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Papers by Caroline Brunetto de Farias

Oncology, 2018

Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchyma... more Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. Methods: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. Results: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ...

NeuroMolecular Medicine, 2022

Changes in epigenetic programming are associated with cancer development during childhood. Compon... more Changes in epigenetic programming are associated with cancer development during childhood. Components of the epigenetic machinery involved in normal embryonic development and hijacked by pediatric cancers include enzymes mediating post-translational modifications of DNA and histones that regulate chromatin structure, such as histone methyltransferases (HMTs). Overexpression of the HMT G9a (euchromatic histone lysine methyltransferase 2, EHMT2) has been described in several cancer types. Medulloblastoma (MB), the main type of malignant brain tumor afflicting children, is currently classified into four molecular subgroups. Here, we show that expression level of the G9a/Ehmt2 gene is higher in MB tumors belonging to the SHH, Group 3, and Group 4 subgroups, compared to Wnt tumors. Remarkably, high G9a expression was significantly associated with shorter overall survival in MB patients. We also present evidence that G9a inhibition dose-dependently reduces MB cell viability. Our findings suggest that higher transcription of G9a may be a predictor of poor prognosis in patients with SHH MB, and that inhibiting G9a activity can display antitumor effects in MB.

Resumo: A família de tumores Sarcoma de Ewing compreende neoplasias com características neuroecto... more Resumo: A família de tumores Sarcoma de Ewing compreende neoplasias com características neuroectodérmicas, na qual tumores menos diferenciados são denominados Sarcoma de Ewing (SE). O diagnóstico é mais frequente na faixa etária até 10 anos e o índice de cura varia de 50-70%. O fator de crescimento epidérmico (EGF) e seu receptor (EGFR) estão amplamente envolvidos no processo de tumorigênese e metástase em câncer de cabeça e pescoço, pulmão e colorretal. As linhagens SK-ES-Palavras-chaves:

Tumores pediátricos representam a primeira causa de óbito por doença em pacientes infanto-juvenis... more Tumores pediátricos representam a primeira causa de óbito por doença em pacientes infanto-juvenis e, dentre as neoplasias, a Leucemia Linfocítica Aguda (LLA) é a mais comum em pacientes nessa faixa etária. Ainda que os protocolos empregados atualmente apresentem considerável taxa de cura, cerca de 30% dos pacientes são refratários ao tratamento e cerca de 15% dos pacientes que respondem aos protocolos apresentam recidiva tardia. Na busca por moléculas preditoras de resposta, por possíveis marcadores terapêuticos e pela melhor compreensão da doença, investigamos o papel do receptor p75NTR em LLA. Esse receptor pertence à família das neurotrofinas, uma família de proteínas envolvidas na sobrevivência, crescimento e diferenciação celulares, e já foi investigado em diversas neoplasias. O objetivo do estudo foi avaliar a expressão de p75NTR em amostras de medula óssea de 18 pacientes pediátricos diagnosticados com LLA, em tratamento no Hospital de Clínicas de Porto Alegre, em dois momentos: no momento do diagnóstico e ao final do período de indução da quimioterapia. Após a extração de RNA das amostras, foi realizada a Reação em Cadeia da Polimerase com Transcriptase Reversa, seguido por migração eletroforética em gel de agarose. Para as análises foi utilizado o Teste de Mann-Whitney. Foi detectada expressão de p75NTR em todas as amostras analisadas; não foram encontradas diferenças estatisticamente significativas quanto ao risco, à idade ao diagnóstico, à doença residual mínima e aos momentos avaliados. Esse estudo foi o primeiro a identificar a expressão de p75NTR em 100% das amostras analisadas, com diversos subtipos de LLA. A ampliação da amostra e o período maior de acompanhamento dos pacientes se faz necessário para melhor investigação do papel do receptor p75NTR em LLA. Palavraschaves: LLA, P75NTR, neurotrofinas brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Lume 5.8

Universidade Federal do Rio Grande do SulCiências Básicas da SaúdeMedicinaDepositad

68 Clin Biomed Res 2016; 36 (Supl.) P 1771 HDAC activity inhibition abolishes pluripotency, proli... more 68 Clin Biomed Res 2016; 36 (Supl.) P 1771 HDAC activity inhibition abolishes pluripotency, proliferation and survival pathways leading Ewing sarcoma cells to a differentiated state Bárbara Kunzler Souza; Patrícia Luciana da Costa Lopez; Pâmela Rossi Menegotto; Igor Araujo Vieira; Nathalia Kersting; Ana Lucia Abujamra; Lauro José Gregianin; Algemir Lunardi Brunetto; Caroline Brunetto de Farias; Rafael Roesler HCPA

Molecular and Cellular Biochemistry, 2021

The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activi... more The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activities in cell function and embryonic development, including driving epithelial-mesenchymal transition. Several aspects of ZEB1 function can be regulated by its functional interactions with noncoding RNA types, namely microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Increasing evidence indicates that ZEB1 importantly influences cancer initiation, tumor progression, metastasis, and resistance to treatment. Cancer is the main disease-related cause of death in children and adolescents. Although the role of ZEB1 in pediatric cancer is still poorly understood, emerging findings have shown that it is expressed and regulates childhood solid tumors including osteosarcoma, retinoblastoma, neuroblastoma, and central nervous system tumors. Here, we review the evidence supporting a role for ZEB1, and its interplays with miRNAs and lncRNAs, in pediatric cancers.

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precurso... more Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markersBMI1andCD133are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression ofBMI1andCD133and increased acetylation in human MB cells. Enrichment analysis of genes associated withCD133orBMI1expression showed mitogen-activated protein ...

The American Journal of Pathology, 1999

This study advances our understanding of the effects of task design on task complexity and second... more This study advances our understanding of the effects of task design on task complexity and second language (L2) performance. The research reported here focused on examining the impact of degree of intentional reasoning, operationalised at two levels of task content and task instructions, on language performance and perceptions of task difficulty. Using a mixed-methods approach, the study drew on quantitative and qualitative data collected from 20 Jordanian L2 learners performing video-based oral narratives and completing retrospective questionnaires. The results suggest that intentional reasoning has a noticeable effect in generating more syntactically complex and accurate language, and also influences perceptions of task difficulty. However, a higher intentional reasoning demand is associated with less lexical diversity and inconsistent patterns of fluency. An important finding of the study is that the link between the cognitive demands and the language used to convey intentional reasoning should be carefully considered when selecting analytic measures of complexity and accuracy. The implications of these findings for two most widely-used models of task complexity, i.e. Cognition Hypothesis (Robinson, 2007) and Limited Capacity model (Skehan, 2009) are discussed.

Molecular Neurobiology, Mar 21, 2013

Increasing evidence suggests that alterations in epigenetic mechanisms regulating chromatin state... more Increasing evidence suggests that alterations in epigenetic mechanisms regulating chromatin state play a role in the pathogenesis of medulloblastoma (MB), the most common malignant brain tumor of childhood. Histone deacetylase (HDAC) inhibitors, which increase chromatin relaxation, have been shown to display anticancer activities. Here we show that the HDAC inhibitor sodium butyrate (NaB) markedly increases cell death and reduces colony formation in human MB cell lines. In addition, NaB increased the mRNA expression of Gria2, a neuronal differentiation marker, in D283 and DAOY cells and reduced the number of neurospheres in D283 cell cultures. Finally, NaB reduced the viability of D283 cells when combined with etoposide. These data show that NaB displays pronounced inhibitory effects on the survival of human MB cells and suggest that NaB might potentiate the effects of etoposide. In addition, our study suggests that HDAC inhibition might promote the neuronal differentiation of MB cells and provides the first evidence that an HDAC inhibitor might suppress the expansion or survival of MB cancer stem cells.

Oncology, 2018

Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchyma... more Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. Methods: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. Results: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ...

NeuroMolecular Medicine, 2022

Changes in epigenetic programming are associated with cancer development during childhood. Compon... more Changes in epigenetic programming are associated with cancer development during childhood. Components of the epigenetic machinery involved in normal embryonic development and hijacked by pediatric cancers include enzymes mediating post-translational modifications of DNA and histones that regulate chromatin structure, such as histone methyltransferases (HMTs). Overexpression of the HMT G9a (euchromatic histone lysine methyltransferase 2, EHMT2) has been described in several cancer types. Medulloblastoma (MB), the main type of malignant brain tumor afflicting children, is currently classified into four molecular subgroups. Here, we show that expression level of the G9a/Ehmt2 gene is higher in MB tumors belonging to the SHH, Group 3, and Group 4 subgroups, compared to Wnt tumors. Remarkably, high G9a expression was significantly associated with shorter overall survival in MB patients. We also present evidence that G9a inhibition dose-dependently reduces MB cell viability. Our findings suggest that higher transcription of G9a may be a predictor of poor prognosis in patients with SHH MB, and that inhibiting G9a activity can display antitumor effects in MB.

Resumo: A família de tumores Sarcoma de Ewing compreende neoplasias com características neuroecto... more Resumo: A família de tumores Sarcoma de Ewing compreende neoplasias com características neuroectodérmicas, na qual tumores menos diferenciados são denominados Sarcoma de Ewing (SE). O diagnóstico é mais frequente na faixa etária até 10 anos e o índice de cura varia de 50-70%. O fator de crescimento epidérmico (EGF) e seu receptor (EGFR) estão amplamente envolvidos no processo de tumorigênese e metástase em câncer de cabeça e pescoço, pulmão e colorretal. As linhagens SK-ES-Palavras-chaves:

Tumores pediátricos representam a primeira causa de óbito por doença em pacientes infanto-juvenis... more Tumores pediátricos representam a primeira causa de óbito por doença em pacientes infanto-juvenis e, dentre as neoplasias, a Leucemia Linfocítica Aguda (LLA) é a mais comum em pacientes nessa faixa etária. Ainda que os protocolos empregados atualmente apresentem considerável taxa de cura, cerca de 30% dos pacientes são refratários ao tratamento e cerca de 15% dos pacientes que respondem aos protocolos apresentam recidiva tardia. Na busca por moléculas preditoras de resposta, por possíveis marcadores terapêuticos e pela melhor compreensão da doença, investigamos o papel do receptor p75NTR em LLA. Esse receptor pertence à família das neurotrofinas, uma família de proteínas envolvidas na sobrevivência, crescimento e diferenciação celulares, e já foi investigado em diversas neoplasias. O objetivo do estudo foi avaliar a expressão de p75NTR em amostras de medula óssea de 18 pacientes pediátricos diagnosticados com LLA, em tratamento no Hospital de Clínicas de Porto Alegre, em dois momentos: no momento do diagnóstico e ao final do período de indução da quimioterapia. Após a extração de RNA das amostras, foi realizada a Reação em Cadeia da Polimerase com Transcriptase Reversa, seguido por migração eletroforética em gel de agarose. Para as análises foi utilizado o Teste de Mann-Whitney. Foi detectada expressão de p75NTR em todas as amostras analisadas; não foram encontradas diferenças estatisticamente significativas quanto ao risco, à idade ao diagnóstico, à doença residual mínima e aos momentos avaliados. Esse estudo foi o primeiro a identificar a expressão de p75NTR em 100% das amostras analisadas, com diversos subtipos de LLA. A ampliação da amostra e o período maior de acompanhamento dos pacientes se faz necessário para melhor investigação do papel do receptor p75NTR em LLA. Palavraschaves: LLA, P75NTR, neurotrofinas brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Lume 5.8

Universidade Federal do Rio Grande do SulCiências Básicas da SaúdeMedicinaDepositad

68 Clin Biomed Res 2016; 36 (Supl.) P 1771 HDAC activity inhibition abolishes pluripotency, proli... more 68 Clin Biomed Res 2016; 36 (Supl.) P 1771 HDAC activity inhibition abolishes pluripotency, proliferation and survival pathways leading Ewing sarcoma cells to a differentiated state Bárbara Kunzler Souza; Patrícia Luciana da Costa Lopez; Pâmela Rossi Menegotto; Igor Araujo Vieira; Nathalia Kersting; Ana Lucia Abujamra; Lauro José Gregianin; Algemir Lunardi Brunetto; Caroline Brunetto de Farias; Rafael Roesler HCPA

Molecular and Cellular Biochemistry, 2021

The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activi... more The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activities in cell function and embryonic development, including driving epithelial-mesenchymal transition. Several aspects of ZEB1 function can be regulated by its functional interactions with noncoding RNA types, namely microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Increasing evidence indicates that ZEB1 importantly influences cancer initiation, tumor progression, metastasis, and resistance to treatment. Cancer is the main disease-related cause of death in children and adolescents. Although the role of ZEB1 in pediatric cancer is still poorly understood, emerging findings have shown that it is expressed and regulates childhood solid tumors including osteosarcoma, retinoblastoma, neuroblastoma, and central nervous system tumors. Here, we review the evidence supporting a role for ZEB1, and its interplays with miRNAs and lncRNAs, in pediatric cancers.

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precurso... more Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markersBMI1andCD133are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression ofBMI1andCD133and increased acetylation in human MB cells. Enrichment analysis of genes associated withCD133orBMI1expression showed mitogen-activated protein ...

The American Journal of Pathology, 1999

This study advances our understanding of the effects of task design on task complexity and second... more This study advances our understanding of the effects of task design on task complexity and second language (L2) performance. The research reported here focused on examining the impact of degree of intentional reasoning, operationalised at two levels of task content and task instructions, on language performance and perceptions of task difficulty. Using a mixed-methods approach, the study drew on quantitative and qualitative data collected from 20 Jordanian L2 learners performing video-based oral narratives and completing retrospective questionnaires. The results suggest that intentional reasoning has a noticeable effect in generating more syntactically complex and accurate language, and also influences perceptions of task difficulty. However, a higher intentional reasoning demand is associated with less lexical diversity and inconsistent patterns of fluency. An important finding of the study is that the link between the cognitive demands and the language used to convey intentional reasoning should be carefully considered when selecting analytic measures of complexity and accuracy. The implications of these findings for two most widely-used models of task complexity, i.e. Cognition Hypothesis (Robinson, 2007) and Limited Capacity model (Skehan, 2009) are discussed.

Molecular Neurobiology, Mar 21, 2013

Increasing evidence suggests that alterations in epigenetic mechanisms regulating chromatin state... more Increasing evidence suggests that alterations in epigenetic mechanisms regulating chromatin state play a role in the pathogenesis of medulloblastoma (MB), the most common malignant brain tumor of childhood. Histone deacetylase (HDAC) inhibitors, which increase chromatin relaxation, have been shown to display anticancer activities. Here we show that the HDAC inhibitor sodium butyrate (NaB) markedly increases cell death and reduces colony formation in human MB cell lines. In addition, NaB increased the mRNA expression of Gria2, a neuronal differentiation marker, in D283 and DAOY cells and reduced the number of neurospheres in D283 cell cultures. Finally, NaB reduced the viability of D283 cells when combined with etoposide. These data show that NaB displays pronounced inhibitory effects on the survival of human MB cells and suggest that NaB might potentiate the effects of etoposide. In addition, our study suggests that HDAC inhibition might promote the neuronal differentiation of MB cells and provides the first evidence that an HDAC inhibitor might suppress the expansion or survival of MB cancer stem cells.