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Pesquisa : Leucemia [Palavras]
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  1 / 255397 MEDLINE  
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[PMID]:29392424
[Au] Autor:Shahkarami S; Mehrasa R; Younesian S; Yaghmaie M; Chahardouli B; Vaezi M; Rezaei N; Nikbakht M; Alimoghaddam K; Ghavamzadeh A; Tavakkoly-Bazzaz J; Ghaffari SH
[Ad] Endereço:Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Minimal residual disease (MRD) detection using rearrangement of immunoglobulin/T cell receptor genes in adult patients with acute lymphoblastic leukemia (ALL).
[So] Source:Ann Hematol;97(4):585-595, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage. An ASO-qPCR technique was then applied for 2.5-year monthly MRD quantification for detection of patient-specific Ig/TCR receptor rearrangements as a molecular target. From 98 patients who were diagnosed as ALL, 72 (73.5%) were enrolled in the present study for MRD detection. MRD was successfully quantified in patients with 1-month interval time. MRD level at the end of induction therapy up to day 88 was the only significant prognostic factor. Regarding MRD level, patients were categorized into two groups of low and high-risk. 2.5-year OS in all three time points (days 28, 58 and 88) were significantly lower in high-risk group (P < 0.008). The results of the 2.5-year MRD detection indicate that MRD level at the end of induction up to about 6 months after the first diagnosis was associated with clinical outcome. This study may highlight the usefulness of PB and the definitions of cut-off level for early prediction of relapse and for stratifying ALL patients. Short-interval time points and frequent PB sampling to monitor MRD level is suggested for early clinical relapse prediction and clinical management of the disease.
[Mh] Termos MeSH primário: Rearranjo Gênico do Linfócito T/efeitos dos fármacos
Quimioterapia de Indução
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
[Mh] Termos MeSH secundário: Adulto
Alelos
Feminino
Seguimentos
Hospitais Universitários
Seres Humanos
Irã (Geográfico)
Masculino
Reação em Cadeia da Polimerase Multiplex
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Neoplasia Residual/diagnóstico
Neoplasia Residual/genética
Neoplasia Residual/metabolismo
Neoplasia Residual/patologia
Oligonucleotídeos/química
Oligonucleotídeos/metabolismo
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
Prognóstico
Estudos Prospectivos
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Medição de Risco
Análise de Sobrevida
Carga Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (Oligonucleotides)
[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:180203
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-018-3230-z


  2 / 255397 MEDLINE  
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[PMID]:29377903
[Au] Autor:Koldehoff M; Lindemann M; Ross SR; Elmaagacli AH
[Ad] Endereço:Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, Essen, Germany.
[Ti] Título:Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line.
[So] Source:PLoS One;13(1):e0191482, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytomegalovirus (HCMV) reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with an increased treatment-related mortality. Recent reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs). Indolamin-2,3-dioxygenase on the other hand led only to a significant dose-dependent effect on IFN-γ secretion without effects on proliferation. The addition of CpG-rich oligonucleotides and ganciclovir reversed those antiproliferative effects. We conclude that HCMV can enhance alloreactivity of PBMCs against Kasumi-1 and NB4 cells in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
[Mh] Termos MeSH primário: Antígenos de Histocompatibilidade Classe II/imunologia
Leucemia Mieloide Aguda/imunologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Técnicas de Cocultura
Seres Humanos
Leucemia Mieloide Aguda/terapia
Leucemia Mieloide Aguda/virologia
Transplante de Células-Tronco
Transplante Homólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histocompatibility Antigens Class II)
[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:180130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191482


  3 / 255397 MEDLINE  
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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]:29332224
[Au] Autor:Tong D; Yu M; Guo L; Li T; Li J; Novakovic VA; Dong Z; Tian Y; Kou J; Bi Y; Wang J; Zhou J; Shi J
[Ad] Endereço:Department of Hematology, First Hospital, Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China.
[Ti] Título:Phosphatidylserine-exposing blood and endothelial cells contribute to the hypercoagulable state in essential thrombocythemia patients.
[So] Source:Ann Hematol;97(4):605-616, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The mechanisms of thrombogenicity in essential thrombocythemia (ET) are complex and not well defined. Our objective was to explore whether phosphatidylserine (PS) exposure on blood cells and endothelial cells (ECs) can account for the increased thrombosis and distinct thrombotic risks among mutational subtypes in ET. Using flow cytometry and confocal microscopy, we found that the levels of PS-exposing erythrocytes, platelets, leukocytes, and serum-cultured ECs were significantly higher in each ET group [JAK2, CALR, and triple-negative (TN) (all P < 0.001)] than those in controls. Among ET patients, those with JAK2 mutations showed higher levels of PS-positive erythrocytes, platelets, neutrophils, and serum-cultured ECs than TN patients or those with CALR mutations, which show similar levels. Coagulation function assays showed that higher levels of PS-positive blood cells and serum-cultured ECs led to markedly shortened coagulation time and dramatically increased levels of FXa, thrombin, and fibrin production. This procoagulant activity could be largely blocked by addition of lactadherin (approx. 70% inhibition). Confocal microscopy showed that the FVa/FXa complex and fibrin fibrils colocalized with PS on ET serum-cultured ECs. Additionally, we found a relationship between D-dimer, prothrombin fragment F1 + 2, and PS exposure. Our study reveals a previously unrecognized link between hypercoagulability and exposed PS on cells, which might also be associated with distinct thrombotic risks among mutational subtypes in ET. Thus, blocking PS-binding sites may represent a new therapeutic target for preventing thrombosis in ET.
[Mh] Termos MeSH primário: Plaquetas/patologia
Endotélio Vascular/patologia
Eritrócitos/patologia
Leucócitos/patologia
Fosfatidilserinas/metabolismo
Trombocitemia Essencial/fisiopatologia
Trombose/etiologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Substituição de Aminoácidos
Plaquetas/metabolismo
Calreticulina/genética
Calreticulina/metabolismo
Células Cultivadas
China/epidemiologia
Endotélio Vascular/metabolismo
Eritrócitos/metabolismo
Feminino
Células Endoteliais da Veia Umbilical Humana/citologia
Células Endoteliais da Veia Umbilical Humana/metabolismo
Seres Humanos
Janus Quinase 2/genética
Janus Quinase 2/metabolismo
Leucócitos/metabolismo
Masculino
Meia-Idade
Mutação
Receptores de Trombopoetina/genética
Receptores de Trombopoetina/metabolismo
Risco
Propriedades de Superfície
Trombocitemia Essencial/genética
Trombocitemia Essencial/metabolismo
Trombocitemia Essencial/patologia
Trombose/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calreticulin); 0 (Phosphatidylserines); 0 (Receptors, Thrombopoietin); 0 (calreticulin, human); 143641-95-6 (MPL protein, human); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)
[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:180115
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-018-3228-6


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[PMID]:29305630
[Au] Autor:Ben Lakhal R; Ghedira H; Bellaaj H; Ben Youssef Y; Menif S; Manai Z; Bedoui M; Lakhal A; M'Sadek F; Elloumi M; Khélif A; Ben Romdhane N; Laatiri MA; Ben Othmen T; Meddeb B
[Ad] Endereço:Hematology Department, Aziza Othmana University Hospital, Tunis, Tunisia. raihane.benlakhal@gmail.com.
[Ti] Título:Chronic myeloid leukemia patients in Tunisia: epidemiology and outcome in the imatinib era (a multicentric experience).
[So] Source:Ann Hematol;97(4):597-604, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Mesilato de Imatinib/uso terapêutico
Leucemia Mieloide de Fase Acelerada/tratamento farmacológico
Leucemia Mieloide de Fase Crônica/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Antineoplásicos/efeitos adversos
Criança
Pré-Escolar
Feminino
Seguimentos
Seres Humanos
Mesilato de Imatinib/efeitos adversos
Leucemia Mieloide de Fase Acelerada/diagnóstico
Leucemia Mieloide de Fase Acelerada/epidemiologia
Leucemia Mieloide de Fase Acelerada/patologia
Leucemia Mieloide de Fase Crônica/diagnóstico
Leucemia Mieloide de Fase Crônica/epidemiologia
Leucemia Mieloide de Fase Crônica/patologia
Masculino
Meia-Idade
Padrões de Prática Médica
Prognóstico
Inibidores de Proteínas Quinases/efeitos adversos
Estudos Retrospectivos
Esplenomegalia/etiologia
Esplenomegalia/patologia
Esplenomegalia/prevenção & controle
Análise de Sobrevida
Carga Tumoral/efeitos dos fármacos
Tunísia/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 8A1O1M485B (Imatinib Mesylate)
[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:180107
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3224-2


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[PMID]:29288428
[Au] Autor:Scappaticci GB; Marini BL; Nachar VR; Uebel JR; Vulaj V; Crouch A; Bixby DL; Talpaz M; Perissinotti AJ
[Ad] Endereço:Department of Pharmacy Services and Clinical Sciences, Michigan Medicine and University of Michigan College of Pharmacy, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.
[Ti] Título:Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.
[So] Source:Ann Hematol;97(4):573-584, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.
[Mh] Termos MeSH primário: Nucleotídeos de Adenina/uso terapêutico
Envelhecimento
Antimetabólitos Antineoplásicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Arabinonucleosídeos/uso terapêutico
Quimioterapia de Indução
Leucemia Mieloide Aguda/tratamento farmacológico
Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/efeitos adversos
Nucleotídeos de Adenina/economia
Idoso
Idoso de 80 Anos ou mais
Antimetabólitos Antineoplásicos/efeitos adversos
Antimetabólitos Antineoplásicos/economia
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Protocolos de Quimioterapia Combinada Antineoplásica/economia
Arabinonucleosídeos/efeitos adversos
Arabinonucleosídeos/economia
Estudos de Casos e Controles
Doença Hepática Induzida por Substâncias e Drogas/economia
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia
Doença Hepática Induzida por Substâncias e Drogas/mortalidade
Doença Hepática Induzida por Substâncias e Drogas/terapia
Estudos de Coortes
Terapia Combinada/economia
Redução de Custos
Custos e Análise de Custo
Citarabina/efeitos adversos
Citarabina/economia
Citarabina/uso terapêutico
Fator Estimulador de Colônias de Granulócitos/efeitos adversos
Fator Estimulador de Colônias de Granulócitos/economia
Fator Estimulador de Colônias de Granulócitos/uso terapêutico
Custos Hospitalares
Seres Humanos
Incidência
Quimioterapia de Indução/efeitos adversos
Quimioterapia de Indução/economia
Tempo de Internação
Leucemia Mieloide Aguda/economia
Leucemia Mieloide Aguda/mortalidade
Michigan/epidemiologia
Meia-Idade
Neutropenia/induzido quimicamente
Neutropenia/economia
Neutropenia/mortalidade
Neutropenia/terapia
Pontuação de Propensão
Estudos Retrospectivos
Análise de Sobrevida
Centros de Atenção Terciária
Vidarabina/efeitos adversos
Vidarabina/economia
Vidarabina/uso terapêutico
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Antimetabolites, Antineoplastic); 0 (Arabinonucleosides); 04079A1RDZ (Cytarabine); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 762RDY0Y2H (clofarabine); FA2DM6879K (Vidarabine)
[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:171231
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3217-1


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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]:29191878
[Au] Autor:Klaeger S; Heinzlmeir S; Wilhelm M; Polzer H; Vick B; Koenig PA; Reinecke M; Ruprecht B; Petzoldt S; Meng C; Zecha J; Reiter K; Qiao H; Helm D; Koch H; Schoof M; Canevari G; Casale E; Depaolini SR; Feuchtinger A; Wu Z; Schmidt T; Rueckert L; Becker W; Huenges J; Garz AK; Gohlke BO; Zolg DP; Kayser G; Vooder T; Preissner R; Hahne H; Tõnisson N; Kramer K; Götze K; Bassermann F; Schlegl J; Ehrlich HC; Aiche S; Walch A; Greif PA; Schneider S; Felder ER; Ruland J; Médard G; Jeremias I; Spiekermann K; Kuster B
[Ad] Endereço:Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), Freising, Germany.
[Ti] Título:The target landscape of clinical kinase drugs.
[So] Source:Science;358(6367), 2017 12 01.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Descoberta de Drogas/métodos
Terapia de Alvo Molecular
Inibidores de Proteínas Quinases/farmacologia
Proteômica/métodos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Linhagem Celular Tumoral
Citocinas/metabolismo
Seres Humanos
Leucemia Mieloide Aguda/tratamento farmacológico
Leucemia Mieloide Aguda/enzimologia
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/enzimologia
Camundongos
Inibidores de Proteínas Quinases/química
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Ensaios Antitumorais Modelo de Xenoenxerto
Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytokines); 0 (Protein Kinase Inhibitors); EC 2.7.1.- (MELK protein, human); EC 2.7.1.- (salt-inducible kinase-2, human); EC 2.7.10.1 (FLT3 protein, human); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:29414952
[Au] Autor:Arriaga-Cázares HE; Cázares-Bellazetin MA; Sánchez-Sánchez LM; Bahena-García AL; Palacios-Saucedo GDC
[Ad] Endereço:Departamento de Pediatría; Centro Médico Nacional del Noreste, Unidad Médica de Alta Especialidad No. 25, Instituto Mexicano del Seguro Social, Monterrey, N.L., México.
[Ti] Título:Alteraciones puberales en adolescentes con leucemia en fase de vigilancia.
[So] Source:Gac Med Mex;153(7):903-906, 2017.
[Is] ISSN:0016-3813
[Cp] País de publicação:Mexico
[La] Idioma:eng
[Ab] Resumo:Objective: To evaluate which factors are associated with alterations in pubertal development in pediatric patients with leukemia in the surveillance phase. Method: A case-control study was carried out, including patients aged 8-14 years with diagnosis of acute lymphoblastic leukemia under surveillance. Demographic data were collected, age at diagnosis, type of leukemia, risk of leukemia, duration and type of treatment received, time of surveillance phase; and pubertal development was assessed by Tanner stage, bone age, pelvic ultrasound for women, and LH levels. Fisher's exact test and Mann-Whitney U-test were used. Results: Twenty-five pediatric patients with a diagnosis of acute lymphoblastic leukemia between 8 and 14 years of age with a median of 8 were included, only 4 (16%) presented pubertal alterations, 1 had pubertal delay and 3 advanced puberty. The history of radiotherapy was related to pubertal alterations (p = 0.03). Conclusions: The antecedent of having received radiotherapy as part of the treatment in patients with acute lymphoblastic leukemia is a risk factor for developing pubertal abnormalities.
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[St] Status:In-Data-Review
[do] DOI:10.24875/GMM.17003098


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[PMID]:28453705
[Au] Autor:Mato AR; Hill BT; Lamanna N; Barr PM; Ujjani CS; Brander DM; Howlett C; Skarbnik AP; Cheson BD; Zent CS; Pu JJ; Kiselev P; Foon K; Lenhart J; Henick Bachow S; Winter AM; Cruz AL; Claxton DF; Goy A; Daniel C; Isaac K; Kennard KH; Timlin C; Fanning M; Gashonia L; Yacur M; Svoboda J; Schuster SJ; Nabhan C
[Ad] Endereço:Center for CLL, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
[Ti] Título:Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.
[So] Source:Ann Oncol;28(5):1050-1056, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem
Intervalo Livre de Doença
Esquema de Medicação
Seres Humanos
Estimativa de Kaplan-Meier
Leucemia Linfocítica Crônica de Células B/mortalidade
Meia-Idade
Modelos de Riscos Proporcionais
Purinas/administração & dosagem
Pirazóis/administração & dosagem
Pirimidinas/administração & dosagem
Quinazolinonas/administração & dosagem
Estudos Retrospectivos
Sulfonamidas/administração & dosagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (PCI 32765); 0 (Purines); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Quinazolinones); 0 (Sulfonamides); N54AIC43PW (venetoclax); YG57I8T5M0 (idelalisib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx031



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