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[PMID]:29349655
[Au] Autor:Lo WJ; Lin CL; Chang YC; Bai LY; Lin CY; Liang JA; Li LY; Chao LM; Chiu CF; Chen CM; Yeh SP
[Ad] Endereço:Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
[Ti] Título:Total body irradiation tremendously impair the proliferation, differentiation and chromosomal integrity of bone marrow-derived mesenchymal stromal stem cells.
[So] Source:Ann Hematol;97(4):697-707, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.
[Mh] Termos MeSH primário: Apoptose/efeitos da radiação
Células da Medula Óssea/efeitos da radiação
Aberrações Cromossômicas/efeitos da radiação
Células-Tronco Hematopoéticas/efeitos da radiação
Células Mesenquimais Estromais/efeitos da radiação
Lesões por Radiação/patologia
Irradiação Corporal Total/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Células-Tronco Adultas/efeitos da radiação
Células da Medula Óssea/citologia
Células da Medula Óssea/patologia
Diferenciação Celular/efeitos da radiação
Proliferação Celular/efeitos da radiação
Células Cultivadas
China
Transtornos Cromossômicos/etiologia
Transtornos Cromossômicos/patologia
Feminino
Transplante de Células-Tronco Hematopoéticas
Células-Tronco Hematopoéticas/citologia
Células-Tronco Hematopoéticas/patologia
Hospitais Universitários
Seres Humanos
Leucemia/patologia
Leucemia/terapia
Masculino
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/patologia
Necrose
Lesões por Radiação/etiologia
Condicionamento Pré-Transplante/efeitos adversos
Células Tumorais Cultivadas
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-018-3231-y


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[PMID]:29247860
[Au] Autor:Schulz-Fincke J; Hau M; Barth J; Robaa D; Willmann D; Kürner A; Haas J; Greve G; Haydn T; Fulda S; Lübbert M; Lüdeke S; Berg T; Sippl W; Schüle R; Jung M
[Ad] Endereço:Institute of Pharmaceutical Sciences, University of Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
[Ti] Título:Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation.
[So] Source:Eur J Med Chem;144:52-67, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals. Here, we show that N-substituted 2-PCPA derivatives without a basic function or even a polar group are still potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture. Yet, these lipophilic inhibitors also block the structurally related monoamine oxidases (MAO-A and MAO-B), which may be of interest for the treatment of neurodegenerative disorders, but this property is undesired for applications in cancer treatment. The introduction of a polar, non-basic function led to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells. Cellular target engagement is shown via a Cellular Thermal Shift Assay (CETSA) for LSD1.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Histona Desmetilases/antagonistas & inibidores
Tranilcipromina/análogos & derivados
Tranilcipromina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Histona Desmetilases/metabolismo
Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/metabolismo
Leucemia/patologia
Camundongos
Modelos Moleculares
Inibidores da Monoaminoxidase/química
Inibidores da Monoaminoxidase/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Monoamine Oxidase Inhibitors); 3E3V44J4Z9 (Tranylcypromine); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


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[PMID]:29302031
[Au] Autor:Guarnerio J; Mendez LM; Asada N; Menon AV; Fung J; Berry K; Frenette PS; Ito K; Pandolfi PP
[Ad] Endereço:Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
[Ti] Título:A non-cell-autonomous role for Pml in the maintenance of leukemia from the niche.
[So] Source:Nat Commun;9(1):66, 2018 01 04.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Disease recurrence after therapy, due to the persistence of resistant leukemic cells, represents a fundamental problem in the treatment of leukemia. Elucidating the mechanisms responsible for the maintenance of leukemic cells, before and after treatment, is therefore critical to identify curative modalities. It has become increasingly clear that cell-autonomous mechanisms are not solely responsible for leukemia maintenance. Here, we report a role for Pml in mesenchymal stem cells (MSCs) in supporting leukemic cells of both CML and AML. Mechanistically, we show that Pml regulates pro-inflammatory cytokines within MSCs, and that this function is critical in sustaining CML-KLS and AML ckit leukemic cells non-cell autonomously.
[Mh] Termos MeSH primário: Leucemia/metabolismo
Células Mesenquimais Estromais/metabolismo
Células-Tronco Neoplásicas/metabolismo
Proteína da Leucemia Promielocítica/metabolismo
Nicho de Células-Tronco
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Proliferação Celular/genética
Células Cultivadas
Citocinas/metabolismo
Leucemia/genética
Leucemia/patologia
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo
Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
Leucemia Mieloide/genética
Leucemia Mieloide/metabolismo
Leucemia Mieloide/patologia
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Proteína da Leucemia Promielocítica/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytokines); 0 (Promyelocytic Leukemia Protein)
[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/s41467-017-02427-x


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[PMID]:29335768
[Au] Autor:Hammrich J; Wittig S; Ernst T; Gruhn B
[Ad] Endereço:Department of Pediatrics, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.
[Ti] Título:CTLA-4 polymorphisms: influence on transplant-related mortality and survival in children undergoing allogeneic hematopoietic stem cell transplantation.
[So] Source:J Cancer Res Clin Oncol;144(3):587-592, 2018 Mar.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for a variety of hematological diseases; however, it is still associated with substantial morbidity and mortality. Transplant-related mortality (TRM) after HSCT depends mainly on the toxicity of the conditioning regimen, infections, and graft-versus-host disease. The purpose of this study was to identify the association between CTLA-4 single nucleotide polymorphisms and TRM in children undergoing allogeneic HSCT. METHODS: 153 donors and 153 children with acute lymphoblastic leukemia, acute myeloid leukemia or juvenile myelomonocytic leukemia who had undergone allogeneic HSCT were genotyped of CTLA-4 gene for rs3087243 (CT60G>A), rs231775 (+ 49 A>G) and rs4553808 using TaqMan real-time polymerase chain reaction. RESULTS: We observed a significant association between the donor's CLTA-4 genotype of rs3087243 and TRM in children undergoing allogeneic HSCT. Genotype AG was found in 78 donors (51%), GG in 44 donors (29%) and 31 donors (20%) were homozygous for AA. 30 patients died as a result of transplant-related causes. Interestingly, we observed a significantly reduced TRM in children who were transplanted from a donor with the CTLA-4 genotype GG in comparison to genotype AG or AA (9 versus 19 versus 36%, P = 0.013). In addition, we found significant differences of event-free survival (EFS) depending on the donor's genotype. The EFS was 64, 46 or 32% if the patient was transplanted from a donor with CTLA-4 genotype GG, AG or AA, respectively (P = 0.043). In multivariate analysis, CTLA-4 genotype of rs3087243 was an independent risk factor for TRM (P = 0.011) and EFS (P = 0.035). CONCLUSION: This study provides first evidence that the CTLA-4 polymorphisms are significant risk factors for TRM and survival in children undergoing allogeneic HSCT and should be evaluated in further trials.
[Mh] Termos MeSH primário: Antígeno CTLA-4/genética
Doença Enxerto-Hospedeiro/genética
Doença Enxerto-Hospedeiro/mortalidade
Transplante de Células-Tronco Hematopoéticas/mortalidade
Leucemia/mortalidade
Leucemia/terapia
Polimorfismo de Nucleotídeo Único
Doadores de Tecidos
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Intervalo Livre de Doença
Feminino
Genótipo
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Seres Humanos
Leucemia/genética
Masculino
Estudos Retrospectivos
Transplante Homólogo/efeitos adversos
Transplante Homólogo/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTLA-4 Antigen); 0 (CTLA4 protein, human)
[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:180117
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-018-2578-8


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[PMID]:29284775
[Au] Autor:Skrypnyk I; Maslova G; Lymanets T; Gusachenko I
[Ad] Endereço:Chair of Internal Medicine â„– 1, Ukrainian Medical Stomatological Academy, Poltava 36011, Ukraine.
[Ti] Título:L-arginine is an effective medication for prevention of endothelial dysfunction, a predictor of anthracycline cardiotoxicity in patients with acute leukemia.
[So] Source:Exp Oncol;39(4):308-311, 2017 Dec.
[Is] ISSN:1812-9269
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:AIM: To evaluate the effectiveness of L-arginine in the prevention of endothelial dysfunction, which may be a predictor of anthracycline-induced myocardial injury, in patients with acute leukemia (AL) on the background of anthracycline antibiotics low cumulative doses from 100 to 200 mg/m . MATERIALS AND METHODS: A total of 81 adult AL patients (38 males and 43 females with the age of 16-59 years) were studied. The patients were divided into two groups: group I (n = 34), AL patients treated with chemotherapy (CT) and L-arginine hydrochloride; group II (n = 47) - AL patients treated with CT only. Cardiac evaluation and endothelial function assessment were performed at baseline and after second CT. Electrocardiography (ECG) parameters, lipid peroxidation activity, antioxidant protection and NO system state were evaluated. RESULTS: The bioelectric activity abnormalities of the myocardium were observed in studied patients with low cardiac risk after induction CT. In case of L-arginine administration, only minimal daily ECG changes were recorded. A significant difference in the lipid peroxidation and antioxidant defense system activity in patients of groups I and II was determined. We noticed deepening of endothelial dysfunction on the background of cytostatic therapy with anthracycline antibiotics compared with baseline values in patients of group II. It was found that prophylactic L-arginine increases superoxide dismutase level and reduces the total NOS activity due to its inducible isoform. CONCLUSION: The leading factor of anthracycline-induced cardiotoxicity is the imbalance between free radical generation and their inactivation that leads to endothelial dysfunction development. L-arginine eliminates the prooxidant-antioxidant imbalance and improves the endothelial function.
[Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos
Antioxidantes/uso terapêutico
Arginina/uso terapêutico
Cardiotoxicidade/prevenção & controle
Leucemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Antraciclinas/efeitos adversos
Endotélio Vascular/efeitos dos fármacos
Endotélio Vascular/patologia
Feminino
Coração/efeitos dos fármacos
Seres Humanos
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthracyclines); 0 (Antineoplastic Agents); 0 (Antioxidants); 94ZLA3W45F (Arginine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE


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[PMID]:29395854
[Au] Autor:Sarradin V; Simon L; Huynh A; Gilhodes J; Filleron T; Izar F
[Ad] Endereço:Department of radiotherapy, IUCT-Oncopole, 1, avenue Irène-Joliot-Curie, 31000 Toulouse, France.
[Ti] Título:Total body irradiation using Helical Tomotherapy : Treatment technique, dosimetric results and initial clinical experience.
[So] Source:Cancer Radiother;22(1):17-24, 2018 Feb.
[Is] ISSN:1769-6658
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Helical TomoTherapy allows precise and homogeneous tumour coverage and excellent sparing of organs at risk. We present here our treatment technique, dosimetric results, and our first clinical data for patients receiving total body irradiation as part of the conditioning regimen before hematopoietic stem cell transplantation. PATIENTS AND METHODS: The cohort consisted of 11 patients who were treated in our institution between August 2014 and January 2016. The total dose was 12Gy in six fractions in three days. We collected the dose distribution information in the treatment volumes, organs at risk and area of junction. We report retrospectively the clinical events during the first 6 months after the procedure. RESULTS: Median age was 31 years (range, 18-57 years). Median D98% was 11.5Gy (range: 6.6-11.9Gy). The median of the mean doses to the lungs was 8.7Gy (range: 8.5-9.3Gy). The mean dose for the junction area was 12Gy (range: 11.9-12.1Gy). All patients had the total procedure, and all underwent successful engraftment. During the first six months, nine patients had at least one grade 3 or 4 toxicity that was due essentially to graft versus host disease. No patient had radiation pneumonitis. The toxicities were both more frequent and of higher grade during the first three months. CONCLUSION: Total body irradiation using helical TomoTherapy is feasible. It allows a very good homogeneity of dose and conformity with an acceptable tolerance. It could deliver higher doses to sites at high risk of recurrence (bone marrow, sanctuary sites), while sparing major normal organs like lungs, liver, and kidneys. This reduction of dose could lead to reduced severity and frequency of late complications.
[Mh] Termos MeSH primário: Radioterapia de Intensidade Modulada
Irradiação Corporal Total
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Coortes
Feminino
Seres Humanos
Leucemia/terapia
Linfoma de Células T/terapia
Masculino
Meia-Idade
Tratamentos com Preservação do Órgão
Órgãos em Risco
Dosagem Radioterapêutica
Radioterapia de Intensidade Modulada/métodos
Estudos Retrospectivos
Transplante de Células-Tronco
Irradiação Corporal Total/métodos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180204
[St] Status:MEDLINE


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[PMID]:29254892
[Au] Autor:Wang ZH; Li DD; Chen WL; You QD; Guo XK
[Ad] Endereço:State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
[Ti] Título:Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy.
[So] Source:Bioorg Med Chem;26(2):356-365, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed.
[Mh] Termos MeSH primário: Histona-Lisina N-Metiltransferase/antagonistas & inibidores
Leucemia/tratamento farmacológico
Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores
Proteínas de Neoplasias/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Histona-Lisina N-Metiltransferase/química
Seres Humanos
Leucemia/genética
Estrutura Molecular
Proteína de Leucina Linfoide-Mieloide/química
Proteínas de Neoplasias/química
Ligação Proteica/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (MLL protein, human); 0 (Neoplasm Proteins); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE


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[PMID]:28456379
[Au] Autor:Rivière I; Sadelain M
[Ad] Endereço:Center for Cell Engineering, Molecular Pharmacology and Immunology Programs, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
[Ti] Título:Chimeric Antigen Receptors: A Cell and Gene Therapy Perspective.
[So] Source:Mol Ther;25(5):1117-1124, 2017 May 03.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immunology, synthetic biology, target identification, cell manufacturing sciences, and regulatory compliance-the central tenets of CAR therapy. Here, we review two of these foundations: the genetic engineering approaches and cell types to engineer.
[Mh] Termos MeSH primário: Antígenos CD19/genética
Terapia Baseada em Transplante de Células e Tecidos/métodos
Leucemia/terapia
Linfoma/terapia
Proteínas Mutantes Quiméricas/genética
Receptores de Antígenos de Linfócitos T/genética
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Antígenos CD19/imunologia
Engenharia Celular/métodos
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/imunologia
Seres Humanos
Imunoterapia/métodos
Lentivirus/genética
Lentivirus/imunologia
Leucemia/genética
Leucemia/imunologia
Leucemia/patologia
Linfoma/genética
Linfoma/imunologia
Linfoma/patologia
Proteínas Mutantes Quiméricas/imunologia
Engenharia de Proteínas/métodos
Receptores de Antígenos de Linfócitos T/imunologia
Retroviridae/genética
Retroviridae/imunologia
Linfócitos T/classificação
Linfócitos T/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antigens, CD19); 0 (CD19 molecule, human); 0 (Mutant Chimeric Proteins); 0 (Receptors, Antigen, T-Cell)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:29298347
[Au] Autor:Grundy M; Seedhouse C; Jones T; Elmi L; Hall M; Graham A; Russell N; Pallis M
[Ad] Endereço:Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom.
[Ti] Título:Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling.
[So] Source:PLoS One;13(1):e0190682, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents-notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors-sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Leucemia/patologia
[Mh] Termos MeSH secundário: Azepinas/farmacologia
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Linhagem Celular Tumoral
Combinação de Medicamentos
Seres Humanos
Indóis/farmacologia
Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Sulfonamidas/farmacologia
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 ((+)-JQ1 compound); 0 (A-1210477); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Drug Combinations); 0 (Indoles); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Sulfonamides); 0 (Triazoles); N54AIC43PW (venetoclax)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190682


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[PMID]:27777140
[Au] Autor:Ruggeri A; Volt F; Locatelli F; Michel G; Diaz de Heredia C; Abecasis M; Zecca M; Vora A; Yakouben K; O'Brien TA; Giardino S; Cornish J; Rocha V; Peters C; Bader P; Gluckman E; Dalle JH
[Ad] Endereço:Service d'Hématologie et Therapie cellulaire, Hôpital Saint Antoine, Paris, France; Eurocord, University Paris VII IUH Paris, France. Electronic address: annalisa.ruggeri@aphp.fr.
[Ti] Título:Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis.
[So] Source:Biol Blood Marrow Transplant;23(1):96-102, 2017 Jan.
[Is] ISSN:1523-6536
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.
[Mh] Termos MeSH primário: Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos
Leucemia/terapia
[Mh] Termos MeSH secundário: Doença Aguda
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade
Doença Enxerto-Hospedeiro/etiologia
Seres Humanos
Lactente
Recém-Nascido
Leucemia/complicações
Leucemia/mortalidade
Leucemia Mieloide Aguda/complicações
Leucemia Mieloide Aguda/mortalidade
Leucemia Mieloide Aguda/terapia
Agonistas Mieloablativos/uso terapêutico
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
Sistema de Registros
Indução de Remissão
Estudos Retrospectivos
Fatores de Risco
Condicionamento Pré-Transplante/métodos
Resultado do Tratamento
Doadores não Relacionados
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Myeloablative Agonists)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE



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