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[PMID]:29390394
[Au] Autor:Wang G; Chen W; Wu Y; Li Y; Leng Y; Liu A
[Ti] Título:Recombinant human thrombopoietin improves the efficacy of intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor in mobilizing peripheral blood stem cells in patients with multiple myeloma: A cohort study.
[So] Source:Medicine (Baltimore);96(50):e9302, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The combination of intermediate-dose cyclophosphamide (ID-CTX) and granulocyte colony-stimulating factor (G-CSF) fails to mobilize peripheral blood stem cells (PBSCs) in approximately 20% of treated patients with multiple myeloma (MM).In this cohort study, patients with MM underwent PBSC mobilization with either an ID-CTX plus G-CSF plus recombinant human thrombopoietin (rhTPO) regimen (72 patients; TPO group), or an ID-CTX plus G-CSF regimen (70 patients; non-TPO group).In the TPO group, the median CD34+ harvest was 5.36 × 10 per kg of body weight (0.50-22.39 × 10 per kg of body weight), with a harvest success rate of 91.7% (66/72), and an excellence rate of 55.6% (40/72). In the non-TPO group, the median CD34+ harvest was 3.30 × 10 per kg of body weight (0.20-21.14 × 10 per kg of body weight), with a harvest success rate of 75.7% (53/70), and an excellence rate of 25.7% (18/70). The median count of the CD34+ cells collected, success rate of collection, and excellence rate of collection were significantly higher in the TPO group than in the non-TPO group (P=.0001, P=.01, and P = .0001, respectively). Time to granulocyte and platelet engraftment was faster among patients in the TPO group than that in those from the non-TPO group. No platelet engraftment delay (>21 days) was observed among patients in the TPO group, while 3 patients in the non-TPO group displayed delayed platelet engraftment.Adding rhTPO to the ID-CTX chemotherapy plus G-CSF regimen improved treatment efficacy in mobilizing PBSCs for autologous hematopoietic stem cell transplantation.
[Mh] Termos MeSH primário: Antineoplásicos Alquilantes/uso terapêutico
Ciclofosfamida/uso terapêutico
Sinergismo Farmacológico
Fator Estimulador de Colônias de Granulócitos/uso terapêutico
Transplante de Células-Tronco Hematopoéticas
Mieloma Múltiplo/tratamento farmacológico
Células-Tronco de Sangue Periférico/efeitos dos fármacos
Trombopoetina/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Quimioterapia Combinada
Feminino
Seres Humanos
Masculino
Meia-Idade
Mieloma Múltiplo/patologia
Estadiamento de Neoplasias
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 8N3DW7272P (Cyclophosphamide); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009302


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[PMID]:28456746
[Au] Autor:Carretta M; de Boer B; Jaques J; Antonelli A; Horton SJ; Yuan H; de Bruijn JD; Groen RWJ; Vellenga E; Schuringa JJ
[Ad] Endereço:Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
[Ti] Título:Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models.
[So] Source:Exp Hematol;51:36-46, 2017 07.
[Is] ISSN:1873-2399
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recently, NOD-SCID IL2Rγ (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34 hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34 cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34 cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.
[Mh] Termos MeSH primário: Diferenciação Celular
Engenharia Genética
Interleucina-3
Células Mesenquimais Estromais/metabolismo
Nicho de Células-Tronco
Trombopoetina
Tecidos Suporte/química
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Xenoenxertos
Seres Humanos
Interleucina-3/biossíntese
Interleucina-3/genética
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/metabolismo
Transplante de Células-Tronco Mesenquimais
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Transplante de Neoplasias
Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo
Trombopoetina/biossíntese
Trombopoetina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IL3 protein, human); 0 (Interleukin-3); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180224
[Lr] Data última revisão:
180224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:28458344
[Au] Autor:Li F; Tang R; Chen LB; Zhang KS; Huang XP; Deng CQ
[Ad] Endereço:Molecular Pathology Laboratory, Hunan University of Chinese Medicine.
[Ti] Título:Effects of Astragalus Combined with Angelica on Bone Marrow Hematopoiesis Suppression Induced by Cyclophosphamide in Mice.
[So] Source:Biol Pharm Bull;40(5):598-609, 2017.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Danggui Buxue Tang (DBT), a combination of Astragalus and Angelica at a 5 : 1 ratio, mainly promotes hematopoiesis. However, in the clinic, the combination ratio of Astragalus and Angelica to treat low hematopoietic function is not an absolute 5 : 1 ratio, suggesting that the herbs may promote hematopoiesis better after being combined at a certain range of ratios. The objective of this study is to investigate the effect of different ratio combinations of Astragalus and Angelica on bone marrow hematopoiesis suppression induced by cyclophosphamide (CTX) and to probe the interaction and mechanism of Astragalus combined with Angelica in promoting hematopoiesis. Following establishment of the model, mice were administered with Astragalus (6.00 g·kg ), Angelica (3.00 g·kg ), and combinations of Astragalus and Angelica at different ratios, including 10 : 1 (Astragalus 9.81 g·kg +Angelica 0.98 g·kg ), 5 : 1 (Astragalus 9.00 g·kg +Angelica 1.80 g·kg ), 2 : 1 (Astragalus 7.71 g·kg +Angelica 3.08 g·kg ), 1 : 1 (Astragalus 5.40 g·kg +Angelica 5.40 g·kg ), 1 : 2.5 (Astragalus 3.08 g·kg +Angelica 7.71 g·kg ), 1 : 5 (Astragalus 1.80 g·kg +Angelica 9.00 g·kg ), and 1 : 10 (Astragalus 0.98 g·kg +Angelica 9.81 g·kg ). Our results suggested that Astragalus mixed with Angelica synergistically promoted hematopoiesis best when the combination ratio of Astragalus and Angelica was 1 : 1, 1 : 2.5 or 1 : 5; moreover, the effect of Angelica was greater than that of Astragalus. The potential mechanisms of the combinations of Astragalus and Angelica that promote hematopoiesis include the dissolution of the effective components, promoting the synthesis and secretion of hematopoietic growth factor (HGF) and the proliferation of hematopoietic progenitor cells (HPCs).
[Mh] Termos MeSH primário: Angelica sinensis/química
Astragalus membranaceus/química
Ciclofosfamida/antagonistas & inibidores
Ciclofosfamida/farmacologia
Medicamentos de Ervas Chinesas/farmacologia
Hematopoese/efeitos dos fármacos
Imunossupressores/farmacologia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/ultraestrutura
Contagem de Células
Combinação de Medicamentos
Composição de Medicamentos
Eritropoetina/metabolismo
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo
Camundongos
Camundongos Endogâmicos ICR
Trombopoetina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drug Combinations); 0 (Drugs, Chinese Herbal); 0 (Immunosuppressive Agents); 0 (Plant Extracts); 0 (danggui buxue decoction); 11096-26-7 (Erythropoietin); 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor); 8N3DW7272P (Cyclophosphamide); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1248/bpb.b16-00802


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[PMID]:29178132
[Au] Autor:Zhang X; Chuai Y; Nie W; Wang A; Dai G
[Ad] Endereço:Department of Oncology, Chinese PLA General Hospital, Beijing, China.
[Ti] Título:Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours.
[So] Source:Cochrane Database Syst Rev;11:CD012035, 2017 11 27.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is defined as a peripheral platelet count less than 100×10 /L, with or without bleeding in cancer patients receiving myelosuppressive chemotherapy. CIT is a significant medical problem during chemotherapy, and it carries the risk of sub-optimal overall survival and bleeding. Alternative interventions to platelet transfusion are limited. Different stages of preclinical and clinical studies have examined the thrombopoietin receptor agonists (TPO-RAs) for CIT in patients with solid tumours. OBJECTIVES: To assess the effects of TPO-RAs to prevent and treat CIT in patients with solid tumours:(1) to prevent CIT in patients without thrombocytopenia before chemotherapy, (2) to prevent recurrence of CIT, and (3) to treat CIT in patients with thrombocytopenia during chemotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, to 28 September 2017), MEDLINE (from 1950 to 28 September 2017), as well as online registers of ongoing trials (Clinical Trials, Chinese Clinical Trial Register, Australian New Zealand Clinical Trial Registry, WHO ICTRP Search Portal, International Standard Randomised Controlled Trial Number registry, GlaxoSmithKline Clinical Study Register, and Amgen Clinical Trials) and conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology, and Conference Proceedings Citation Index-Science, from 2002 up to September 2017) for studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing TPO-RAs alone, or in combination with other drugs, to placebo, no treatment, other drugs, or another TPO-RAs for CIT in patients with solid tumours. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard methodological methods expected by Cochrane. MAIN RESULTS: We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs.We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes).To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes.To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×10 /L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported.The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life. AUTHORS' CONCLUSIONS: No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.
[Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos
Benzoatos/administração & dosagem
Hidrazinas/administração & dosagem
Pirazóis/administração & dosagem
Receptores Fc/administração & dosagem
Receptores de Trombopoetina/agonistas
Proteínas Recombinantes de Fusão/administração & dosagem
Trombocitopenia/tratamento farmacológico
Trombocitopenia/prevenção & controle
Trombopoetina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Seres Humanos
Meia-Idade
Neoplasias/tratamento farmacológico
Ensaios Clínicos Controlados Aleatórios como Assunto
Trombocitopenia/induzido quimicamente
Trombocitopenia/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzoates); 0 (Hydrazines); 0 (Pyrazoles); 0 (Receptors, Fc); 0 (Receptors, Thrombopoietin); 0 (Recombinant Fusion Proteins); 9014-42-0 (Thrombopoietin); GN5XU2DXKV (romiplostim); S56D65XJ9G (eltrombopag)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180111
[Lr] Data última revisão:
180111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD012035.pub2


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[PMID]:29069007
[Au] Autor:Gao Y; Gong M; Zhang C; Kong X; Ma Y
[Ad] Endereço:aDepartment of Hematology bDepartment of Pharmacology, China-Japan Friendship Hospital, Beijing, China.
[Ti] Título:Successful eltrombopag treatment of severe refractory thrombocytopenia in chronic myelomonocytic leukemia: Two cases reports: A CARE-compliant article.
[So] Source:Medicine (Baltimore);96(43):e8337, 2017 Oct.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Thrombocytopenia in chronic myelomonocytic leukemia (CMML) is usually attributed to impaired marrow production resulting from cytotoxic drug use or CMML itself ("CMML-induced thrombocytopenia"). In very rare cases, immune thrombocytopenia (ITP) can be a complication of CMML ("CMML-associated ITP"). However, treatment of severe thrombocytopenia in patients with CMML is still a challenge. PATIENT CONCERNS: Case 1 was a 61-year-old female patient admitted to our hospital because of skin petechiae and purpura for 6 days. She had increased monocyte cell count (1.82 × 10/L), markedly decreased platelet count (2 × 10/L), hypercellularity of the megakaryocyte lineage with many immature megakaryocytes, and ZRSR2(zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) mutation. She failed to the treatment of corticosteroids, intravenous immunoglobulin (IVIg), TPO (thrombopoietin), and cyclosporin A (CsA). Case 2 was a 72-year-old female patient with thrombocytosis and monocytosis for 4 years, and thrombocytopenia for 6 months. After 10 courses of decitabine therapy, she had a persistent severe thrombocytopenia and decreased number of megakaryocytes, TET2 (tet methylcytosine dioxygenase 2) and SRSF2 (serine and arginine rich splicing factor 2) mutations were detected. She was dependent on platelet transfusion. DIAGNOSES: Case 1 was diagnosed as CMML-associated ITP, and case 2 as CMML with decitabine therapy-induced thrombocytopenia. INTERVENTIONS: Both patients were treated with eltrombopag. OUTCOMES: In both patients, the platelet counts returned to the normal within 1 week after eltrombopag therapy. The platelet count in case 1 patient remained stable at 141-200 × 10/L for 20 months with stopping therapy for 3 months. In case 2 patient, eltrombopag was stopped 1 month later. Her platelet count decreased to 41 × 10/L, but was stable at ∼30 × 10/L for 3 months with platelet transfusion independency for 12 months. Both patients had no adverse effects with eltrombopag. LESSONS: CMML-associated ITP is very rare and easily misdiagnosed. To the best of our knowledge, case 1 is the first reported case of the successful treatment of CMML-associated ITP with eltrombopag. Both CMML-associated ITP and decitabine therapy-induced thrombocytopenia in these 2 patients were highly sensitive and safe to eltrombopag therapy.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Benzoatos/administração & dosagem
Hidrazinas/administração & dosagem
Leucemia Mielomonocítica Crônica
Púrpura Trombocitopênica Idiopática
Pirazóis/administração & dosagem
Trombocitopenia
Trombopoetina/agonistas
[Mh] Termos MeSH secundário: Idoso
Antimetabólitos Antineoplásicos/efeitos adversos
Azacitidina/efeitos adversos
Proteínas de Ligação a DNA/genética
Monitoramento de Medicamentos
Feminino
Fármacos Hematológicos/administração & dosagem
Seres Humanos
Leucemia Mielomonocítica Crônica/sangue
Leucemia Mielomonocítica Crônica/complicações
Leucemia Mielomonocítica Crônica/diagnóstico
Leucemia Mielomonocítica Crônica/tratamento farmacológico
Meia-Idade
Mutação
Proteínas Nucleares/genética
Contagem de Plaquetas/métodos
Proteínas Proto-Oncogênicas/genética
Púrpura Trombocitopênica Idiopática/diagnóstico
Púrpura Trombocitopênica Idiopática/tratamento farmacológico
Púrpura Trombocitopênica Idiopática/etiologia
Púrpura Trombocitopênica Idiopática/fisiopatologia
Ribonucleoproteínas/genética
Fatores de Processamento de Serina-Arginina/genética
Trombocitopenia/induzido quimicamente
Trombocitopenia/diagnóstico
Trombocitopenia/tratamento farmacológico
Trombocitopenia/fisiopatologia
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Benzoates); 0 (DNA-Binding Proteins); 0 (Hematologic Agents); 0 (Hydrazines); 0 (Nuclear Proteins); 0 (Proto-Oncogene Proteins); 0 (Pyrazoles); 0 (Ribonucleoproteins); 0 (TET2 protein, human); 0 (ZRSR2 protein, human); 147153-65-9 (SRSF2 protein, human); 170974-22-8 (Serine-Arginine Splicing Factors); 776B62CQ27 (decitabine); 9014-42-0 (Thrombopoietin); M801H13NRU (Azacitidine); S56D65XJ9G (eltrombopag)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008337


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[PMID]:28783756
[Au] Autor:Kostyak JC; Liverani E; Kunapuli SP
[Ad] Endereço:Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, United States of America.
[Ti] Título:PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.
[So] Source:PLoS One;12(8):e0182867, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: It has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKCε remains elusive. OBJECTIVE: To delineate the role of PKCε in megakaryopoiesis. APPROACH AND RESULTS: We used a PKCε knockout mouse model to examine the effect of PKCε deficiency on platelet mass, megakaryocyte mass, and bone marrow progenitor cell distribution. We also investigated platelet recovery in PKCε null mice and TPO-mediated signaling in PKCε null megakaryocytes. PKCε null mice have higher platelet counts due to increased platelet production compared to WT littermate controls (p<0.05, n = 8). Furthermore, PKCε null mice have more bone marrow megakaryocyte progenitor cells than WT littermate control mice. Additionally, thrombopoietin-mediated signaling is perturbed in PKCε null mice as Akt and ERK1/2 phosphorylation are enhanced in PKCε null megakaryocytes stimulated with thrombopoietin. Finally, in response to immune-induced thrombocytopenia, PKCε null mice recovered faster and had higher rebound thrombocytosis than WT littermate control mice. CONCLUSIONS: Enhanced platelet recovery could be due to an increase in megakaryocyte progenitor cells found in PKCε null mice as well as enhanced thrombopoietin-mediated signaling observed in PKCε deficient megakaryocytes. These data suggest that PKCε is a negative regulator of megakaryopoiesis.
[Mh] Termos MeSH primário: Técnicas de Inativação de Genes
Proteína Quinase C-épsilon/deficiência
Proteína Quinase C-épsilon/genética
Células-Tronco/citologia
Células-Tronco/metabolismo
Trombopoese
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/citologia
Diferenciação Celular/efeitos dos fármacos
Megacariócitos/citologia
Megacariócitos/efeitos dos fármacos
Camundongos
Contagem de Plaquetas
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
Células-Tronco/efeitos dos fármacos
Trombocitopenia/enzimologia
Trombocitopenia/imunologia
Trombopoese/efeitos dos fármacos
Trombopoese/genética
Trombopoetina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9014-42-0 (Thrombopoietin); EC 2.7.11.13 (Protein Kinase C-epsilon)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182867


  7 / 2845 MEDLINE  
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[PMID]:28630121
[Au] Autor:Kong Z; Qin P; Xiao S; Zhou H; Li H; Yang R; Liu X; Luo J; Li Z; Ji G; Cui Z; Bai Y; Wu Y; Shao L; Peng J; Ma J; Hou M
[Ad] Endereço:Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
[Ti] Título:A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy.
[So] Source:Blood;130(9):1097-1103, 2017 Aug 31.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to determine the safety and efficacy of recombinant human thrombopoietin (rhTPO) for the management of immune thrombocytopenia (ITP) during pregnancy. Pregnant patients with ITP were enrolled in the study if they had a platelet count less than 30 × 10 /L, were experiencing bleeding manifestations, had failed to respond to corticosteroids and/or intravenous immunoglobulin (IVIG), and had developed refractoriness to platelet transfusion. Thirty-one patients received rhTPO at an initial dose of 300 U/kg once daily for 14 days. Twenty-three patients responded (74.2%), including 10 complete responders (>100 × 10 /L) and 13 responders (30-100 × 10 /L). It appears that rhTPO ameliorated the bleeding symptoms remarkably, even in the nonresponders. rhTPO was well tolerated. Dizziness, fatigue, and pain at an injection site were reported in 1 patient each. No congenital disease or developmental delays were observed in the infants in a median follow-up of 53 (range, 39-68) weeks. In conclusion, rhTPO is a potentially safe and effective treatment choice for patients with ITP during pregnancy. Our work has paved the way for further study on the clinical application of rhTPO and other thrombopoietic agents for the management of ITP during pregnancy. This study is registered at www.clinicaltrials.gov as NCT02391272.
[Mh] Termos MeSH primário: Complicações Hematológicas na Gravidez/tratamento farmacológico
Púrpura Trombocitopênica Idiopática/tratamento farmacológico
Proteínas Recombinantes/uso terapêutico
Trombopoetina/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Feminino
Hemorragia/tratamento farmacológico
Seres Humanos
Recém-Nascido
Contagem de Plaquetas
Gravidez
Complicações Hematológicas na Gravidez/sangue
Púrpura Trombocitopênica Idiopática/sangue
Proteínas Recombinantes/efeitos adversos
Trombopoetina/efeitos adversos
Trombopoetina/sangue
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Recombinant Proteins); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-01-761262


  8 / 2845 MEDLINE  
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[PMID]:28630120
[Au] Autor:Machlus KR; Wu SK; Vijey P; Soussou TS; Liu ZJ; Shacham E; Unger TJ; Kashyap T; Klebanov B; Sola-Visner M; Crochiere M; Italiano JE; Landesman Y
[Ad] Endereço:Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
[Ti] Título:Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis.
[So] Source:Blood;130(9):1132-1143, 2017 Aug 31.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Selinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905.
[Mh] Termos MeSH primário: Hidrazinas/efeitos adversos
Megacariócitos/metabolismo
Megacariócitos/patologia
Transdução de Sinais/efeitos dos fármacos
Trombocitopenia/induzido quimicamente
Trombocitopenia/metabolismo
Trombopoese/efeitos dos fármacos
Trombopoetina/metabolismo
Triazóis/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Plaquetas/efeitos dos fármacos
Plaquetas/patologia
Medula Óssea/efeitos dos fármacos
Medula Óssea/patologia
Contagem de Células
Diferenciação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Feto/patologia
Fígado/embriologia
Megacariócitos/efeitos dos fármacos
Megacariócitos/ultraestrutura
Camundongos Knockout
Ativação Plaquetária/efeitos dos fármacos
Células-Tronco/citologia
Trombocitopenia/sangue
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydrazines); 0 (KPT-330); 0 (Triazoles); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-752840


  9 / 2845 MEDLINE  
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[PMID]:28616874
[Au] Autor:Fenaux P; Muus P; Kantarjian H; Lyons RM; Larson RA; Sekeres MA; Becker PS; Orejudos A; Franklin J
[Ad] Endereço:Service d'Hématologie Clinique, Hôpital St. Louis and Paris 7 University, Paris, France.
[Ti] Título:Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy.
[So] Source:Br J Haematol;178(6):906-913, 2017 Sep.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Romiplostim can improve platelet counts in about 50% of patients with low- or intermediate 1-risk (lower risk) myelodysplastic syndromes (MDS) and thrombocytopenia, but its long-term toxicity and efficacy are not known. This open-label extension study evaluated the long-term safety and efficacy of romiplostim in 60 patients with lower risk MDS and platelet counts ≤50 × 10 /l. The primary endpoint was adverse event (AE) incidence. Secondary endpoints were efficacy parameters, including bleeding events and platelet response. Median (range) treatment time in the extension study and the median observation times thereafter were 25 (2-181) and 57 (11-209) weeks, respectively. Treatment-related AEs and serious AEs were reported in 14/60 (23%) and 4/60 (7%) patients, respectively. Progression to acute myeloid leukaemia (AML) occurred in two patients after 44 and 46 weeks. Patients (n = 34, 57%) with a platelet response were further evaluated for length of response. Median (range) response duration was 33 (7-174) weeks; 28/34 (82%) patients had a continuous response. Five of 34 patients (15%) had grade ≥3 bleeding events; three when the platelet count was >50 × 10 /l. There were no new safety concerns and the rate of progression to AML was low; response to romiplostim was maintained for most patients.
[Mh] Termos MeSH primário: Fármacos Hematológicos/efeitos adversos
Síndromes Mielodisplásicas/tratamento farmacológico
Proteínas Recombinantes de Fusão/efeitos adversos
Trombocitopenia/tratamento farmacológico
Trombopoetina/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Progressão da Doença
Esquema de Medicação
Feminino
Seguimentos
Fármacos Hematológicos/administração & dosagem
Fármacos Hematológicos/uso terapêutico
Hemorragia/induzido quimicamente
Seres Humanos
Leucemia Mieloide Aguda/induzido quimicamente
Masculino
Meia-Idade
Síndromes Mielodisplásicas/sangue
Contagem de Plaquetas
Receptores Fc/administração & dosagem
Receptores Fc/uso terapêutico
Receptores de Trombopoetina/agonistas
Proteínas Recombinantes de Fusão/administração & dosagem
Proteínas Recombinantes de Fusão/uso terapêutico
Trombocitopenia/sangue
Trombopoetina/administração & dosagem
Trombopoetina/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Hematologic Agents); 0 (Receptors, Fc); 0 (Receptors, Thrombopoietin); 0 (Recombinant Fusion Proteins); 143641-95-6 (MPL protein, human); 9014-42-0 (Thrombopoietin); GN5XU2DXKV (romiplostim)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14792


  10 / 2845 MEDLINE  
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[PMID]:28571971
[Au] Autor:Graf ME; Sookthai D; Johnson T; Schübel R; Katzke V; Bugert P; Hoffmeister M; Kaaks R; Kühn T
[Ad] Endereço:Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
[Ti] Título:Biological reproducibility of circulating P-Selectin, Thrombopoietin, GPIIb/IIIa and Thrombomodulin over one year.
[So] Source:Clin Biochem;50(16-17):942-946, 2017 Nov.
[Is] ISSN:1873-2933
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Enhanced platelet activation has been implicated in several pathophysiological processes. Here, we evaluated the biological reproducibility of circulating P-Selectin, Thrombomodulin (TM), Thrombopoietin (TPO), and Glycoprotein IIb/IIIa (GPIIb/IIIa) to assess whether these analytes can be used as reliable biomarkers of platelet activation in epidemiological studies. METHODS: We measured circulating P-Selectin, TM, TPO and GPIIb/IIIa by immunoassays in two blood samples of 78 participants of the EPIC Heidelberg study (47-80years, 50% female) that were collected one year apart. Biological reproducibility of biomarker levels over time and associations with routine biochemistry parameters were assessed by Spearman's correlation coefficients. RESULTS: Statistical analyses revealed good reproducibility over one year for two of the analyzed markers, with Spearman coefficients of ρ=0.80 (P-Selectin) and ρ=0.73 (TPO) and reasonable reproducibility for TM (ρ=0.63) and GPIIb/IIIa (ρ=0.51). Levels of P-Selectin, TM, TPO and GPIIb/IIIa were not significantly associated with routine biochemistry parameters, such as glucose, HbA1c, LDL, HDL, Triglycerides and CRP. CONCLUSIONS: Our findings suggest that a single assessment of P-Selectin, TM, TPO and GPIIb/IIIa at baseline in prospective epidemiological studies is appropriate to investigate associations between platelet activation and risks of chronic diseases.
[Mh] Termos MeSH primário: Selectina-P/sangue
Ativação Plaquetária
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/análise
Trombomodulina/sangue
Trombopoetina/sangue
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores/sangue
Feminino
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (P-Selectin); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (SELP protein, human); 0 (THBD protein, human); 0 (Thrombomodulin); 9014-42-0 (Thrombopoietin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE



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