ALOISIO SOUZA FELIPE DA SILVA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
SVANPA-62, Hospital Universitário
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
SVANPA-62, Hospital Universitário
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
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- TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors(2021) OLIVEIRA, Erica Aparecida de; CHAUHAN, Jagat; SILVA, Julia Rezende da; CARVALHO, Larissa Anastacio da Costa; DIAS, Diogo; CARVALHO, Danielle Goncalves de; WATANABE, Luis Roberto Masao; REBECCA, Vito W.; MILLS, Gordon; LU, Yiling; SILVA, Aloisio Souza Felipe da; CONSOLARO, Marcia Edilaine Lopes; HERLYN, Meenhard; POSSIK, Patricia A.; GODING, Colin R.; MARIA-ENGLER, Silvya StuchiIn melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance.
- Tumour-derived transforming growth factor-beta signalling contributes to fibrosis in patients with cancer cachexia(2019) LIMA, Joanna D. C. C.; SIMOES, Estefania; CASTRO, Gabriela de; MORAIS, Mychel Raony P. T.; MATOS-NETO, Emidio M. de; ALVES, Michele J.; I, Nelson Pinto; FIGUEREDO, Raquel G.; ZORN, Telma M. T.; FELIPE-SILVA, Aloisio S.; TOKESHI, Flavio; OTOCH, Jose P.; ALCANTARA, Paulo; CABRAL, Fernanda J.; FERRO, Emer S.; LAVIANO, Alessandro; SEELAENDER, MariliaBackground Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. Results Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-alpha, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of alpha-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-beta 1, TGF-beta 2, and TGF-beta 3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1 alpha mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005). Conclusions Our results demonstrate TGF-beta pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-beta-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.
- DNA methylation mediates a randomized controlled trial home-visiting intervention during pregnancy and the Bayley infant's cognitive scores at 12 months of age(2022) EUCLYDES, Veronica L. V.; GASTALDI, Vinicius D.; FELTRIN, Arthur S.; HOFFMAN, Daniel J.; GOUVEIA, Gisele; COGO, Hugo; FELIPE-SILVA, Aloisio; VIEIRA, Rossana P.; MIGUEL, Euripedes C.; V, Guilherme Polanczyk; CHIESA, Anna; FRACOLLI, Lislaine; MATIJASEVICH, Alicia; FERRARO, Alexandre; ARGEU, Adriana; MASCHIETTO, Mariana; BRENTANI, Helena P.The crosstalk between maternal stress exposure and fetal development may be mediated by epigenetic mechanisms, including DNA methylation (DNAm). To address this matter, we collect 32 cord blood samples from low-income Brazilian pregnant adolescents participants of a pilot randomized clinical intervention study (ClinicalTrials.gov, Identifier: NCT02807818). We hypothesized that the association between the intervention and infant neurodevelopmental outcomes at 12 months of age would be mediated by DNAm. First, we searched genome methylation differences between cases and controls using different approaches, as well as differences in age acceleration (AA), represented by the difference of methylation age and birth age. According to an adjusted p-value <= 0.05 we identified 3090 differentially methylated positions- CpG sites (DMPs), 21 differentially methylated regions (DMRs) and one comethylated module weakly preserved between groups. The intervention group presented a smaller AA compared to the control group (p = 0.025). A logistic regression controlled by sex and with gestational age indicated a coefficient of -0.35 towards intervention group (p = 0.016) considering AA. A higher cognitive domain score from Bayley III scale was observed in the intervention group at 12 months of age. Then, we performed a potential causal mediation analysis selecting only DMPs highly associated with the cognitive domain (adj. R (2) > 0.4), DMRs and CpGs of hub genes from the weakly preserved comethylated module and epigenetic clock as raw values. DMPs in STXBP6, and PF4 DMR, mediated the association between the maternal intervention and the cognitive domain at 12 months of age. In conclusion, DNAm in different sites and regions mediated the association between intervention and cognitive outcome.
- Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa(2019) COSTA, Raquel G. F.; CARO, Paula L.; MATOS-NETO, Emidio M. de; LIMA, Joanna D. C. C.; RADLOFF, Katrin; ALVES, Michele J.; CAMARGO, Rodolfo G.; PESSOA, Ana Flavia M.; SIMOES, Estefania; GAMA, Patricia; CARA, Denise C.; SILVA, Aloisio S. F. da; PEREIRA, Welbert O.; MAXIMIANO, Linda F.; ALCANTARA, Paulo S. M. de; OTOCH, Jose P.; TRINCHIERI, Giorgio; LAVIANO, Alessandro; MUSCARITOLI, Maurizio; SEELAENDER, MariliaBackground Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia-related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. Methods Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex (R) xMAP) analyses. Results There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL-6) and IL-8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL-7, IL-13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte-colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL-13 and transforming growth factor beta 3. Conclusions The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.