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1.
Br J Haematol ; 203(3): 468-476, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37654088

RESUMO

To determine the prevalence and clinical relevance of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cell populations (paroxysmal nocturnal haemoglobinuria [PNH]-type cells) in patients with acquired aplastic anaemia (AA) or myelodysplastic syndrome (MDS), we prospectively studied peripheral blood samples of 2402 patients (1075 with AA, 900 with MDS, 144 with PNH, and 283 with other anaemia) using a high-sensitivity flow cytometry assay in a nationwide multi-centre observational study. PNH-type cells were detected in 52.6% of AA and 13.7% of MDS patients. None of the 35 patients with refractory anaemia (RA) with ringed sideroblasts or the 86 patients with RA with excess of blasts carried PNH-type cells. Among the 317 patients possessing PNH-type granulocytes, the percentage of PNH-type granulocytes increased by ≥10% in 47 patients (14.8%), remained unchanged in 240 patients (75.7%), and decreased by ≥10% in 30 patients (9.5%) during 3 years of follow-up. PNH-type granulocyte expansion occurred more frequently (27.1%) in the 144 patients who originally carried PNH-type granulocytes ≥1% than in the 173 patients with PNH-type granulocytes <1% (4.6%). This study confirmed that PNH-type cells are undetectable in authentic clonal MDS patients, and the presence of ≥1% PNH-type granulocytes predicts a higher likelihood of PNH-type cell expansion than with <1% PNH-type granulocytes.

2.
Fukushima J Med Sci ; 68(3): 175-178, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130907

RESUMO

Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.


Assuntos
Hemoglobinúria Paroxística , Masculino , Humanos , Idoso , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Angina Instável/tratamento farmacológico
3.
Ann Hematol ; 100(8): 1975-1982, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33095337

RESUMO

Small populations of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cells accounting for up to 0.01% of total granulocytes can be accurately detected by a high-sensitivity flow cytometry (FCM) assay established by the Clinical and Laboratory Standards Institute (CLSI method) and have a prognostic value in bone marrow failure (BMF); however, the significance of GPI(-) granulocytes accounting for 0.001-0.009% of granulocytes remains unclear. To clarify this issue, we examined the peripheral blood of 21 BMF patients in whom minor (around 0.01%) populations of GPI(-) granulocytes had been previously detected by a different high-resolution FCM method (OPTIMA method, which defines ≥ 0.003% GPI(-) granulocytes as an abnormal increase) using both the CLSI and OPTIMA methods simultaneously. These two methods detected an "abnormal increase" in GPI(-) granulocytes in 10 patients (48%) and 17 patients (81%), respectively. CLSI detected 0.002-0.005% (median, 0.004%) GPI(-) granulocytes in 7 patients who were deemed positive for PNH-type cells according to the OPTIMA method, which detected 0.003-0.012% (median 0.006%) GPI(-) granulocytes. The clone sizes of GPI(-) cells detected by each assay were positively correlated (r = 0.994, p < 0.001). Of the seven patients who were judged positive for PNH-type cells by OPTIMA alone, five received immunosuppressive therapy, and all of them achieved a partial or complete response. GPI(-) granulocytes detected in BMF patients by the CLSI method should thus be considered significant, even at percentages of < 0.01%.


Assuntos
Transtornos da Insuficiência da Medula Óssea/patologia , Proteínas Ligadas por GPI/análise , Granulócitos/patologia , Hemoglobinúria Paroxística/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Serviços de Laboratório Clínico , Feminino , Hemoglobinúria Paroxística/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Ann Hematol ; 97(12): 2289-2297, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30039297

RESUMO

Minor populations of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cells in the peripheral blood may have a prognostic value in bone marrow failure (BMF). Our objective is to establish the optimal flow cytometry (FCM) assay that can discriminate GPI(-) populations specific to BMF from those of healthy individuals. To identify a cut-off that discriminates GPI(-) rare cells from GPI(+) cells, we determined a position of the borderline that separates the GPI(-) from GPI(+) cells on a scattergram by testing more than 30 healthy individuals, such that no GPI(-) dot fell into the upper left quadrant where fluorescein-labeled aerolysin (FLAER)-CD11b+ granulocytes and CD55-CD59- glycophorin A+ erythrocytes were positioned. This method allowed us to define ≥ 0.003% CD11b+FLAER- granulocytes and ≥ 0.005% glycophorin A+CD55-CD59- erythrocytes to be specific to BMF patients. Longitudinal cross-validation studies showed minimal (< 0.02%) inter-laboratory differences in the GPI(-) cell percentage. An analysis of 1210 patients with BMF revealed a GPI(-) cell population in 56.3% of patients with aplastic anemia and 18.5% of patients with myelodysplastic syndrome. The GPI(-) granulocyte percentages was 0.003-0.01% in 3.7% of patients. This FCM assay effectively identified an increase in the percentage of GPI(-) rare cells that are specific to BMF patients and allowed different laboratories to accurately detect 0.003-0.01% of pathological GPI(-) cells.


Assuntos
Anemia Aplástica , Antígenos CD/sangue , Doenças da Medula Óssea , Eritrócitos , Citometria de Fluxo/métodos , Granulócitos , Hemoglobinúria Paroxística , Anemia Aplástica/sangue , Anemia Aplástica/patologia , Doenças da Medula Óssea/sangue , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Eritrócitos/metabolismo , Eritrócitos/patologia , Feminino , Granulócitos/metabolismo , Granulócitos/patologia , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/patologia , Humanos , Masculino
6.
Int J Hematol ; 107(6): 656-665, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29383624

RESUMO

In paroxysmal nocturnal hemoglobinuria (PNH), various symptoms due to intravascular hemolysis exert a negative impact on patients' quality of life (QOL). To determine clinical factors related with improvements in QOL in PNH patients treated, we analyzed changes in QOL scales in PNH patients treated with eculizumab based on data collected from post-marketing surveillance in Japan. Summary statistics were obtained using figures from QOL scoring systems and laboratory values, and evaluated by t test. One-year administration of eculizumab improved the most QOL items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values. Changes in serum lactate dehydrogenase (LDH) and hemoglobin showed strong correlations with QOL improvement. Quality of life improvement was independent of patients' baseline characteristics of co-occurrence of bone marrow failure (BMF), or the degree of LDH. In this analysis, we found that the degree of QOL improvement was independent of the baseline LDH before eculizumab treatment and of co-occurrence of BMF. Paroxysmal nocturnal hemoglobinuria patients who have not received eculizumab treatment due to mild hemolysis may benefit from eculizumab treatment.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Inativadores do Complemento/administração & dosagem , Hemoglobinúria Paroxística/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Feminino , Hemoglobinas , Hemoglobinúria Paroxística/sangue , Humanos , Hidroliases/sangue , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
Int J Hematol ; 104(5): 548-558, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27464489

RESUMO

Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month's treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 109/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Vigilância de Produtos Comercializados/métodos , Anticorpos Monoclonais Humanizados/efeitos adversos , Transfusão de Sangue/estatística & dados numéricos , Hemoglobinas/análise , Hemólise/efeitos dos fármacos , Humanos , Japão , Rim/fisiologia , Resultado do Tratamento
10.
Int J Hematol ; 103(6): 703-12, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26857155

RESUMO

Pregnancy with paroxysmal nocturnal hemoglobinuria (PNH) is associated with significant risk of complications, such as life-threatening thrombosis. Recently, eculizumab has come into clinical use and revolutionized the treatment of PNH. However, clinical information regarding eculizumab use for PNH during pregnancy is limited. The present report describes pregnancies with PNH treated with eculizumab that were registered with the Japan PNH study group and reviews the literature. In case 1, the patient received eculizumab throughout pregnancy and delivered a healthy neonate at term, although breakthrough hemolysis occurred at 20 weeks of gestation. In case 2, the patient discontinued eculizumab before pregnancy and developed preeclampsia at 27 weeks of gestation. She received eculizumab and delivered a preterm, but healthy, neonate by cesarean section. In case 3, the patient received eculizumab from 18 weeks of gestation and delivered a healthy neonate at term without any complications. Reports of 11 pregnant women treated with eculizumab were identified in the literature. Of 14 pregnancies, including our own cases, breakthrough hemolysis and preeclampsia occurred in five and two cases, respectively. There were no thrombotic complications, maternal or neonatal deaths, or fetal structural abnormalities. Thus, eculizumab appears to be safe and effective for managing PNH during pregnancy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Adulto , Feminino , Humanos , Gravidez , Resultado da Gravidez
11.
N Engl J Med ; 370(7): 632-9, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24521109

RESUMO

BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear. METHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients. RESULTS: Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. CONCLUSIONS: The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/genética , Resistência a Medicamentos/genética , Hemoglobinúria Paroxística/genética , Mutação de Sentido Incorreto , Anticorpos Monoclonais Humanizados/farmacocinética , Povo Asiático , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/etnologia , Humanos , Japão , Análise de Sequência de DNA
12.
Biomark Res ; 2(1): 2, 2014 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-24451620

RESUMO

We applied our new method, maturity-dependent fractionation of bone marrow-derived neutrophil progenitors, to a study of gene expression profiles during granulopoiesis in myelodysplastic syndromes. CD34+ cells with low density [F1], CD11b-/CD16- [F2], CD11b+/CD16- [F3] and CD11b+/CD16low [F4] with intermediate density, CD11b+/CD16int [F5] and CD11b+/CD16high [F6] with high density were isolated from six patients. Although AML1 and C/EBP-ϵ mRNA peaked at F1 and F4, respectively, in healthy individuals, C/EBP-ϵ was maximized at F2/F3 in all patients, two of whom showed simultaneous peaks of AML1 at F2. Thus, this fractionation is useful to detect mistimed induction of granulopoiesis-regulating genes in myelodysplastic syndromes.

13.
Int J Hematol ; 98(4): 406-16, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23934275

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive hematopoietic stem cell disorder characterized by chronic complement-mediated hemolysis leading to life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal complement activation, reduces hemolysis, decreases the risk of thrombosis, and improves renal function and quality of life in PNH patients. The long-term efficacy and safety of eculizumab in Japanese patients were assessed in a 2-year extension to a 12-week, open-label study (AEGIS). Eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis (P < 0.001) and red blood cell transfusions (P = 0.0016) compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment. The majority of patients had stable (56 %) or improved (41 %) renal function and an improved quality of life (P = 0.015), with sustained reductions in fatigue and dyspnea. Eculizumab was well tolerated; no deaths or serious hemolytic events were reported, and the rate of infections declined over time. There were no significant differences in the response to eculizumab in patients with or without bone marrow dysfunction. These results demonstrate that eculizumab is an effective, well-tolerated long-term treatment for Japanese PNH patients and leads to continued amelioration of some hemolytic complications.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Complemento C5/antagonistas & inibidores , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
14.
PLoS One ; 8(4): e61107, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593403

RESUMO

Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3'UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (P<0.01). To our knowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.


Assuntos
Granulócitos/metabolismo , Síndromes Mielodisplásicas/genética , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Estabilidade de RNA/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Estudos de Casos e Controles , Proteínas ELAV/metabolismo , Emetina/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Granulócitos/efeitos dos fármacos , Granulócitos/enzimologia , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Int J Hematol ; 96(5): 624-30, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23054649

RESUMO

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n = 27) or Hodgkin lymphoma (HD n = 3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67 months (56-133 months). The major toxicities were anorexia (94 %), diarrhea (80 %), nausea (79 %), febrile neutropenia (70 %), alopecia (67 %) and mucositis (60 %). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6 %. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n = 13) and transformed FL (n = 2) patients, OS and EFS at 3 years were 72 and 46 %, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Taxa de Sobrevida , Transplante Autólogo
16.
Int J Hematol ; 95(6): 660-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22527853

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is characterized by a post-thymic immunophenotype, salient chromosome abnormalities, and an aggressive clinical course. However, cases in which these features are absent have been occasionally reported in Japan. Here, clinical and biological features of 13 T-PLL cases, diagnosed between 1992 and 2009 in the Tohoku region of Japan, were compared with three Western series. Median age was 64 (range 40-78) years old, and the male to female ratio (12:1) was higher than that of the Western series (P < 0.04). Presented manifestations were similar to those of Western cases, but central nervous system involvement, which is rare in Western cases, was observed in 3 of 13 cases (23 %) (P < 0.04). Immunophenotypic patterns were similar to those of Western cases, but HLA-DR was positive in 6 of 9 cases (67 %), which is distinct from Western cases (0-9 %) (P < 0.002). By chromosome analyses, 14q11 abnormality and trisomy 8q, which are common among Western cases (70-80 %), were not observed in any cases (P < 0.002). Morphologically, seven were classified as typical type, five as a small-cell variant, and one as a cerebriform variant. Seven cases experienced an aggressive course, whereas six experienced an indolent course over a median follow-up of 50 months. In contrast to Western cases, clinical courses were closely correlated with morphological types; 86 % of typical types were aggressive, whereas 83 % of small-cell types were indolent (P = 0.025). On the basis of these observations, together with previous Japanese cases in the literature, we propose that Japanese cases of T-PLL may constitute a variant.


Assuntos
Leucemia Prolinfocítica de Células T/diagnóstico , Adulto , Idoso , Antígenos CD/metabolismo , Células Sanguíneas/patologia , Feminino , Humanos , Imunofenotipagem , Japão , Leucemia Prolinfocítica de Células T/classificação , Leucemia Prolinfocítica de Células T/mortalidade , Masculino , Pessoa de Meia-Idade
17.
Exp Hematol ; 40(8): 675-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22484554

RESUMO

To investigate differentiation-dependent gene expression during granulopoiesis, we established a new method to isolate six sequential differentiation stages of neutrophil progenitors from bone marrow. Neutrophil progenitors were divided into three populations by density centrifugation, followed by depletion of other lineages, and further separated by fluorescence-activated cell sorting based on the expressions of CD34, CD11b, and CD16: CD34(+) fraction from a low-density population (F1), CD11b(-)/CD16(-) (F2), CD11b(+)/CD16(-) (F3), and CD11b(+)/CD16(low) (F4) fractions with intermediate density, and CD11b(+)/CD16(int) (F5) and CD11b(+)/CD16(high) (F6) fractions from a high-density population. To examine whether this fractionation was applicable to the study of in vivo gene expression profiles during granulopoiesis, we analyzed messenger RNA levels of AML-1 and CCAAT/enhancer binding protein (EBP)-ε and two target genes of C/EBP-ε, granulocyte-macrophage colony-stimulating factor receptor common ß subunit and lactoferrin, in the six fractions and peripheral blood-derived neutrophils (F7). Expression of AML-1 and C/EBP-ε peaked at F1 and F4, respectively, followed by a gradual decrease. Although granulocyte-macrophage colony-stimulating factor receptor common ß subunit messenger RNA levels remained low from F1 through F6 and elevated at F7, lactoferrin messenger RNA showed a drastic increase at F3 and dropped at F5. The difference in the expression profiles of the two C/EBP-ε target genes suggests the involvement of regulators other than C/EBP-ε in the induction of the two genes. The new fractionation method is able to provide new information on maturation-dependent gene expression during granulopoiesis.


Assuntos
Diferenciação Celular , Fracionamento Celular/métodos , Perfilação da Expressão Gênica/métodos , Células-Tronco Hematopoéticas/fisiologia , Neutrófilos/fisiologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Centrifugação com Gradiente de Concentração , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Hematopoese , Humanos , Lactoferrina/genética
18.
Br J Haematol ; 156(3): 383-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22017592

RESUMO

Patients with paroxysmal nocturnal haemoglobinuria (PNH) have expanded clonal cells bearing a somatic mutation in the PIGA gene. Our previous study on two PNH patients with chromosome 12 rearrangements demonstrated the involvement of HMGA2 expression in clonal expansion. The present study investigated HMGA2 expression in PNH patients without chromosomal abnormalities. The expression of short HMGA2 with latent exon was significantly high in peripheral blood cells from 18 of 24 patients. Over-expression of truncated HMGA2 in mouse bone marrow cells caused expansion in recipient mice. These results support the idea that deregulated expression of HMGA2 causes expansion of PNH cells.


Assuntos
Proteína HMGA2/fisiologia , Hemoglobinúria Paroxística/metabolismo , Processamento Alternativo , Anemia Aplástica/patologia , Animais , Células da Medula Óssea/patologia , Divisão Celular , Células Cultivadas/transplante , Células Clonais/patologia , Ensaio de Unidades Formadoras de Colônias , Éxons/genética , Regulação da Expressão Gênica , Proteína HMGA2/biossíntese , Proteína HMGA2/genética , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/patologia , Humanos , Proteínas de Membrana/deficiência , Camundongos , Quimera por Radiação , Proteínas Recombinantes de Fusão/fisiologia , Transdução Genética
19.
J Clin Exp Hematop ; 51(1): 29-35, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21628858

RESUMO

To clarify the clinical outcome of peripheral T-cell lymphomas (PTCLs), we conducted a retrospective review comparing the outcomes of patients with PTCL (nodal peripheral T-cell lymphoma, unspecified, n=34 ; angioimmunoblastic T-cell lymphoma, n=12) to those with diffuse large B-cell lymphoma (DLBCL, n=48). All patients received CHOP-based chemotherapy without rituximab. PTCL patients presented at a more advanced clinical stage (91% vs. 65%, P<0.002) with a poorer performance status (26% vs. 17%, P<0.002) than DLBCL patients. The complete response rate among PTCL patients was significantly lower than among DLBCL patients (39% vs. 67%, P<0.008), as was the 3-year overall survival rate (26% vs. 50%, P=0.005), and Cox multivariate analysis revealed immunophenotype, performance status, and extranodal site involved to be significantly associated with shorter overall survival (P=0.045, P=0.007, and P=0.034, respectively). Our findings suggest that PTCL patients tend to have a poor prognosis associated with several initial risk factors. Moreover, the T-cell phenotype itself appears to have a significant impact on overall survival. Thus, standard CHOP chemotherapy may be inadequate for PTCLs, especially in patients with high-risk factors. The development of newly stratified therapies for the treatment of PTCLs would be highly desirable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto Jovem
20.
Ann Clin Biochem ; 48(Pt 5): 474-7, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21606072

RESUMO

A 52-year-old Japanese woman was referred to our hospital because of fever and coxalgia. She had a white blood cell count of 241 × 10(2)/µL with 59.6% blasts, which had a high nuclear/cytoplasmic ratio and variably condensed nuclear chromatin. Flow cytometry and chromosomal analysis of bone marrow cells indicated positive findings of CD10, CD19, CD34, HLA-DR antigens and t(9; 22)(q34; q11.2), respectively. No rearrangements of bcr/abl in peripheral blood neutrophils were found by fluorescence in situ hybridization, suggesting that she had B-acute lymphoblastic leukaemia with Ph chromosome. Blood glucose and HbA(1c) (glycated haemoglobin) levels on admission were 23.4 mmol/L and 21.0%, respectively. The results of 1.5 anhydro-d-glucitol and glycoalbumin tests revealed that she certainly had diabetes mellitus (DM). Insulin therapy was initiated. Her high level of HbA(1c) also suggested the possibility that the patient suffered from haemoglobinopathies in addition to DM. Sequencing analyses of α1-, α2- and ß-globin genes were all normal. The patient achieved complete remission (CR) by one month after her first course of chemotherapy, and the HbA(1c) level decreased to 10.4% following insulin therapy and chemotherapy, which were initiated when she attained CR. Her extremely high HbA(1c) level was due mainly to DM. Also, suppression of erythropoiesis by proliferation of leukaemic cells and latent iron deficiency might have partially contributed to the increased HbA(1c). This could result in a transient but extremely high HbA(1c) level. To our knowledge, this is the first report of an acute leukaemia patient who expressed an extremely high level of HbA(1c).


Assuntos
Hemoglobinas Glicadas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão
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