in a city of approximately 150,000 inhabitants in Southeast region of Brazil, vaginal swabs were obtained of 109 participants, including women who only had sex with women (n = 54) and women who only had sex with man (n = 55). Sociodemographic data, sexual and intimated hygiene practices of the participants were also assessed. Vaginal microbiota was assessed by sequencing the hypervariable regions V3 and V4 of 16 S ribosomal nucleic acid gene (Illumina 250 PE). Alpha diversity (Shannon index) was compared between the two groups by the Mann-Whitney test. Logistic regression analyses were performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between covariates with the Lactobacillus-deprived community state type IV. Results showed that overall distribution of vaginal CSTs did not differ between the two study groups (P = 0.19). However, alpha diversity was increased in women that only have sex with women (P = 0.0018). Lactobacillus-deprived community state type IV was associated with lower income (OR: 4.15, 95% CI: 1.04–16.46) and use of sex toys (OR: 3.97, 95% CI: 1.09–14.45). In conclusion, nearly one-third of women that only have sex with women had a sub-optimal vaginal microbiome and show evidence of sex transmissibility of CST-IV associated organisms.
Integrating the secretome and interactome to identify novel biomarkers and therapeutic targets in colorectal cancer Gabriel Henrique Caxali, Mirian Carolini Esgoti Aal, Catherine Wesselka Garcia Osvaldo, Jakeline Santos Oliveira, Lucas Tadeu Bidinotto, Robson Francisco Carvalho, Flávia Karina Delella Cell Communication and Signaling, 2025 Background Cancer is extensively studied, yet its origins and progression remain unclear. A key question is why tumors of the same type vary in aggressiveness and treatment response. In colorectal cancer (CRC), the third most common cancer, this variability led to the identification of molecular subtypes (CMS). However, the tumor microenvironment remains poorly understood and may be crucial for understanding carcinogenesis and drug resistance. A promising approach is analyzing cell interactions through ligand-receptor expression. This study used bioinformatics to examine CRC in different anatomical locations, identify diagnostic and prognostic biomarkers, and propose targeted drugs. Methods Expression data were obtained from the TCGA-COAD database. All samples were filtered based on the tumor’s region of origin and purity. RNA-seq expression analysis was then conducted to assess molecular differences according to tumor location and purity, identifying region-specific ligands and receptors using the secretome list as a reference. Once these differences were identified, an interactome was constructed to depict cell interactions within the tumor microenvironment. The most relevant genes were then evaluated for their prognostic potential through survival analysis, and their susceptibility to pharmacological modulation was assessed to identify potential new drug candidates for CRC treatment. Results The integration of secretome data and the construction of the interactome proved to be a valuable approach for detecting novel biomarkers specific to right- and left-sided CRC. Through this approach, FGFR4, FLT1, and WNT5A were identified as key biomarkers involved in tumor carcinogenesis, modulating distinct processes in each region, such as fibroblast recruitment and cell division. Based on these biomarkers, Dovitinib and Nintedanib were predicted as potential therapeutic agents, as they target multiple identified markers. Conclusion This study highlights FGFR4, FLT1, and WNT5A as key diagnostic and therapeutic biomarkers for CRC, with their relevance varying based on the tumor’s site of origin. Leveraging these findings, we propose Dovitinib and Nintedanib as promising targeted therapies for CRC. These insights can enhance current treatment strategies and pave the way for future in vivo and in vitro studies, driving progress in CRC research and therapy.
Low EGFL7 expression is associated with high lymph node spread and invasion of lymphatic vessels in colorectal cancer Cristiane de Oliveira, Sandra Fátima Fernandes Martins, Paola Gyuliane Gonçalves, Gabriel Augusto Limone, Adhemar Longatto-Filho, Rui Manuel Reis, Lucas Tadeu Bidinotto Scientific Reports, 2023 Studies indicate EGFL7 as an important gene in controlling angiogenesis and cancer growth, including in colorectal cancer (CRC). Anti-EGFL7 agents are being explored, yet without promising results. Therefore, the role of EGFL7 in CRC carcinogenesis should be investigated. This study aimed to evaluate the prognostic value of EGFL7 expression in CRC and the signaling pathways influenced by this gene. EGFL7 expression was evaluated through immunohistochemistry in 463 patients diagnosed with CRC and further associated with clinicopathological data, angiogenesis markers and survival. In silico analyzes were performed with colon adenocarcinoma data from The Cancer Genome Atlas. Analysis of enriched gene ontology and pathways were performed using the differentially expressed genes. 77.7% of patients presented low EGFL7 expression, which was associated with higher lymph node spread and invasion of lymphatic vessels, with no impact on survival. Additionally, low EGFL7 expression was associated with high VEGFR2 expression. Finally, we found in silico that EGFL7 expression was associated with cell growth, angiogenesis, and important pathways such as VEGF, Rap-1, MAPK and PI3K/Akt. Expression of EGFL7 in tumor cells may be associated with important pathways that can alter functions related to tumor invasive processes, preventing recurrence and metastatic process.
Patient’s safety and satisfaction on same day discharge after robotic and laparoscopic radical prostatectomy versus discharge after 24 or 48 h: a longitudinal randomized prospective study Eliney Ferreira Faria, Roberto Dias Machado, Rodrigo José Costa Gualberto, Marina Assunção Valadares Milani, Lucas Tadeu Bidinotto, Marcos Tobias Machado, Ricardo dos Reis, Daniele Natália Pacharone Bertolini Bidinotto BMC Urology, 2023 Background There is a tendency of prompted global health systems to reduce the length of hospital stay without compromising patient safety or satisfaction. We evaluated the safety and viability of early discharge in patients undergoing minimally invasive radical prostatectomy (MIRP), as well as patient satisfaction with this strategy. Methods This longitudinal prospective study included 72 patients who underwent MIRP for prostate cancer. Three groups were performed according to the day of hospital discharge following surgery: same day (G1), first day after (G2), and second day after (G3). Satisfaction, adverse events, and readmission were analyzed for each group. Associations between clinicopathologic variables and same-day discharge were analyzed by comparing data between G1 patients who did and did not achieve same-day discharge. Results 16.7% of patients were not discharged according to randomization (10 randomized to G1). 80% of G1 patients who did not achieve same-day discharge had Gleason scores of 3 + 4 or 4 + 3, which were observed in 35.7% of patients discharged on the same day (P < 0.05). Average prostate weight was significantly lower in patients who achieved same-day discharge than in those who did not (P < 0.01). Univariable logistic regression points to Gleason scores of 3 + 4 or 4 + 3 as the main factors associated with unsuccessful same-day discharge (P < 0.05). There were no significant differences in satisfaction scores. Conclusions Same-day discharge was both safe and feasible and does not appear to affect satisfaction in a subset of patients with prostate cancer. Surgeons should consider the Gleason score when determining whether same-day discharge is appropriate.
Role of EGFL7 in human cancers: A review Cristiane de Oliveira, Paola Gyuliane Gonçalves, Lucas Tadeu Bidinotto Journal of Cellular Physiology, 2023 EGFL7 is a proangiogenic factor. It has been widely described with having a vital role in tubulogenesis and regulation of angiogenesis, mainly during embryogenesis and organogenesis. It has been mainly associated with NOTCH pathway, but there are reports showing association with MAPK and integrin pathways. Given its association with angiogenesis and these other pathways, there are several studies associating EGFL7 with carcinogenesis. In fact, most of the studies have pointed to EGFL7 as an oncogene, and some of them suggest EGFL7 expression as a possible biomarker of prognosis or use for a patient's follow-up. Here, we review the molecular pathways which EGFL7 is associated and highlight several studies describing the role of EGFL7 in tumorigenesis, separated by tumor type. Besides its role on angiogenesis, EGFL7 may act in other pathways as oncogene, which makes it a possible biomarker and a candidate to targeted therapy.
Maternal dietary zinc status alters offspring female mammary gland development and response to acute 7,12-dimethylbenzanthracene insult Flávia R. M. da Silva, Joyce R. Zapaterini, Tony F. Grassi, Lucas T. Bidinotto, Ana Angélica H. Fernandes, Luis F. Barbisan Biotechnic and Histochemistry, 2023 We evaluated the effects of prenatal and postnatal dietary zinc (Zn) deficiency or supplementation on mammary gland morphology and on acute response to 7,12-dimethylbenzanthracene (DMBA) in pubertal female rats. On gestational day 10 (GD 10), rat dams were allocated randomly into three experimental groups of 10: a Zn-adequate diet group (ZnA) fed 35 mg Zn/kg chow, a Zn-deficient diet group (ZnD) fed 3 mg ZN/kg chow and a Zn-supplemented diet group (ZnS) fed 180 mg Zn/kg chow. After weaning, female offspring were fed the same diet as their dams until postnatal day 53 (PND 53). All animals received a single 50 mg/kg dose of DMBA on PND 51 and were euthanized on PND 53. Female ZnD offspring exhibited significantly less weight gain compared to the ZnA group and reduced mammary gland development compared to the ZnD and ZnA groups. By PND 53, the Ki-67 labeling index in mammary gland epithelial cells was significantly greater for the ZnS group than for the ZnA and ZnD groups. Apoptosis and ER-α indices did not differ among groups. The ZnD group exhibited significantly increased lipid hydroperoxide (LOOH) levels and decreased catalase and glutathione peroxidase (GSH-Px) activity compared to the ZnA and ZnS groups. The ZnS group exhibited significantly reduced superoxide dismutase (SOD) activity compared to the ZnA and ZnS groups. We observed atypical ductal hyperplasia in the mammary gland of female ZnS group offspring compared to the ZnA and ZnD groups and decreased expression of the Api5 and Ercc1 genes related to apoptosis inhibition and DNA damage repair, respectively. Both the Zn-deficient and Zn-supplemented diet exerted adverse effects on offspring mammary gland morphology and acute response to DMBA.
Significance of Chr9p22.1-p21.3 Deletion in Cancer Development: A Pan-cancer In Silico Analysis PAOLA G. GONÇALVES, RUI M. REIS, LUCAS T. BIDINOTTO Anticancer Research, 2022 Background/Aim: Deletions in chr9p22.1-21.3 locus have been related to the development of several types of cancer, mainly due to the presence of CDKN2A and CDKN2B genes. However, there are several other genes in the region with potential importance in tumorigenesis. We, therefore, aimed to analyze in silico the potential prognostic significance of alterations in copy number and expression of genes present in the chr9p22.1-21.3 locus in 33 TCGA datasets (approximately 10,000 patients). Materials and Methods: We analyzed which of the 27 genes are expressed in the datasets. Additionally, we associated the deletion of the locus with survival (log rank analysis) and hazard ratio (HR) (univariate cox regression). Finally, we performed univariate, multivariate, and overall survival analyses in 13 datasets considering the expression of 10 genes present in the locus. Results: We identified 10 genes of the chr9p22.1-21.3 locus expressed in the datasets (MLLT3, FOCAD, PTPLAD2, KLHL9, IFNE, MTAP, CDKN2A, CDKN2B, DMRTA1 and ELAVL2). Moreover, we found that deletion in at least 1 of these genes was associated with poor survival and increased HR in 13 datasets: adrenocortical carcinoma (ACC), glioblastoma (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), low-grade glioma (LGG), lung adenocarcinoma (LUAD), mesothelioma (MESO), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC). Finally, we found an association of survival/HR and altered expression of MLLT3 in the MESO dataset, of FOCAD in the READ dataset, of PTPLAD2 in the KIRP dataset, of KLHL9 in the LGG and UCEC datasets, of IFNE in ACC, GBM, KIRC and LUAD datasets, of MTAP in LGG, LUAD and MESO datasets, of CDKN2A in the HNSC, KIRC and MESO datasets, of CDKN2B in the LGG and READ datasets, of DMRTA1 in SARC datasets and of ELAVL2 in the LGG dataset (p<0.01 for all associations). Conclusion: Besides CDKN2A and CDKN2B, numerous other genes are possibly related to cancer development, requiring further investigation.
Alpha2beta1 Integrin Polymorphism in Diffuse Astrocytoma Patients Silvia A. Teixeira, Regislaine V. Burim, Mariano S. Viapiano, Lucas T. Bidinotto, Suely K. Nagashi Marie, Suzana M. Fleury Malheiros, Sueli M. Oba-Shinjo, Augusto F. Andrade, Carlos G. Carlotti Frontiers in Oncology, 2022 Integrins are heterodimeric transmembrane glycoproteins resulting from the non-covalent association of an α and β chain. The major integrin receptor for collagen/laminin, α2β1 is expressed on a wide variety of cell types and plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Integrin-triggered signaling pathways promote the invasion and survival of glioma cells by modifying the brain microenvironment. In this study, we investigated the association of a specific genetic polymorphism of integrin α2β1 with the incidence of diffusely infiltrating astrocytoma and the progression of these tumors. Single-nucleotide polymorphism in intron 7 of the integrin ITGA2 gene was examined in 158 patients and 162 controls using polymerase chain reaction and restriction enzyme analysis. The ITGA2 genotype +/+ (with a BglII restriction site in both alleles) exhibited higher frequency in grade II astrocytoma compared to control (P = 0.02) whereas the genotype -/- (lacking the BglII site) correlated with the poorest survival rate (P = 0.04). In addition, in silico analyses of ITGA2 expression from low-grade gliomas (LGG, n = 515) and glioblastomas (GBM, n = 159) indicated that the higher expression of ITGA2 in LGG was associated with poor overall survival (P &lt; 0.0001). However, the distribution of integrin ITGA2 BglII genotypes (+/+, +/-, -/-) was not significantly different between astrocytoma subgroups III and IV (P = 0.65, 0.24 and 0.33; 0.29, 0.48, 0.25, respectively) compared to control. These results suggest a narrow association between the presence of this SNP and indicate that further studies with larger samples are warranted to analyze the relation between tumor grade and overall survival, highlighting the importance of determining these polymorphisms for prognosis of astrocytomas.
EGFL7 expression profile in IDH-wildtype glioblastomas is associated with poor patient outcome Bruno Henrique Bressan da Costa, Aline Paixão Becker, Luciano Neder, Paola Gyuliane Gonçalves, Cristiane de Oliveira, Allan Dias Polverini, Carlos Afonso Clara, Gustavo Ramos Teixeira, Rui Manuel Reis, Lucas Tadeu Bidinotto Journal of Pathology and Translational Medicine, 2022 Background: Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches.Methods: Spearman’s correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients’ samples, and was associated with clinicopathological data and overall survival.Results: In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase–Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041).Conclusions: This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.
Maternal Low-Protein Diet Deregulates DNA Repair and DNA Replication Pathways in Female Offspring Mammary Gland Leading to Increased Chemically Induced Rat Carcinogenesis in Adulthood Joyce R. Zapaterini, Antonio R. B. Fonseca, Lucas T. Bidinotto, Ketlin T. Colombelli, André L. D. Rossi, Laura Kass, Luis A. Justulin, Luis F. Barbisan Frontiers in Cell and Developmental Biology, 2022 Studies have shown that maternal malnutrition, especially a low-protein diet (LPD), plays a key role in the developmental mechanisms underlying mammary cancer programming in female offspring. However, the molecular pathways associated with this higher susceptibility are still poorly understood. Thus, this study investigated the adverse effects of gestational and lactational low protein intake on gene expression of key pathways involved in mammary tumor initiation after a single dose of N-methyl-N-nitrosourea (MNU) in female offspring rats. Pregnant Sprague–Dawley rats were fed a normal-protein diet (NPD) (17% protein) or LPD (6% protein) from gestational day 1 to postnatal day (PND) 21. After weaning (PND 21), female offspring (n = 5, each diet) were euthanized for histological analysis or received NPD (n = 56 each diet). At PND 28 or 35, female offspring received a single dose of MNU (25 mg/kg body weight) (n = 28 each diet/timepoint). After 24 h, some females (n = 10 each diet/timepoint) were euthanized for histological, immunohistochemical, and molecular analyses at PDN 29 or 36. The remaining animals (n = 18 each diet/timepoint) were euthanized when tumors reached ≥2 cm or at PND 250. Besides the mammary gland development delay observed in LPD 21 and 28 groups, the gene expression profile demonstrated that maternal LPD deregulated 21 genes related to DNA repair and DNA replication pathways in the mammary gland of LPD 35 group after MNU. We further confirmed an increased γ-H2AX (DNA damage biomarker) and in ER-α immunoreactivity in mammary epithelial cells in the LPD group at PND 36. Furthermore, these early postnatal events were followed by significantly higher mammary carcinogenesis susceptibility in offspring at adulthood. Thus, the results indicate that maternal LPD influenced the programming of chemically induced mammary carcinogenesis in female offspring through increase in DNA damage and deregulation of DNA repair and DNA replication pathways. Also, Cidea upregulation gene in the LPD 35 group may suggest that maternal LPD could deregulate genes possibly leading to increased risk of mammary cancer development and/or poor prognosis. These findings increase the body of evidence of early-transcriptional mammary gland changes influenced by maternal LPD, resulting in differential response to breast tumor initiation and susceptibility and may raise discussions about lifelong prevention of breast cancer risk.
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, Sara Temelso, Sergey Popov, Valeria Molinari, Pichai Raman, Angela J. Waanders, Harry J. Han, Saumya Gupta, Lynley Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry C. Mandeville, Leslie R. Bridges, Andrew J. Martin, Safa Al-Sarraj, Christopher Chandler, Ho-Keung Ng, Xingang Li, Kun Mu, Saoussen Trabelsi, Dorra H’mida-Ben Brahim, Alexei N. Kisljakov, Dmitry M. Konovalov, Andrew S. Moore, Angel Montero Carcaboso, Mariona Sunol, Carmen de Torres, Ofelia Cruz, Jaume Mora, Ludmila I. Shats, João N. Stavale, Lucas T. Bidinotto, Rui M. Reis, Natacha Entz-Werle, Michael Farrell, Jane Cryan, Darach Crimmins, John Caird, Jane Pears, Michelle Monje, Marie-Anne Debily, David Castel, Jacques Grill, Cynthia Hawkins, Hamid Nikbakht, Nada Jabado, Suzanne J. Baker, Stefan M. Pfister, David T.W. Jones, Maryam Fouladi, André O. von Bueren, Michael Baudis, Adam Resnick, Chris Jones Cancer Cell, 2017
Low mutation percentage of KRAS and BRAF genes in Brazilian anal tumors Lucas Tadeu Bidinotto, Carlos A R Véo, Edgar Aleman Loaiza, Alessandra Paulino Santos De França, Adriana Tarla Lorenzi, Luciana Albina Reis Rosa, Cristina Mendes De Oliveira, José Eduardo Levi, Cristovam Scapulatempo-Neto, Adhemar Longatto-Filho, Rui Manuel Reis Molecular Medicine Reports, 2016
Copy number profiling of Brazilian astrocytomas Lucas Tadeu Bidinotto, Raul Torrieri, Alan Mackay, Gisele Caravina Almeida, Marta Viana-Pereira, Adriana Cruvinel-Carloni, Maria Luisa Spina, Nathalia Cristina Campanella, Weder Pereira de Menezes, Carlos Afonso Clara, Aline Paixão Becker, Chris Jones, Rui Manuel Reis G3 Genes Genomes Genetics, 2016
Molecular profiling of a rare rosette-forming glioneuronal tumor arising in the spinal cord Lucas Tadeu Bidinotto, Cristovam Scapulatempo-Neto, Alan Mackay, Gisele Caravina de Almeida, Bernd Walter Scheithauer, Gustavo Noriz Berardinelli, Raul Torrieri, Carlos Afonso Clara, Leonir Terezinha Feltrin, Marta Viana-Pereira, Marileila Varella-Garcia, Chris Jones, Rui Manuel Reis Plos One, 2015
