Fernanda Roversi | Universidade Estadual de Campinas (original) (raw)
Papers by Fernanda Roversi
Biomedicine & Pharmacotherapy
Revista Espanola De Enfermedades Digestivas, 2022
Revista Recien - Revista Científica de Enfermagem
Trata-se de um estudo retrospectivo onde foram coletados e analisados os dados de 38 prontuários ... more Trata-se de um estudo retrospectivo onde foram coletados e analisados os dados de 38 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que a maioria dos pacientes com câncer colorretal submetidos a tratamento quimioterápico apresentaram as seguintes características: média de idade de 64,5 ± 14,4 anos, sendo que 26,3% tiveram metástase, 7,9% são etilistas, 15,8% possuem sonda nasogástrica e 10,5% sonda nasoenteral e 26,3% eram portadores de colostomia. Como relação aos sinais e sintomas as principais informações detectadas foram que 23,7% deles têm hipertensão, 13,2% são diabéticos, 86,8% têm o gânglio não palpável, 21,1% possuem pele descorada, enquanto 60,5% apresentavam abdome flácido. O direcionamento assertivo na conduta e orientação que a equipe de enfermagem faz para o paciente e/ou seu cuidador é essencial para a boa...
Frontiers in Cell and Developmental Biology, 2021
The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and th... more The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy resistance. In acute myeloid leukemia (AML), leukemic stem/progenitor cells (LSC) anchored in the protective BM microenvironment, reprogram and transform this niche into a leukemia-supporting and chemoprotective environment. One most important player involved in this crosstalk are CXCL12, produced by the BM mesenchymal stromal cells, and its receptor CXCR4, present onto HSC. The downstream molecular mechanisms involved in CXCL12/CXCR4 axis have many targets, including the Src family members of non-receptor tyrosine kinase (SFK). We herein study the role of one SFK member, the Hematopoietic Cell Kinase (HCK), in CXCL12/CXCR4 pathway and its contribution to the AML pathogenesis. We verified that the inhibition of HCK severely impaired CXCL12-...
Hematology, Transfusion and Cell Therapy, 2020
<jats:title>Abstract</jats:title> <jats:p>Background: The crosstalk between hem... more <jats:title>Abstract</jats:title> <jats:p>Background: The crosstalk between hematopoietic cells and bone marrow (BM) microenvironment in hematological malignancies is related to disease initiation, maintenance and relapse. BM niche sustains a protective response against currently available treatments that have shown unwanted adverse effects and high levels of toxicity for patients. WNT5a is a glycoprotein secreted by mesenchymal stromal cells (MSC) that activates the WNT non-canonical pathway in hematopoietic cells, modulating important biological processes related to neoplasia development.</jats:p> <jats:p>Aims: To investigate WNT5a mRNA expression, protein levels and methylation pattern in Myelodysplastic Syndrome (MDS) and de novo Acute Myeloid Leukemia (AML) patients and their impact on clinical outcomes, and to analyze effects of Foxy-5 (WNTResearch), a new WNT5a-mimicking compound.</jats:p> <jats:p>Methods: WNT5a mRNA expression was analyzed in mononuclear cells (MC) from 371 AML patients (212 male, median age 61 years [range: 2-87]) (Ohsu, Nature 2018). BMMSC and BM biopsies from 5 healthy donors (HD), 6 MDS and 13 AML patients at diagnosis were submitted to analysis of WNT5a mRNA expression and methylation after Azacytidine (1μM) treatment by real-time PCR, and WNT5a protein levels by immunohistochemistry and immunofluorescence (IF). A panel of myeloid leukemia cell lines (U937, HL60, THP1, KG1a, K562) were treated with Foxy-5 (1 to 100μM) for 72h in monoculture, coculture and 3D-coculture (with MSC) and evaluated for ROS production (DCFDA dye), cell proliferation (Ki-67 stain), autophagy (acridine orange dye), chemotaxis (Transwell), actin polymerization (phalloidin stain), cell cycle (PI/RNAse stain), cell viability (MTT assay), apoptosis (Annexin-V stain) and protein expression (Western blot, WB). MC and CD34+ cells from HD were submitted to cytotoxic assays. Statistical analyzes were performed using ANOVA or Mann-Whitney tests, as appropriate.</jats:p> <jats:p>Results: WNT5a gene expression was reduced in MC from AML patients with adverse cytogenetic risk compared to favorable and intermediate cytogenetic risk (fold-decrease [FD]: 42.9; 18.8, respectively) (P&lt;.05) and in BMMSC from AML compared to HD (FD: 53.3) (P&lt;.05). Accordingly, WNT5a gene expression in MDS and AML BMMSC treated with Azacytidine was restored (fold-increase [FI]: 3.99; 1.50, respectively). WNT5a protein expression were diminished in BMMSC from MDS and AML patients compared to HD onto a 3D-coculture (IF)(P&lt;.05) and immunohistochemically detected in all BM hematopoietic lineages. Foxy-5 reduced ROS production in U937 (FD of mean fluorescence intensity [MFI]: 48.2; 46.6), HL60 (FD: 47.1; 115.0), KG1a (FD: 34.9; 20.7) and K562 (FD: 19.0; 24.3) at 100μM in monoculture and coculture, respectively (P&lt;.05). Foxy-5 also significantly decreased proliferation in U937 (FD: 41.0), HL60 (FD: 18.0), THP1 (FD: 36.0) and K562 (FD: 68.0) at 100μM (P&lt;.05), confirmed by a 3D-coculture containing these cell lines and MSC. Foxy-5 reduced monocyte differentiation and inhibited CD11b expression in U937 (FD: 16.4) and THP1 (FD: 14.4). Cell cycle progression was blocked in sub G0/G1 phase in all cell lines (P&lt;.05) after Foxy-5 treatment, probably mediated by the reduction of cyclin D1 protein levels, as verified by WB. Further, Foxy-5 reduced AKT1/2/3 and ERK1/2 phosphorylation levels, possibly by beta-catenin inhibition, with disruption of actin polymerization (U937 (FD: 65.3), HL60 (FD: 35.9), THP1 (FD: 58.5), K562 (FD: 15.0)) at 100μM (P&lt;.05) and consequent impairment of CXCL12-induced chemotaxis (U937 (FD: 27.9), HL60 (FD: 42.5), THP1 (FD: 82.4), K562 (FD: 45.1)) at 100μM (P&lt;.05). In coculture, cell autophagy was reduced in U937 (FD: 27.8), HL60 (FD: 35.9), KG1a (FD: 16.4) and K562 (FD: 35.8) when treated with Foxy-5 at 100μM (P&lt;.05). Finally, Foxy-5 treatment did not affect cytotoxicity in MC and CD34+ cells from HD.</jats:p> <jats:p>Conclusion: WNT5a downregulation in MDS and AML patients occurs probably by methylation and contributes to poor prognosis. Foxy-5, by restoring WNT5a levels, could represent a strategy to counterbalance several oncogenic processes present in leukemia by reducing ROS production and, consequently, inhibiting cell growth and differentiation, downregulating PI3K and MAPK pathways, disrupting actin polymerization and decreasing autophagy. Thus, Foxy-5 treatment may be an important approach to impair leukemia growth and maintenance and arises as a promising therapeutic target.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
Durante o desenvolvimento ontogenetico, ocorrem alteracoes na expressao dos genes das globinas, c... more Durante o desenvolvimento ontogenetico, ocorrem alteracoes na expressao dos genes das globinas, caracterizando o switching de hemoglobina. Apos o nascimento ha o silenciamento do gene da globina ? concomitante a ativacao do gene da globina ?. Todavia, algumas delecoes genicas no grupamento dos genes das globinas e algumas mutacoes de ponto no promotor do gene da globina ? sao responsaveis pela expressao continuada do gene da globina , resultando em niveis elevados de hemoglobina fetal (HbF) na vida adulta, caracterizando, respectivamente, a Persistencia Hereditaria de Hemoglobina Fetal delecional e a nao delecional (ndPHHF). A mutacao de ponto C?G na posicao -195 do promotor do gene da globina ?A caracteriza a ndPHHF tipo Brasileira (ndPHHF-B), com aumento nos niveis de HbF entre 6% e 16%. Todavia, o mecanismo molecular responsavel pela reativacao do gene da globina ?A na ndPHHF-B nao esta elucidado. Estudos anteriores demonstraram que na ndPHHF tipo Brasileira (-195) a elevacao nos...
Transfusion Clinique et Biologique
Background: Multiple myeloma is characterized by abnormal plasmocytes proliferation in the bone m... more Background: Multiple myeloma is characterized by abnormal plasmocytes proliferation in the bone marrow, resulting in an immunoglobulin oversecretion, which can cause bone pain, anemia, kidney dysfunction, and infections. The present study evaluates prognostic factors and the bone involvement in patients who had a confirmed diagnosis of MM. Methods: A retrospective study was conducted in hospital universitario Sao Francisco of Braganca Paulista. Patient demographic data, laboratory parameters and treatment received were recorded. We also analyzed the variables related to diagnosis and the development of bone lesions in MM patients. Results: A total of 42 patients had a confirmed diagnosis of MM, out of which most (54.76%) were older than 65. Most patients (45.24%) had beta-2-microglobulin values greater than 5.5 mcg/dl, indicating an advanced stage of the disease and consequently a less favorable prognosis. The main clinical manifestation observed was anemia in 61.90% (26/42) and bon...
Ciências da Saúde: Da Teoria à Prática 5, Jun 13, 2019
O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilida... more O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais.
O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pe... more O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pescoço. O câncer de cabeça e pescoço envolve um conjunto de localizações variadas e a incidência de algumas formas vem subindo. Portanto, a determinação de quais sinais e sintomas ocorrem com o paciente com câncer de cabeça e pescoço durante o tratamento pode auxiliar na proposição de estratégias de melhora na qualidade de vida do paciente. Este foi um estudo retrospectivo onde foram coletados e analisados os dados de 21 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que os pacientes com câncer cabeça e
Journal of Cellular and Molecular Medicine
The role of tumour microenvironment in neoplasm initiation and malignant evolution has been incre... more The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz-type2 (SPINT2/HAI-2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI-2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5-Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS-and de novo AML-BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI-2 levels up-regulation. Moreover, Aza treatment of HD-BMMSC did not improve SPINT2/HAI-2 levels. To understand the role of SPINT2/HAI-2 down-regulation in BMMSC physiology, SPINT2/HAI-2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS-5 stromal cells and improved survival of CD34 + de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI-2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI-2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down-regulation in SPINT2/HAI-2 gene expression, due to methylation in MDS-BMMSC and de novo AML-BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.
Brazilian Journal of Development
O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pe... more O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pescoço. O câncer de cabeça e pescoço envolve um conjunto de localizações variadas e a incidência de algumas formas vem subindo. Portanto, a determinação de quais sinais e sintomas ocorrem com o paciente com câncer de cabeça e pescoço durante o tratamento pode auxiliar na proposição de estratégias de melhora na qualidade de vida do paciente. Este foi um estudo retrospectivo onde foram coletados e analisados os dados de 21 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que os pacientes com câncer cabeça e
AME Case Reports
Although tyrosine kinase inhibitors (TKI) are commonly used as targeted treatment options for chr... more Although tyrosine kinase inhibitors (TKI) are commonly used as targeted treatment options for chronic myeloid leukemia (CML), its use is associated to UGT1A1 polymorphisms and, consequently, are related to a higher risk of manifesting Gilbert's syndrome, a genetic disorder associated to hyperbilirubinemia. The report of concomitant condition of CML and Gilbert's Syndrome is uncommon. Therefore, the aim of this study was to report the clinical case of a patient diagnosed with CML and subsequently, with Gilbert's Syndrome. A 34-year-old female was diagnosed with CML. On physical examination, spleen and liver were palpable, indicating hepatosplenomegaly. Laboratory findings of peripheral blood showed leukocytosis (165,190/mm 3), 6% of blasts and a bone marrow biopsy showed hypercellularity by granulocytic series with moderate maturation delay. After diagnosis, the patient immediately started chemotherapy with the TKI Imatinib. One year after treatment, due to the partial response, the therapy was changed to Nilotinib, resulting in a complete response. Despite the absence of hyperbilirubinemia, a genetic study by polymerase chain reaction (PCR) verified a positivity for Gilbert's Syndrome. TKIs are also inhibitors of the enzyme UDPGT1, leading to deficient glucuronidation, causing manifestation of Gilbert's Syndrome. This report demonstrates the case of a patient that, besides having two coexisting conditions that could cause hyperbilirubinemia, did not have bilirubin alterations and it highlights the importance of having genetic investigations in cancer patients, in order to identify secondary diseases that could worsen the course of treatment.
Blood
Introduction. Hematopoietic cell kinase (HCK) belongs to the Src kinase family (SFK) involved in ... more Introduction. Hematopoietic cell kinase (HCK) belongs to the Src kinase family (SFK) involved in the oncogenic process and hematological malignancy. Some SFK inhibitors are currently under investigation in clinical trials for leukemia after demonstrating efficacy in patients with solid tumors. We have previously reported that HCK is overexpressed in leukemic cells and its inhibition by lentivirus resulted in reduction of cell growth and increased cell death (Roversi et al. BBA Mol Basis Dis. 2017, 1863(2):450-61). In light of the genomic and molecular diversity of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), the development of chemical compounds specific for new molecular targets is currently an important subject. Aims. To investigate the in vitro and in vivo effects of a new chemical compound targeting HCK inhibition (iHCK), alone or in combination with the most used drugs for treatment of MDS and AML (Azacytidine - Aza - or Cytarabine - Ara-C). Methods. After ...
Blood
Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSC) characteri... more Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, an important role is also played by the hematopoietic microenvironment niche that has as key component the mesenchymal stromal cells (MSC). The MSC of MDS patients have morphological and functional abnormalities. Recently, our group identified new possible target genes involved in MDS pathophysiology through microarray analysis of MSC from MDS patients. An interesting underexpressed gene found was SPINT2, a gene that encodes a transmembrane protein which inhibits the hepatocyte growth factor activator (HGFA), the enzyme responsible for the conversion of hepatocyte growth factor (HGF) into its active form. SPINT2 is downregulated in some types of solid cancer and correlated with their prognostic and progression; however, the functional role of SPINT2 in MDS remains unknown. We herein investigated the role of SPINT2 in MSC, stud...
Blood
3195 The hereditary persistence of fetal hemoglobin (HPFH) is the consequence of impaired switchi... more 3195 The hereditary persistence of fetal hemoglobin (HPFH) is the consequence of impaired switching in adult life, which results in the continued expression of gamma globin gene. The Brazilian HPFH type is characterized by a C → G substitution at the –195 position of the A gamma globin gene promoter, and associated with HbF levels ranging from 6 to 16% in the heterozygote state. This study was undertaken to identify genes that may be involved in hemoglobin switching and/or maintenance of elevated HbF levels in Brazilian HPHF subjects. The Suppressive Subtractive Hybridization libraries were constructed using a pool of RNA extracted from reticulocytes of peripheral blood in individuals with normal hematological data and from subjects with Brazilian and 55 and 57 overexpressed genes were identified in the normal and Brazilian HPFH library, respectively; findings were validated by qRT-PCR and Western blotting. One transcription factor identified was FOXO3a, whose expression was increas...
Blood
3201 During erythroid differentiation, the expression profile of erythroid-specific genes follows... more 3201 During erythroid differentiation, the expression profile of erythroid-specific genes follows a precise timing that is controlled by a complex network of transcription factors (TFs) and microRNAs (miRNAs) that regulate the expression of a set of target genes. The aim of this study was to analyze the expression profile in sickle cell anemia (SCA) and β-thalassemia (BT) patients of the TFs GATA-1, TAL-1, NFE-2, LDB1, LMO2, EKLF and of the miRNAs 24, 144, 155, 210, 221, 222, 223 and 451, which all of have been previously described in normal erythropoiesis. Reticulocytes were separated from peripheral blood samples of subjects with normal hematological data (n≥8), from untransfused BT IVS-I-6 (T→C) homozygous patients (n=9) and from SCA patients (n=8), without HU therapy. Spherocytosis patient samples were included in the results analysis. Extraction of RNA and miRNA, transcription to cDNAs and qRT-PCR were performed to analyze TFs and miRNAs expressions. In BT patients, statistical...
Biomedicine & Pharmacotherapy
Revista Espanola De Enfermedades Digestivas, 2022
Revista Recien - Revista Científica de Enfermagem
Trata-se de um estudo retrospectivo onde foram coletados e analisados os dados de 38 prontuários ... more Trata-se de um estudo retrospectivo onde foram coletados e analisados os dados de 38 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que a maioria dos pacientes com câncer colorretal submetidos a tratamento quimioterápico apresentaram as seguintes características: média de idade de 64,5 ± 14,4 anos, sendo que 26,3% tiveram metástase, 7,9% são etilistas, 15,8% possuem sonda nasogástrica e 10,5% sonda nasoenteral e 26,3% eram portadores de colostomia. Como relação aos sinais e sintomas as principais informações detectadas foram que 23,7% deles têm hipertensão, 13,2% são diabéticos, 86,8% têm o gânglio não palpável, 21,1% possuem pele descorada, enquanto 60,5% apresentavam abdome flácido. O direcionamento assertivo na conduta e orientação que a equipe de enfermagem faz para o paciente e/ou seu cuidador é essencial para a boa...
Frontiers in Cell and Developmental Biology, 2021
The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and th... more The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy resistance. In acute myeloid leukemia (AML), leukemic stem/progenitor cells (LSC) anchored in the protective BM microenvironment, reprogram and transform this niche into a leukemia-supporting and chemoprotective environment. One most important player involved in this crosstalk are CXCL12, produced by the BM mesenchymal stromal cells, and its receptor CXCR4, present onto HSC. The downstream molecular mechanisms involved in CXCL12/CXCR4 axis have many targets, including the Src family members of non-receptor tyrosine kinase (SFK). We herein study the role of one SFK member, the Hematopoietic Cell Kinase (HCK), in CXCL12/CXCR4 pathway and its contribution to the AML pathogenesis. We verified that the inhibition of HCK severely impaired CXCL12-...
Hematology, Transfusion and Cell Therapy, 2020
<jats:title>Abstract</jats:title> <jats:p>Background: The crosstalk between hem... more <jats:title>Abstract</jats:title> <jats:p>Background: The crosstalk between hematopoietic cells and bone marrow (BM) microenvironment in hematological malignancies is related to disease initiation, maintenance and relapse. BM niche sustains a protective response against currently available treatments that have shown unwanted adverse effects and high levels of toxicity for patients. WNT5a is a glycoprotein secreted by mesenchymal stromal cells (MSC) that activates the WNT non-canonical pathway in hematopoietic cells, modulating important biological processes related to neoplasia development.</jats:p> <jats:p>Aims: To investigate WNT5a mRNA expression, protein levels and methylation pattern in Myelodysplastic Syndrome (MDS) and de novo Acute Myeloid Leukemia (AML) patients and their impact on clinical outcomes, and to analyze effects of Foxy-5 (WNTResearch), a new WNT5a-mimicking compound.</jats:p> <jats:p>Methods: WNT5a mRNA expression was analyzed in mononuclear cells (MC) from 371 AML patients (212 male, median age 61 years [range: 2-87]) (Ohsu, Nature 2018). BMMSC and BM biopsies from 5 healthy donors (HD), 6 MDS and 13 AML patients at diagnosis were submitted to analysis of WNT5a mRNA expression and methylation after Azacytidine (1μM) treatment by real-time PCR, and WNT5a protein levels by immunohistochemistry and immunofluorescence (IF). A panel of myeloid leukemia cell lines (U937, HL60, THP1, KG1a, K562) were treated with Foxy-5 (1 to 100μM) for 72h in monoculture, coculture and 3D-coculture (with MSC) and evaluated for ROS production (DCFDA dye), cell proliferation (Ki-67 stain), autophagy (acridine orange dye), chemotaxis (Transwell), actin polymerization (phalloidin stain), cell cycle (PI/RNAse stain), cell viability (MTT assay), apoptosis (Annexin-V stain) and protein expression (Western blot, WB). MC and CD34+ cells from HD were submitted to cytotoxic assays. Statistical analyzes were performed using ANOVA or Mann-Whitney tests, as appropriate.</jats:p> <jats:p>Results: WNT5a gene expression was reduced in MC from AML patients with adverse cytogenetic risk compared to favorable and intermediate cytogenetic risk (fold-decrease [FD]: 42.9; 18.8, respectively) (P&lt;.05) and in BMMSC from AML compared to HD (FD: 53.3) (P&lt;.05). Accordingly, WNT5a gene expression in MDS and AML BMMSC treated with Azacytidine was restored (fold-increase [FI]: 3.99; 1.50, respectively). WNT5a protein expression were diminished in BMMSC from MDS and AML patients compared to HD onto a 3D-coculture (IF)(P&lt;.05) and immunohistochemically detected in all BM hematopoietic lineages. Foxy-5 reduced ROS production in U937 (FD of mean fluorescence intensity [MFI]: 48.2; 46.6), HL60 (FD: 47.1; 115.0), KG1a (FD: 34.9; 20.7) and K562 (FD: 19.0; 24.3) at 100μM in monoculture and coculture, respectively (P&lt;.05). Foxy-5 also significantly decreased proliferation in U937 (FD: 41.0), HL60 (FD: 18.0), THP1 (FD: 36.0) and K562 (FD: 68.0) at 100μM (P&lt;.05), confirmed by a 3D-coculture containing these cell lines and MSC. Foxy-5 reduced monocyte differentiation and inhibited CD11b expression in U937 (FD: 16.4) and THP1 (FD: 14.4). Cell cycle progression was blocked in sub G0/G1 phase in all cell lines (P&lt;.05) after Foxy-5 treatment, probably mediated by the reduction of cyclin D1 protein levels, as verified by WB. Further, Foxy-5 reduced AKT1/2/3 and ERK1/2 phosphorylation levels, possibly by beta-catenin inhibition, with disruption of actin polymerization (U937 (FD: 65.3), HL60 (FD: 35.9), THP1 (FD: 58.5), K562 (FD: 15.0)) at 100μM (P&lt;.05) and consequent impairment of CXCL12-induced chemotaxis (U937 (FD: 27.9), HL60 (FD: 42.5), THP1 (FD: 82.4), K562 (FD: 45.1)) at 100μM (P&lt;.05). In coculture, cell autophagy was reduced in U937 (FD: 27.8), HL60 (FD: 35.9), KG1a (FD: 16.4) and K562 (FD: 35.8) when treated with Foxy-5 at 100μM (P&lt;.05). Finally, Foxy-5 treatment did not affect cytotoxicity in MC and CD34+ cells from HD.</jats:p> <jats:p>Conclusion: WNT5a downregulation in MDS and AML patients occurs probably by methylation and contributes to poor prognosis. Foxy-5, by restoring WNT5a levels, could represent a strategy to counterbalance several oncogenic processes present in leukemia by reducing ROS production and, consequently, inhibiting cell growth and differentiation, downregulating PI3K and MAPK pathways, disrupting actin polymerization and decreasing autophagy. Thus, Foxy-5 treatment may be an important approach to impair leukemia growth and maintenance and arises as a promising therapeutic target.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
Durante o desenvolvimento ontogenetico, ocorrem alteracoes na expressao dos genes das globinas, c... more Durante o desenvolvimento ontogenetico, ocorrem alteracoes na expressao dos genes das globinas, caracterizando o switching de hemoglobina. Apos o nascimento ha o silenciamento do gene da globina ? concomitante a ativacao do gene da globina ?. Todavia, algumas delecoes genicas no grupamento dos genes das globinas e algumas mutacoes de ponto no promotor do gene da globina ? sao responsaveis pela expressao continuada do gene da globina , resultando em niveis elevados de hemoglobina fetal (HbF) na vida adulta, caracterizando, respectivamente, a Persistencia Hereditaria de Hemoglobina Fetal delecional e a nao delecional (ndPHHF). A mutacao de ponto C?G na posicao -195 do promotor do gene da globina ?A caracteriza a ndPHHF tipo Brasileira (ndPHHF-B), com aumento nos niveis de HbF entre 6% e 16%. Todavia, o mecanismo molecular responsavel pela reativacao do gene da globina ?A na ndPHHF-B nao esta elucidado. Estudos anteriores demonstraram que na ndPHHF tipo Brasileira (-195) a elevacao nos...
Transfusion Clinique et Biologique
Background: Multiple myeloma is characterized by abnormal plasmocytes proliferation in the bone m... more Background: Multiple myeloma is characterized by abnormal plasmocytes proliferation in the bone marrow, resulting in an immunoglobulin oversecretion, which can cause bone pain, anemia, kidney dysfunction, and infections. The present study evaluates prognostic factors and the bone involvement in patients who had a confirmed diagnosis of MM. Methods: A retrospective study was conducted in hospital universitario Sao Francisco of Braganca Paulista. Patient demographic data, laboratory parameters and treatment received were recorded. We also analyzed the variables related to diagnosis and the development of bone lesions in MM patients. Results: A total of 42 patients had a confirmed diagnosis of MM, out of which most (54.76%) were older than 65. Most patients (45.24%) had beta-2-microglobulin values greater than 5.5 mcg/dl, indicating an advanced stage of the disease and consequently a less favorable prognosis. The main clinical manifestation observed was anemia in 61.90% (26/42) and bon...
Ciências da Saúde: Da Teoria à Prática 5, Jun 13, 2019
O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilida... more O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais.
O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pe... more O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pescoço. O câncer de cabeça e pescoço envolve um conjunto de localizações variadas e a incidência de algumas formas vem subindo. Portanto, a determinação de quais sinais e sintomas ocorrem com o paciente com câncer de cabeça e pescoço durante o tratamento pode auxiliar na proposição de estratégias de melhora na qualidade de vida do paciente. Este foi um estudo retrospectivo onde foram coletados e analisados os dados de 21 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que os pacientes com câncer cabeça e
Journal of Cellular and Molecular Medicine
The role of tumour microenvironment in neoplasm initiation and malignant evolution has been incre... more The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz-type2 (SPINT2/HAI-2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI-2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5-Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS-and de novo AML-BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI-2 levels up-regulation. Moreover, Aza treatment of HD-BMMSC did not improve SPINT2/HAI-2 levels. To understand the role of SPINT2/HAI-2 down-regulation in BMMSC physiology, SPINT2/HAI-2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS-5 stromal cells and improved survival of CD34 + de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI-2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI-2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down-regulation in SPINT2/HAI-2 gene expression, due to methylation in MDS-BMMSC and de novo AML-BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.
Brazilian Journal of Development
O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pe... more O carcinoma de células escamosas é o tumor maligno mais comum que ocorre na região da cabeça e pescoço. O câncer de cabeça e pescoço envolve um conjunto de localizações variadas e a incidência de algumas formas vem subindo. Portanto, a determinação de quais sinais e sintomas ocorrem com o paciente com câncer de cabeça e pescoço durante o tratamento pode auxiliar na proposição de estratégias de melhora na qualidade de vida do paciente. Este foi um estudo retrospectivo onde foram coletados e analisados os dados de 21 prontuários de assistência de enfermagem oncológica, ficha preenchida durante o processo de tratamento quimioterápico. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A partir dos resultados, observou-se que os pacientes com câncer cabeça e
AME Case Reports
Although tyrosine kinase inhibitors (TKI) are commonly used as targeted treatment options for chr... more Although tyrosine kinase inhibitors (TKI) are commonly used as targeted treatment options for chronic myeloid leukemia (CML), its use is associated to UGT1A1 polymorphisms and, consequently, are related to a higher risk of manifesting Gilbert's syndrome, a genetic disorder associated to hyperbilirubinemia. The report of concomitant condition of CML and Gilbert's Syndrome is uncommon. Therefore, the aim of this study was to report the clinical case of a patient diagnosed with CML and subsequently, with Gilbert's Syndrome. A 34-year-old female was diagnosed with CML. On physical examination, spleen and liver were palpable, indicating hepatosplenomegaly. Laboratory findings of peripheral blood showed leukocytosis (165,190/mm 3), 6% of blasts and a bone marrow biopsy showed hypercellularity by granulocytic series with moderate maturation delay. After diagnosis, the patient immediately started chemotherapy with the TKI Imatinib. One year after treatment, due to the partial response, the therapy was changed to Nilotinib, resulting in a complete response. Despite the absence of hyperbilirubinemia, a genetic study by polymerase chain reaction (PCR) verified a positivity for Gilbert's Syndrome. TKIs are also inhibitors of the enzyme UDPGT1, leading to deficient glucuronidation, causing manifestation of Gilbert's Syndrome. This report demonstrates the case of a patient that, besides having two coexisting conditions that could cause hyperbilirubinemia, did not have bilirubin alterations and it highlights the importance of having genetic investigations in cancer patients, in order to identify secondary diseases that could worsen the course of treatment.
Blood
Introduction. Hematopoietic cell kinase (HCK) belongs to the Src kinase family (SFK) involved in ... more Introduction. Hematopoietic cell kinase (HCK) belongs to the Src kinase family (SFK) involved in the oncogenic process and hematological malignancy. Some SFK inhibitors are currently under investigation in clinical trials for leukemia after demonstrating efficacy in patients with solid tumors. We have previously reported that HCK is overexpressed in leukemic cells and its inhibition by lentivirus resulted in reduction of cell growth and increased cell death (Roversi et al. BBA Mol Basis Dis. 2017, 1863(2):450-61). In light of the genomic and molecular diversity of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), the development of chemical compounds specific for new molecular targets is currently an important subject. Aims. To investigate the in vitro and in vivo effects of a new chemical compound targeting HCK inhibition (iHCK), alone or in combination with the most used drugs for treatment of MDS and AML (Azacytidine - Aza - or Cytarabine - Ara-C). Methods. After ...
Blood
Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSC) characteri... more Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, an important role is also played by the hematopoietic microenvironment niche that has as key component the mesenchymal stromal cells (MSC). The MSC of MDS patients have morphological and functional abnormalities. Recently, our group identified new possible target genes involved in MDS pathophysiology through microarray analysis of MSC from MDS patients. An interesting underexpressed gene found was SPINT2, a gene that encodes a transmembrane protein which inhibits the hepatocyte growth factor activator (HGFA), the enzyme responsible for the conversion of hepatocyte growth factor (HGF) into its active form. SPINT2 is downregulated in some types of solid cancer and correlated with their prognostic and progression; however, the functional role of SPINT2 in MDS remains unknown. We herein investigated the role of SPINT2 in MSC, stud...
Blood
3195 The hereditary persistence of fetal hemoglobin (HPFH) is the consequence of impaired switchi... more 3195 The hereditary persistence of fetal hemoglobin (HPFH) is the consequence of impaired switching in adult life, which results in the continued expression of gamma globin gene. The Brazilian HPFH type is characterized by a C → G substitution at the –195 position of the A gamma globin gene promoter, and associated with HbF levels ranging from 6 to 16% in the heterozygote state. This study was undertaken to identify genes that may be involved in hemoglobin switching and/or maintenance of elevated HbF levels in Brazilian HPHF subjects. The Suppressive Subtractive Hybridization libraries were constructed using a pool of RNA extracted from reticulocytes of peripheral blood in individuals with normal hematological data and from subjects with Brazilian and 55 and 57 overexpressed genes were identified in the normal and Brazilian HPFH library, respectively; findings were validated by qRT-PCR and Western blotting. One transcription factor identified was FOXO3a, whose expression was increas...
Blood
3201 During erythroid differentiation, the expression profile of erythroid-specific genes follows... more 3201 During erythroid differentiation, the expression profile of erythroid-specific genes follows a precise timing that is controlled by a complex network of transcription factors (TFs) and microRNAs (miRNAs) that regulate the expression of a set of target genes. The aim of this study was to analyze the expression profile in sickle cell anemia (SCA) and β-thalassemia (BT) patients of the TFs GATA-1, TAL-1, NFE-2, LDB1, LMO2, EKLF and of the miRNAs 24, 144, 155, 210, 221, 222, 223 and 451, which all of have been previously described in normal erythropoiesis. Reticulocytes were separated from peripheral blood samples of subjects with normal hematological data (n≥8), from untransfused BT IVS-I-6 (T→C) homozygous patients (n=9) and from SCA patients (n=8), without HU therapy. Spherocytosis patient samples were included in the results analysis. Extraction of RNA and miRNA, transcription to cDNAs and qRT-PCR were performed to analyze TFs and miRNAs expressions. In BT patients, statistical...