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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]: 29330228 [Au] Autor: McCormack A; Dekkers OM; Petersenn S; Popovic V; Trouillas J; Raverot G; Burman P; ESE survey collaborators [Ad] Endereço: St Vincent's Hospital and Garvan Institute of Medical ResearchSydney, Australia. [Ti] Título: Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. [So] Source: Eur J Endocrinol;178(3):265-276, 2018 03. [Is] ISSN: 1479-683X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment. DESIGN: Electronic survey to ESE members Dec 2015-Nov 2016. RESULTS: Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4-79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%. CONCLUSION: This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies. [Mh] Termos MeSH primário: Adenoma/terapia Antineoplásicos Alquilantes/uso terapêutico Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Carcinoma/terapia Irradiação Craniana Dacarbazina/análogos & derivados Procedimentos Neurocirúrgicos Neoplasias Hipofisárias/terapia [Mh] Termos MeSH secundário: Adenoma/metabolismo Adenoma/patologia Adolescente Adulto Idoso Bevacizumab/administração & dosagem Capecitabina/administração & dosagem Carcinoma/metabolismo Carcinoma/patologia Carmustina/administração & dosagem Criança Pré-Escolar Metilases de Modificação do DNA/metabolismo Enzimas Reparadoras do DNA/metabolismo Dacarbazina/administração & dosagem Dacarbazina/uso terapêutico Endocrinologia Europa (Continente) Feminino Seres Humanos Antígeno Ki-67/metabolismo Masculino Meia-Idade Invasividade Neoplásica Neoplasias Hipofisárias/metabolismo Neoplasias Hipofisárias/patologia Sociedades Médicas Inquéritos e Questionários Talidomida/administração & dosagem Proteínas Supressoras de Tumor/metabolismo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents, Alkylating); 0 (Ki-67 Antigen); 0 (Tumor Suppressor Proteins); 2S9ZZM9Q9V (Bevacizumab); 4Z8R6ORS6L (Thalidomide); 6804DJ8Z9U (Capecitabine); 7GR28W0FJI (Dacarbazine); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes); U68WG3173Y (Carmustine); YF1K15M17Y (temozolomide) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180114 [St] Status: MEDLINE [do] DOI: 10.1530/EJE-17-0933

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[PMID]: 27776349 [Au] Autor: De Summa S; Guida M; Tommasi S; Strippoli S; Pellegrini C; Fargnoli MC; Pilato B; Natalicchio I; Guida G; Pinto R [Ad] Endereço: IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy. [Ti] Título: Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a Caucasian family. [So] Source: Oncotarget;8(18):29751-29759, 2017 May 02. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model. [Mh] Termos MeSH primário: Albinismo/genética Estudos de Associação Genética Predisposição Genética para Doença Mutação em Linhagem Germinativa Melanoma/genética Mutação Neoplasias Primárias Múltiplas/genética [Mh] Termos MeSH secundário: Albinismo/diagnóstico Biomarcadores Biologia Computacional/métodos Metilação de DNA Metilases de Modificação do DNA/química Metilases de Modificação do DNA/genética Análise Mutacional de DNA Enzimas Reparadoras do DNA/química Enzimas Reparadoras do DNA/genética Família Feminino Genótipo Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Masculino Melanoma/diagnóstico Meia-Idade Modelos Moleculares Anotação de Sequência Molecular Neoplasias Primárias Múltiplas/diagnóstico Linhagem Filogenia Conformação Proteica Irmãos Proteínas Supressoras de Tumor/química Proteínas Supressoras de Tumor/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (Tumor Suppressor Proteins); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes) [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: 161025 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.12777

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[PMID]: 28448738 [Au] Autor: Anton T; Bultmann S [Ad] Endereço: a Department of Biology II and Center for Integrated Protein Science Munich (CIPSM) , LMU Munich , Martinsried , Germany. [Ti] Título: Site-specific recruitment of epigenetic factors with a modular CRISPR/Cas system. [So] Source: Nucleus;8(3):279-286, 2017 May 04. [Is] ISSN: 1949-1042 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Dissecting the complex network of epigenetic modifications requires tools that combine precise recognition of DNA sequences with the capability to modify epigenetic marks. The CRISPR/Cas system has been proven to be a valuable addition to existing methodologies that fulfill these tasks. So far, sequence-specific editing of epigenetic modifications such as DNA methylation and histone posttranslational modifications relied on direct fusions of enzymatically inactivated Cas9 (dCas9) with epigenetic effectors. Here, we report a novel, modular system that facilitates the recruitment of any GFP-tagged protein to desired genomic loci. By fusing dCas9 to a GFP-binding nanobody (GBP) we demonstrate that prevalent epigenetic modifications at mouse major satellite repeats can be erased or set de novo by recruiting GFP-coupled catalytic domains of TET1 and DNMT3A, respectively. Furthermore, we construct an inducible expression system that enables a temporally controlled expression of both GBP-dCas9 and the effector protein. Thus, our approach further expands the CRISPR/Cas toolbox for site-specific manipulation of epigenetic modifications with a modular and easy-to-use system. [Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética Epigênese Genética [Mh] Termos MeSH secundário: Animais Sequência de Bases Sítios de Ligação Linhagem Celular Metilases de Modificação do DNA/metabolismo Doxiciclina/farmacologia Proteínas de Fluorescência Verde/genética Camundongos Regiões Promotoras Genéticas/genética Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 147336-22-9 (Green Fluorescent Proteins); EC 2.1.1.- (DNA Modification Methylases); N12000U13O (Doxycycline) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1080/19491034.2017.1292194

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[PMID]: 29352318 [Au] Autor: William D; Walther M; Schneider B; Linnebacher M; Classen CF [Ad] Endereço: University Children's and Adolescents' Hospital, University Medicine of Rostock, Rostock, Germany. [Ti] Título: Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma. [So] Source: PLoS One;13(1):e0191511, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment. [Mh] Termos MeSH primário: Antineoplásicos Alquilantes/efeitos adversos Neoplasias Encefálicas/tratamento farmacológico Neoplasias Encefálicas/patologia Dacarbazina/análogos & derivados Glioblastoma/tratamento farmacológico Glioblastoma/patologia [Mh] Termos MeSH secundário: Antibacterianos/administração & dosagem Antineoplásicos Alquilantes/administração & dosagem Biomarcadores Tumorais/metabolismo Neoplasias Encefálicas/metabolismo Diferenciação Celular/efeitos dos fármacos Linhagem Celular Tumoral Metilases de Modificação do DNA/genética Enzimas Reparadoras do DNA/genética Dacarbazina/administração & dosagem Dacarbazina/efeitos adversos Doxiciclina/administração & dosagem Resistência a Medicamentos Antineoplásicos Fucosiltransferases/metabolismo Glioblastoma/metabolismo Seres Humanos Antígeno Lewis X/metabolismo Mitocôndrias/efeitos dos fármacos Células-Tronco Neoplásicas/efeitos dos fármacos Células-Tronco Neoplásicas/metabolismo Células-Tronco Neoplásicas/patologia Nestina/metabolismo Ensaio Tumoral de Célula-Tronco Proteínas Supressoras de Tumor/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Antineoplastic Agents, Alkylating); 0 (Biomarkers, Tumor); 0 (Lewis X Antigen); 0 (NES protein, human); 0 (Nestin); 0 (Tumor Suppressor Proteins); 7GR28W0FJI (Dacarbazine); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 2.4.1.- (FUT4 protein, human); EC 2.4.1.- (Fucosyltransferases); EC 6.5.1.- (DNA Repair Enzymes); N12000U13O (Doxycycline); YF1K15M17Y (temozolomide) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180121 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191511

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[PMID]: 27775109 [Au] Autor: Zhang XR; Zhang Y; Chen FT; Li Y; Zhang SS [Ad] Endereço: Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China. [Ti] Título: Visual detection of single-nucleotide polymorphisms and DNA methyltransferase based on cation-exchange of CuS nanoparticles and click chemistry of functionalized gold nanoparticles. [So] Source: Chem Commun (Camb);52(90):13261-13264, 2016 Nov 03. [Is] ISSN: 1364-548X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A novel biosensor was developed based on the cation-exchange of CuS nanoparticles (NPs) and Cu(i)-based click chemistry of functionalized gold nanoparticles (AuNPs). As a proof-of-principle, novel applications of this method as a versatile biosensor for single-nucleotide polymorphisms (SNPs) and DNA methyltransferase (MTase) were presented. [Mh] Termos MeSH primário: Técnicas Biossensoriais/métodos Calorimetria/métodos Cobre/química Metilases de Modificação do DNA/metabolismo Ouro/química Nanopartículas Metálicas/química Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Química Click Troca Iônica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 7440-57-5 (Gold); 789U1901C5 (Copper); EC 2.1.1.- (DNA Modification Methylases); KL4YU612X7 (cupric sulfide) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180205 [Lr] Data última revisão: 180205 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161104 [St] Status: MEDLINE

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[PMID]: 28993285 [Au] Autor: Lu K; Chen X; Li W; Li Y; Zhang Z; Zhou Q [Ad] Endereço: College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, PR China; State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China. [Ti] Título: Insulin-like peptides and DNA/tRNA methyltransferases are involved in the nutritional regulation of female reproduction in Nilaparvata lugens (Stål). [So] Source: Gene;639:96-105, 2018 Jan 10. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Insulin-like peptides (ILPs) sense and transduce nutritional information and are linked to female reproduction in many insect species. Our previous studies have shown that "Target of rapamycin" (TOR) pathway functions through juvenile hormone (JH) to regulate amino acids-mediated vitellogenesis in the brown planthopper, Nilaparvata lugens, one of the most destructive rice pests in Asia. Recent reports have demonstrated that DNA methyltransferases (Dnmts) are also involved in female reproduction of N. lugens. However, the roles of ILPs and Dnmts in the nutritional regulation of female reproduction have not been fully elucidated. ILPs and Dnmts are highly expressed in the adult females after a supplement of amino acids, indicating nutrition-stimulated expression patterns of these genes. RNA interference-mediated depletion of NlILP2 or NlILP4 dramatically decreased the expression levels of NlDnmt1 and NlDnmt2 (tRNA methyltransferase), and resulted in severely impaired ovary growth as well as the substantial reduction of fecundity. Notably, NlILP2 or NlILP4 knockdown led to reduced mRNA accumulation of S6 kinase (S6K), a downstream target of the nutritional TOR pathway, and decreased vitellogenin content in the fat body. Silencing NlDnmt1 or NlDnmt2 effectively suppressed ovary development and decreased female fecundity. However, NlDnmt1 or NlDnmt2 knockdown did not influence the expression of NlILP2 and NlILP4. We infer that amino acids act on ILPs and Dnmts to regulate vitellogenesis and oocyte maturation in N. lugens. [Mh] Termos MeSH primário: Metilases de Modificação do DNA/metabolismo Hemípteros/fisiologia Insulina/fisiologia Peptídeos/fisiologia tRNA Metiltransferases/metabolismo [Mh] Termos MeSH secundário: Animais Metilases de Modificação do DNA/genética Feminino Regulação da Expressão Gênica no Desenvolvimento Regulação Enzimológica da Expressão Gênica Inativação Gênica Insulina/química Interferência de RNA Reprodução tRNA Metiltransferases/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Insulin); 0 (Peptides); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.- (tRNA Methyltransferases) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171227 [Lr] Data última revisão: 171227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171011 [St] Status: MEDLINE

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[PMID]: 28834127 [Au] Autor: Kinoshita M; Yamada A; Sawa D; Kamimura S; Miyachi M; Moritake H [Ad] Endereço: Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. [Ti] Título: Successful treatment of metastatic alveolar rhabdomyosarcoma with MGMT gene promoter methylation by temozolomide-based combination chemotherapy. [So] Source: Pediatr Blood Cancer;65(1), 2018 Jan. [Is] ISSN: 1545-5017 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A 3-year-old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Serum microRNA-206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC). Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR-206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients. [Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem Quimiorradioterapia Metilação de DNA Metilases de Modificação do DNA/metabolismo Enzimas Reparadoras do DNA/metabolismo DNA de Neoplasias/metabolismo Regiões Promotoras Genéticas Rabdomiossarcoma Alveolar Proteínas Supressoras de Tumor/metabolismo [Mh] Termos MeSH secundário: Camptotecina/administração & dosagem Camptotecina/análogos & derivados Pré-Escolar Ciclofosfamida/administração & dosagem Dacarbazina/administração & dosagem Dacarbazina/análogos & derivados Dactinomicina/administração & dosagem Seres Humanos Masculino MicroRNAs/metabolismo Metástase Neoplásica RNA Neoplásico/metabolismo Rabdomiossarcoma Alveolar/metabolismo Rabdomiossarcoma Alveolar/patologia Rabdomiossarcoma Alveolar/terapia Vincristina/administração & dosagem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA, Neoplasm); 0 (MIRN206 microRNA, human); 0 (MicroRNAs); 0 (RNA, Neoplasm); 0 (Tumor Suppressor Proteins); 1CC1JFE158 (Dactinomycin); 5J49Q6B70F (Vincristine); 7673326042 (irinotecan); 7GR28W0FJI (Dacarbazine); 8N3DW7272P (Cyclophosphamide); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes); XT3Z54Z28A (Camptothecin); YF1K15M17Y (temozolomide) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171129 [Lr] Data última revisão: 171129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170824 [St] Status: MEDLINE [do] DOI: 10.1002/pbc.26750

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[PMID]: 29036186 [Au] Autor: Hsu CY; Ho HL; Lin SC; Ho TD; Ho DM [Ad] Endereço: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. [Ti] Título: The MGMT promoter single-nucleotide polymorphism rs1625649 had prognostic impact on patients with MGMT methylated glioblastoma. [So] Source: PLoS One;12(10):e0186430, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Promoter methylation is the most significant mechanism to regulate O6-methylguanine-DNA-methyltransferase (MGMT) expression. Single-nucleotide polymorphisms (SNPs) in the MGMT promoter region may also play a role. The aim of this study was to evaluate the clinical significance of SNPs in the MGMT promoter region of glioblastoma. Genomic DNAs from 118 glioblastomas were collected for polymerase chain reaction (PCR) amplification. Sanger sequencing was used to sequence the MGMT promoter region to detect SNPs. The results were correlated with MGMT status and patient survival. Rs1625649 was the only polymorphic SNP located at the MGMT promoter region in 37.5% of glioblastomas. Homozygous rs1625649 (AA genotype) was correlated with a higher MGMT methylation level and a lower protein expression, but the result was not statistically significant. In patients with MGMT methylated glioblastoma, cases with homozygous rs1625649 (AA genotype) were significantly associated with a lack of MGMT protein expression and a better progression-free survival (PFS) than the cases with wild type rs1625649 (CC genotype) or heterozygous rs1625649 (CA genotype). The survival impact was significant in multivariate analyses. In conclusion, the MGMT promoter homozygous rs1625649 (AA genotype) was found to correlate with a better PFS in patients with MGMT methylated glioblastoma. [Mh] Termos MeSH primário: Metilação de DNA Metilases de Modificação do DNA/genética Enzimas Reparadoras do DNA/genética Glioblastoma/diagnóstico Glioblastoma/genética Polimorfismo de Nucleotídeo Único Proteínas Supressoras de Tumor/genética [Mh] Termos MeSH secundário: Feminino Seres Humanos Masculino Meia-Idade Prognóstico Regiões Promotoras Genéticas/genética Análise de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Tumor Suppressor Proteins); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 6.5.1.- (DNA Repair Enzymes) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171017 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186430

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[PMID]: 28969371 [Au] Autor: Thiepold AL; Lorenz NI; Foltyn M; Engel AL; Divé I; Urban H; Heller S; Bruns I; Hofmann U; Dröse S; Harter PN; Mittelbronn M; Steinbach JP; Ronellenfitsch MW [Ad] Endereço: Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. [Ti] Título: Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death. [So] Source: Brain;140(10):2623-2638, 2017 Oct 01. [Is] ISSN: 1460-2156 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -ß). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations. [Mh] Termos MeSH primário: Morte Celular/efeitos dos fármacos Hipóxia Celular/fisiologia Complexos Multiproteicos/metabolismo Serina-Treonina Quinases TOR/metabolismo [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Metilases de Modificação do DNA/genética Enzimas Reparadoras do DNA/genética Glioma/genética Glioma/patologia Glucose/metabolismo Seres Humanos Isocitrato Desidrogenase/genética Ácido Láctico/metabolismo Alvo Mecanístico do Complexo 1 de Rapamicina Complexos Multiproteicos/genética Mutação/genética Consumo de Oxigênio PTEN Fosfo-Hidrolase/genética Espécies Reativas de Oxigênio/metabolismo Serina-Treonina Quinases TOR/genética Proteína Supressora de Tumor p53 Proteínas Supressoras de Tumor/genética Proteínas Supressoras de Tumor/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Multiprotein Complexes); 0 (Reactive Oxygen Species); 0 (Tumor Suppressor Protein p53); 0 (Tumor Suppressor Proteins); 33X04XA5AT (Lactic Acid); 4JG2LF96VF (tuberous sclerosis complex 2 protein); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 1.1.1.42. (IDH1 protein, human); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human); EC 6.5.1.- (DNA Repair Enzymes); IY9XDZ35W2 (Glucose) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 171004 [St] Status: MEDLINE [do] DOI: 10.1093/brain/awx196

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