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[PMID]:29216900
[Au] Autor:Ribas L; Vanezis K; Imués MA; Piferrer F
[Ad] Endereço:Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Passeig Marítim, 37-45, 08003, Barcelona, Spain.
[Ti] Título:Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads.
[So] Source:Epigenetics Chromatin;10(1):59, 2017 12 08.
[Is] ISSN:1756-8935
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The role of epigenetic modifications such as DNA methylation during vertebrate sexual development is far from being clear. Using the zebrafish model, we tested the effects of one of the most common DNA methyltransferase (dnmt) inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), which is approved for the treatment of acute myeloid leukaemia and is under active investigation for the treatment of solid tumours. Several dose-response experiments were carried out during two periods, including not only the very first days of development (0-6 days post-fertilization, dpf), as done in previous studies, but also, and as a novelty, the period of gonadal development (10-30 dpf). RESULTS: Early treatment with 5-aza-dC altered embryonic development, delayed hatching and increased teratology and mortality, as expected. The most striking result, however, was an increase in the number of females, suggesting that alterations induced by 5-aza-dC treatment can affect sexual development as well. Results were confirmed when treatment coincided with gonadal development. In addition, we also found that the adult gonadal transcriptome of 5-aza-dC-exposed females included significant changes in the expression of key reproduction-related genes (e.g. cyp11a1, esr2b and figla), and that several pro-female-related pathways such as the Fanconi anaemia or the Wnt signalling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g. dnmt1, dicer, cbx4) was also observed. CONCLUSIONS: Taken together, our results indicate that treatment with a DNA methylation inhibitor can also alter the sexual development in zebrafish, with permanent alterations of the adult gonadal transcriptome, at least in females. Our results show the importance of DNA methylation for proper control of sexual development, open new avenues for the potential control of sex ratios in fish (aquaculture, population control) and call attention to possibly hidden long-term effects of dnmt therapy when used, for example, in the treatment of prepuberal children affected by some types of cancer.
[Mh] Termos MeSH primário: Metilases de Modificação do DNA/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Feminização/induzido quimicamente
Ovário/efeitos dos fármacos
Peixe-Zebra/embriologia
[Mh] Termos MeSH secundário: Animais
Azacitidina/análogos & derivados
Azacitidina/farmacologia
Relação Dose-Resposta a Droga
Feminino
Masculino
Ovário/metabolismo
Razão de Masculinidade
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 776B62CQ27 (decitabine); EC 2.1.1.- (DNA Modification Methylases); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180310
[Lr] Data última revisão:
180310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1186/s13072-017-0168-7


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[PMID]:29339738
[Au] Autor:Luo N; Nixon MJ; Gonzalez-Ericsson PI; Sanchez V; Opalenik SR; Li H; Zahnow CA; Nickels ML; Liu F; Tantawy MN; Sanders ME; Manning HC; Balko JM
[Ad] Endereço:Department of Anatomy and Histology, School of Medicine, Nankai University, Tianjin, 300071, China.
[Ti] Título:DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer.
[So] Source:Nat Commun;9(1):248, 2018 01 16.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Neoplasias da Mama/metabolismo
DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Genes MHC Classe I/fisiologia
Linfócitos T Citotóxicos/fisiologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Azacitidina/farmacologia
Linhagem Celular Tumoral
DNA (Citosina-5-)-Metiltransferase 1/genética
DNA (Citosina-5-)-Metiltransferase 1/metabolismo
Feminino
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Genes MHC Classe I/genética
Seres Humanos
Neoplasias Mamárias Experimentais
Camundongos
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 2KT4YN1DP7 (guadecitabine); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1); EC 2.1.1.37 (DNMT1 protein, human); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02630-w


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[PMID]:29302025
[Au] Autor:Guéant JL; Chéry C; Oussalah A; Nadaf J; Coelho D; Josse T; Flayac J; Robert A; Koscinski I; Gastin I; Filhine-Tresarrieu P; Pupavac M; Brebner A; Watkins D; Pastinen T; Montpetit A; Hariri F; Tregouët D; Raby BA; Chung WK; Morange PE; Froese DS; Baumgartner MR; Benoist JF; Ficicioglu C; Marchand V; Motorin Y; Bonnemains C; Feillet F; Majewski J; Rosenblatt DS
[Ad] Endereço:INSERM, UMR_S954 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), 54505, Nancy, France. jean-louis.gueant@univ-lorraine.fr.
[Ti] Título:APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.
[So] Source:Nat Commun;9(1):67, 2018 01 04.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.
[Mh] Termos MeSH primário: Proteínas de Transporte/genética
Epistasia Genética
Erros Inatos do Metabolismo/genética
Mutação
Peroxirredoxinas/genética
Vitamina B 12/metabolismo
[Mh] Termos MeSH secundário: Alelos
Azacitidina/farmacologia
Sequência de Bases
Inibidores Enzimáticos/farmacologia
Saúde da Família
Feminino
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Heterozigoto
Seres Humanos
Masculino
Erros Inatos do Metabolismo/metabolismo
Linhagem
Sequenciamento Completo do Genoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Enzyme Inhibitors); 0 (MMACHC protein, human); EC 1.11.1.15 (PRDX1 protein, human); EC 1.11.1.15 (Peroxiredoxins); M801H13NRU (Azacitidine); P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02306-5


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[PMID]:29200853
[Au] Autor:Briot T; Roger E; Lautram N; Verger A; Clavreul A; Lagarce F
[Ad] Endereço:Micro & Nanomédecines Translationelles - MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, MINT IBS-CHU.
[Ti] Título:Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia.
[So] Source:Int J Nanomedicine;12:8427-8442, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol HP (THP-LNCs) and LNCs associated with a mixture of Transcutol HP and Tween 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5 nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Portadores de Fármacos/química
Leucemia Mieloide Aguda/tratamento farmacológico
Nanocápsulas/administração & dosagem
[Mh] Termos MeSH secundário: Administração Oral
Antimetabólitos Antineoplásicos/administração & dosagem
Antimetabólitos Antineoplásicos/farmacocinética
Azacitidina/administração & dosagem
Azacitidina/farmacocinética
Disponibilidade Biológica
Células CACO-2
Linhagem Celular Tumoral
Portadores de Fármacos/administração & dosagem
Liberação Controlada de Fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Estabilidade de Medicamentos
Etilenoglicóis/química
Seres Humanos
Lipídeos/química
Nanocápsulas/química
Polissorbatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Drug Carriers); 0 (Ethylene Glycols); 0 (Lipids); 0 (Nanocapsules); 0 (Polysorbates); 776B62CQ27 (decitabine); A1A1I8X02B (carbitol); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S147659


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[PMID]:28463020
[Au] Autor:Saini M; Selokar NL; Agrawal H; Singla SK; Chauhan MS; Manik RS; Palta P
[Ad] Endereço:Embryo Biotechnology Laboratory, Animal Biotechnology Centre, ICAR-National Dairy Research Institute , Karnal, India .
[Ti] Título:Treatment of Donor Cells and Reconstructed Embryos with a Combination of Trichostatin-A and 5-aza-2'-Deoxycytidine Improves the Developmental Competence and Quality of Buffalo Embryos Produced by Handmade Cloning and Alters Their Epigenetic Status and Gene Expression.
[So] Source:Cell Reprogram;19(3):208-215, 2017 Jun.
[Is] ISSN:2152-4998
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The application of cloning technology on a large scale is limited by very low offspring rate primarily due to aberrant or incomplete epigenetic reprogramming. Trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferases, are widely used for altering the epigenetic status of cloned embryos. We optimized the doses of these epigenetic modifiers for production of buffalo embryos by handmade cloning and examined whether combined treatment with these epigenetic modifiers offered any advantage over treatment with the individual epigenetic modifier. Irrespective of whether donor cells or reconstructed embryos or both were treated with 50 nM TSA +7.5 nM 5-aza-dC, (1) the blastocyst rate was significantly higher (71.6 ± 3.5, 68.3 ± 2.6, and 71.8 ± 2.4, respectively, vs. 43.1 ± 3.4 for controls, p < 0.05); (2) the apoptotic index was lower (5.4 ± 1.1, 9.5 ± 1.0, and 7.4 ± 1.3, respectively, vs. 19.5 ± 2.1 for controls, p < 0.05) and was similar to that of in vitro fertilization blastocysts (6.0 ± 0.8); (3) the global level of H3K18ac was higher (p < 0.01) and that of H3K27me3 lower (p < 0.05) than in controls and was similar among all treatment groups; and (4) the expression level of epigenetic-(HDAC1, DNMT1, and DNMT3a), pluripotency-(OCT4 and NANOG), and development-related (FGF4) genes, but not that of SOX2 and CDX2, was similar among all treatment groups. These results demonstrate that similar levels of beneficial effects can be obtained following treatment of either donor cells or reconstructed embryos or both with the combination of TSA +5-aza-dC. Therefore, there is no advantage in treating both donor cells and reconstructed embryos when the combination of TSA and 5-aza-dC is used.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Búfalos
Clonagem de Organismos/métodos
Embrião de Mamíferos/metabolismo
Epigênese Genética/efeitos dos fármacos
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Ácidos Hidroxâmicos/farmacologia
[Mh] Termos MeSH secundário: Animais
Azacitidina/farmacologia
Búfalos/embriologia
Búfalos/genética
Embrião de Mamíferos/citologia
Feminino
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxamic Acids); 3X2S926L3Z (trichostatin A); 776B62CQ27 (decitabine); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1089/cell.2016.0061


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[PMID]:28746590
[Au] Autor:Campregher PV; Mattos VRP; Salvino MA; Santos FPS; Hamerschlak N
[Ad] Endereço:Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
[Ti] Título:Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases.
[So] Source:Einstein (Sao Paulo);15(3):355-358, 2017 Jul-Sep.
[Is] ISSN:2317-6385
[Cp] País de publicação:Brazil
[La] Idioma:eng; por
[Ab] Resumo:Acute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Azacitidina/administração & dosagem
Quimioterapia de Indução
Leucemia Mieloide Aguda/terapia
Transfusão de Linfócitos
Niacinamida/análogos & derivados
Compostos de Fenilureia/administração & dosagem
Tirosina Quinase 3 Semelhante a fms/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Terapia Combinada/métodos
Feminino
Seres Humanos
Leucemia Mieloide Aguda/genética
Masculino
Meia-Idade
Recidiva Local de Neoplasia/terapia
Niacinamida/administração & dosagem
Recidiva
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); EC 2.7.10.1 (FLT3 protein, human); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


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[PMID]:29195073
[Au] Autor:Topper MJ; Vaz M; Chiappinelli KB; DeStefano Shields CE; Niknafs N; Yen RC; Wenzel A; Hicks J; Ballew M; Stone M; Tran PT; Zahnow CA; Hellmann MD; Anagnostou V; Strissel PL; Strick R; Velculescu VE; Baylin SB
[Ad] Endereço:Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA; The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
[Ti] Título:Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.
[So] Source:Cell;171(6):1284-1300.e21, 2017 Nov 30.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/ß-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/terapia
Quimioterapia Combinada
Neoplasias Pulmonares/terapia
Evasão Tumoral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno/efeitos dos fármacos
Antineoplásicos/uso terapêutico
Azacitidina/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/imunologia
Linhagem Celular Tumoral
Inibidores de Histona Desacetilases/uso terapêutico
Ácidos Hidroxâmicos/uso terapêutico
Imunoterapia
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/imunologia
Camundongos
Linfócitos T/imunologia
Transcriptoma
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); M801H13NRU (Azacitidine); Z02132R2QQ (givinostat hydrochloride)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:28465359
[Au] Autor:Bulstrode H; Johnstone E; Marques-Torrejon MA; Ferguson KM; Bressan RB; Blin C; Grant V; Gogolok S; Gangoso E; Gagrica S; Ender C; Fotaki V; Sproul D; Bertone P; Pollard SM
[Ad] Endereço:Medical Research Council (MRC) Centre for Regenerative Medicine.
[Ti] Título:Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators.
[So] Source:Genes Dev;31(8):757-773, 2017 04 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glioblastoma multiforme (GBM) is an aggressive brain tumor driven by cells with hallmarks of neural stem (NS) cells. GBM stem cells frequently express high levels of the transcription factors FOXG1 and SOX2. Here we show that increased expression of these factors restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative NS cell state. Transcriptional targets include cell cycle and epigenetic regulators (e.g., , , , , , and ). is a critical repressed downstream effector that is controlled via a conserved FOXG1/SOX2-bound -regulatory element. loss, combined with exposure to the DNA methylation inhibitor 5-azacytidine, enforces astrocyte dedifferentiation. DNA methylation profiling in differentiating astrocytes identifies changes at multiple polycomb targets, including the promoter of In patient-derived GBM stem cells, CRISPR/Cas9 deletion of does not impact proliferation in vitro; however, upon transplantation in vivo, -null cells display increased astrocyte differentiation and up-regulate FOXO3. In contrast, SOX2 ablation attenuates proliferation, and mutant cells cannot be expanded in vitro. Thus, FOXG1 and SOX2 operate in complementary but distinct roles to fuel unconstrained self-renewal in GBM stem cells via transcriptional control of core cell cycle and epigenetic regulators.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/fisiopatologia
Epigenômica
Fatores de Transcrição Forkhead/genética
Regulação Neoplásica da Expressão Gênica
Glioblastoma/fisiopatologia
Proteínas do Tecido Nervoso/genética
Células-Tronco Neurais/citologia
Fatores de Transcrição SOXB1/genética
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Astrócitos/citologia
Astrócitos/efeitos dos fármacos
Azacitidina/farmacologia
Neoplasias Encefálicas/genética
Ciclo Celular/efeitos dos fármacos
Ciclo Celular/genética
Diferenciação Celular/efeitos dos fármacos
Diferenciação Celular/genética
Cromatina/metabolismo
Metilação de DNA
Proteína Forkhead Box O3/genética
Proteína Forkhead Box O3/metabolismo
Fatores de Transcrição Forkhead/metabolismo
Regulação Neoplásica da Expressão Gênica/genética
Glioblastoma/genética
Seres Humanos
Mutação
Proteínas do Tecido Nervoso/metabolismo
Ligação Proteica
Fatores de Transcrição SOXB1/metabolismo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Chromatin); 0 (FOXG1 protein, human); 0 (Forkhead Box Protein O3); 0 (Forkhead Transcription Factors); 0 (Nerve Tissue Proteins); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180130
[Lr] Data última revisão:
180130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1101/gad.293027.116


  9 / 5988 MEDLINE  
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[PMID]:27774847
[Au] Autor:DeZern AE; Zeidan AM; Barnard J; Hand W; Al Ali N; Brown F; Zimmerman C; Roboz GJ; Garcia-Manero G; Steensma DP; Komrokji RS; Sekeres MA; Evans MDS Clinical Research Consortium
[Ad] Endereço:a Department of Oncology , Sidney Kimmel Cancer Center , Baltimore , MD , USA.
[Ti] Título:Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC).
[So] Source:Leuk Lymphoma;58(6):1325-1331, 2017 Jun.
[Is] ISSN:1029-2403
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:First-line therapy for higher-risk myelodysplastic syndromes (MDS) includes decitabine (DAC) or azacitidine (AZA). Variables have not identified differential response rates between these. We assessed the influence of patient sex on outcomes including overall survival (OS) in 642 patients with higher-risk MDS treated with AZA or DAC. DAC-treated patients (35% of females, 31% of males) had marginally better OS than AZA-treated patients (p = .043), (median OS of 18.7 months versus 16.4 months), but the difference varied strongly by sex. Female patients treated with DAC had a longer median OS (21.1 months, 95% CI: 16.0-28.0) than female patients treated with AZA (13.2 months, 95% CI: 11.0-15.9; p = .0014), while for males there was no significant difference between HMAs (median OS 18.3 months with DAC versus 17.9 months for AZA, p = .59). The biological reason for this variability is unclear, but may be a consequence of differences in cytidine deaminase activity between men and women.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/uso terapêutico
Metilação de DNA/efeitos dos fármacos
Síndromes Mielodisplásicas/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Azacitidina/análogos & derivados
Azacitidina/uso terapêutico
Progressão da Doença
Feminino
Seres Humanos
Masculino
Meia-Idade
Síndromes Mielodisplásicas/diagnóstico
Síndromes Mielodisplásicas/genética
Síndromes Mielodisplásicas/mortalidade
Fatores Sexuais
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 776B62CQ27 (decitabine); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1080/10428194.2016.1246726


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[PMID]:29190771
[Au] Autor:Mundre RS; Koka P; Dhanaraj P; Khatri N; Vig S; Chandramohan Y; Dhanasekaran A
[Ad] Endereço:Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India.
[Ti] Título:Synergistic role of 5-azacytidine and ascorbic acid in directing cardiosphere derived cells to cardiomyocytes in vitro by downregulating Wnt signaling pathway via phosphorylation of ß-catenin.
[So] Source:PLoS One;12(11):e0188805, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cardiosphere derived cells (CDCs) represent a valuable source in stem cell based therapy for cardiovascular diseases, yet poor differentiation rate hinders the transplantation efficiency. The aim of this study is to check the ability of 5-Azacytidine (Aza) alone and in combination with ascorbic acid (Aza+AA) in delineating CDCs to cardiomyogenesis and the underlying Wnt signaling mechanism in induced differentiation. METHODS: CDCs were treated with Aza and Aza+AA for a period of 14 days to examine the expression of cardiac specific markers and Wnt downstream regulators by immunofluorescence, real time PCR and western blot. RESULTS: Results revealed that Aza+AA induced efficient commitment of CDCs to cardiomyogenic lineage. Immunofluorescence analysis showed significant augment for Nkx 2.5, GATA 4 and α-Sarcomeric actinin markers in Aza+AA group than control group (p = 0.0118, p = 0.009 and p = 0.0091, respectively). Relative upregulation of cardiac markers, Nkx 2.5 (p = 0.0156), GATA 4 (p = 0.0087) and down regulation of Wnt markers, ß-catenin (p = 0.0107) and Cyclin D1 (p = 0. 0116) in Aza+AA group was revealed by RNA expression analysis. Moreover, the Aza+AA induced prominent expression of GATA 4, α-Sarcomeric actinin and phospho ß-catenin while non phospho ß-catenin and Cyclin D1 expression was significantly suppressed as displayed in protein expression analysis. Generation of spontaneous beating in Aza+AA treated CDCs further reinforced that Aza+AA accelerates the cardiomyogenic potential of CDCs. CONCLUSION: Combined treatment of Aza along with AA implicit in inducing cardiomyogenic potential of CDCs and is associated with down regulating Wnt signaling pathway. Altogether, CDCs represent a valuable tool for the treatment of cardiovascular disorders.
[Mh] Termos MeSH primário: Ácido Ascórbico/farmacologia
Azacitidina/farmacologia
Regulação para Baixo/efeitos dos fármacos
Coração/efeitos dos fármacos
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sinergismo Farmacológico
Técnicas In Vitro
Masculino
Fosforilação
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (beta Catenin); M801H13NRU (Azacitidine); PQ6CK8PD0R (Ascorbic Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188805



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