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1.
Oncotarget ; 9(69): 33202-33214, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30237862

RESUMO

Nature is always the best inspiration for basic research. A family with severe thrombosis and antithrombin deficiency, the strongest anticoagulant, carried a new mutation affecting the translation-start codon of SERPINC1, the gene encoding antithrombin. Expression of this variant in a eukaryotic cell system produced three different antithrombins. Two downstream methionines were used as alternative initiation codons, generating highly expressed small aglycosylated antithrombins with cytoplasmic localization. Wild-type antithrombin was generated by the use of the mutated AUU as initiation codon. Actually, any codon except for the three stop codons might be used to initiate translation in this strong Kozak context. We show unexpected consequences of natural mutations affecting translation-start codons. Downstream alternative initiation AUG codons may be used when the start codon is mutated, generating smaller molecules with potential different cell localization, biochemical features and unexplored consequences. Additionally, our data further support the use of other codons apart from AUG for initiation of translation in eukaryotes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

3.
J Med Case Rep ; 12(1): 105, 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29685167

RESUMO

BACKGROUND: Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. CASE PRESENTATION: A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient's neutropenia. CONCLUSIONS: Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.


Assuntos
Leucemia de Células Pilosas/complicações , Leucemia Mieloide Aguda/etiologia , Policitemia Vera/complicações , Mielofibrose Primária/sangue , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais , Medula Óssea/patologia , Cladribina/administração & dosagem , Progressão da Doença , Evolução Fatal , Humanos , Janus Quinase 2/sangue , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucopenia/sangue , Leucopenia/complicações , Masculino , Neutropenia/sangue , Úlceras Orais/etiologia , Policitemia Vera/sangue , Mielofibrose Primária/complicações , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/etiologia , Esplenomegalia/patologia , Trombocitopenia/sangue , Trombocitopenia/complicações
4.
J Allergy Clin Immunol ; 139(1): 232-245, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27577878

RESUMO

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.


Assuntos
Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-27252783

RESUMO

BACKGROUND: Hematopoietic stem cell renewal and differentiation are regulated through epigenetic processes. The conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) by ten-eleven-translocation enzymes provides new insights into the epigenetic regulation of gene expression during development. Here, we studied the potential gene regulatory role of 5hmC during human hematopoiesis. RESULTS: We used reduced representation of 5-hydroxymethylcytosine profiling (RRHP) to characterize 5hmC distribution in CD34+ cells, CD4+ T cells, CD19+ B cells, CD14+ monocytes and granulocytes. In all analyzed blood cell types, the presence of 5hmC at gene bodies correlates positively with gene expression, and highest 5hmC levels are found around transcription start sites of highly expressed genes. In CD34+ cells, 5hmC primes for the expression of genes regulating myeloid and lymphoid lineage commitment. Throughout blood cell differentiation, intragenic 5hmC is maintained at genes that are highly expressed and required for acquisition of the mature blood cell phenotype. Moreover, in CD34+ cells, the presence of 5hmC at enhancers associates with increased binding of RUNX1 and FLI1, transcription factors essential for hematopoiesis. CONCLUSIONS: Our study provides a comprehensive genome-wide overview of 5hmC distribution in human hematopoietic cells and new insights into the epigenetic regulation of gene expression during human hematopoiesis.

6.
Acta Derm Venereol ; 96(5): 602-12, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26694951

RESUMO

Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.


Assuntos
Mastocitose/diagnóstico , Mastocitose/terapia , Congressos como Assunto , Consenso , Diagnóstico Diferencial , Humanos , Mastocitose/classificação , Mastocitose/epidemiologia , Guias de Prática Clínica como Assunto , Prevalência , Países Escandinavos e Nórdicos/epidemiologia , Organização Mundial da Saúde
7.
Tidsskr Nor Laegeforen ; 134(16): 1569-75, 2014 Sep 02.
Artigo em Norueguês | MEDLINE | ID: mdl-25178233

RESUMO

BACKGROUND: Allogeneic stem cell transplantation (ASCT) has been a treatment option for patients with serious diseases of the blood and haematopoietic organs in Norway since 1985. Such treatment is potentially curative for selected patients who have a relatively short predicted survival with other treatment modalities. This article summarises the experience and results from ASCT at Oslo University Hospital Rikshospitalet. MATERIAL AND METHOD: The study included all of the 734 adult patients who had undergone allogeneic stem cell transplantation at the Department of Haematology, Rikshospitalet, later Oslo University Hospital Rikshospitalet, from November 1985 to October 2012. RESULTS: At the time of analysis, altogether 384 patients were alive, and the five and ten-year survival rates were 54% and 48% respectively. The median follow-up time was six years. A total of 339 patients (46%) had developed acute graft-versus-host disease (GvHD), and 250 (73%) of these had GvHD ≥ grade II. Altogether 280 out of 602 patients who lived ≥ 100 days after the transplantation (46.5%) developed chronic GvHD. The most frequent causes of death included recurrence of the initial disease in 116 patients (33.1 %), multi organ failure after transplantation in 88 patients (25.4%), infections in 54 patients (16%) and GvHD in 33 patients (9.4%). INTERPRETATION: ASCT is a treatment option with a curative potential for patients with serious haematological diseases when other forms of treatment provide few prospects for recovery. The total survival rate in our study is in accordance with international results for the same time period, and the indications have consistently been in line with what is accepted internationally.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Hospitais Universitários , Humanos , Leucemia Linfoide/epidemiologia , Leucemia Linfoide/terapia , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Noruega , Complicações Pós-Operatórias/epidemiologia , Taxa de Sobrevida , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Transplante Homólogo/estatística & dados numéricos
8.
Cancer Cell ; 25(6): 794-808, 2014 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-24835589

RESUMO

Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.


Assuntos
Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Animais , Antígenos CD/biossíntese , Antígenos CD/imunologia , Deleção Cromossômica , Cromossomos Humanos Par 5 , Citometria de Fluxo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Mutação , Síndromes Mielodisplásicas/imunologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Prognóstico
9.
Haematologica ; 96(7): 963-71, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21719884

RESUMO

BACKGROUND: Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). DESIGN AND METHODS: Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. RESULTS: Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations. CONCLUSIONS: Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).


Assuntos
Antineoplásicos/administração & dosagem , Aberrações Cromossômicas , Cromossomos Humanos Par 5/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Sequência de Bases , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Lenalidomida , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas WT1/genética , Proteínas WT1/metabolismo
10.
Tidsskr Nor Laegeforen ; 128(22): 2563-6, 2008 Nov 20.
Artigo em Norueguês | MEDLINE | ID: mdl-19023351

RESUMO

BACKGROUND: The success rate for chemotherapy of adults with acute lymphoblastic leukaemia in Norway compares favourably with that in international reports, but improvements are still needed. Allogeneic stem cell transplantation is an option for patients up to 60 years and may contribute to improving the outcome for these patients. MATERIAL AND METHODS: Allogen stem cell transplantation was performed in 61 high-risk patients (38 men and 23 women) with acute lymphoblastic leukaemia at Rikshospitalet between 1985 and 2005. 19 patients were transplanted in first remission and 42 at a later stage of the disease. RESULTS: At the end of 2006, 26 patients (43%) were alive; 21 (35%) in complete remission and 5 with relapse. Median survival time was 1.5 years. Relapse was the most important cause of treatment failure (38%), but transplantation-related mortality (25%) was also a substantial problem. Estimated 5-year actuarial leukemia-free survival was 35 %. INTERPRETATION: Our results are in line with international reports on the results of allogen stem cell transplantation in high-risk acute lymphoblastic leukaemia. This treatment offers cure for patients with an otherwise dismal prognosis. A larger number of patients should be offered such treatment during the first remission than what was the case in the 20-year period this study took place.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Fatores de Risco , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
12.
J Clin Oncol ; 26(21): 3607-13, 2008 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-18559873

RESUMO

PURPOSE: To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS). PATIENTS AND METHODS: We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex). RESULTS: The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype. CONCLUSION: The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Lesões Pré-Cancerosas/tratamento farmacológico , Idoso , Anemia/tratamento farmacológico , Anemia/etiologia , Transfusão de Sangue , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade
13.
Blood ; 106(3): 803-11, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15840690

RESUMO

We report long-term results of treatment of myelodysplastic syndrome (MDS) with erythropoietin and granulocyte colony-stimulating factor (G-CSF). A total of 129 patients were followed up 45 months after last inclusion in the Nordic MDS Group studies. Erythroid response rate was 39% and median response duration 23 months (range, 3-116 months or more). Complete responders showed longer response duration than partial responders (29 versus 12 months, P = .006). The International Prognostic Scoring System (IPSS) groups Low/Intermediate-1 (Low/Int-1) had longer response duration than Int-2/High (25 versus 7 months, P = .002). The time until 25% developed acute myeloid leukemia (AML) was longer in the good and intermediate predictive groups for erythroid response compared with the poor predictive group (52 versus 13 months, P = .008). Only 1 of 20 long-term responders developed AML. We assessed the effect on long-term outcome by comparing treated patients with untreated patients selected from the IPSS database using multivariate Cox regression, adjusting for major prognostic variables. There was no difference in survival (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2; P = .55) or risk of AML evolution (OR, 1.3; 95% CI, 0.7-2.2; P = .40) between treated and untreated patients. Patients with high/intermediate probability of response and with IPSS Low/Int-1 show frequent and durable responses without adverse effects on outcome, while other patients should not be considered candidates for this treatment.


Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Anemia/etiologia , Transformação Celular Neoplásica , Feminino , Humanos , Leucemia Mieloide/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
14.
J Immunol ; 174(2): 752-7, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15634895

RESUMO

Whereas multiple growth-promoting cytokines have been demonstrated to be involved in regulation of the hemopoietic stem cell (HSC) pool, the potential role of negative regulators is less clear. However, IFN-gamma, if overexpressed, can mediate bone marrow suppression and has been directly implicated in a number of bone marrow failure syndromes, including graft-vs-host disease. Whether IFN-gamma might directly affect the function of repopulating HSCs has, however, not been investigated. In the present study, we used in vitro conditions promoting self-renewing divisions of human HSCs to investigate the effect of IFN-gamma on HSC maintenance and function. Although purified cord blood CD34(+)CD38(-) cells underwent cell divisions in the presence of IFN-gamma, cycling HSCs exposed to IFN-gamma in vitro were severely compromised in their ability to reconstitute long-term cultures in vitro and multilineage engraft NOD-SCID mice in vivo (>90% reduced activity in both HSC assays). In vitro studies suggested that IFN-gamma accelerated differentiation of targeted human stem and progenitor cells. These results demonstrate that IFN-gamma can negatively affect human HSC self-renewal.


Assuntos
Diferenciação Celular/imunologia , Inibidores do Crescimento/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Interferon gama/fisiologia , ADP-Ribosil Ciclase/metabolismo , ADP-Ribosil Ciclase 1 , Animais , Antígenos CD/metabolismo , Antígenos CD34/biossíntese , Linhagem da Célula/imunologia , Células Cultivadas , Células Clonais , Relação Dose-Resposta Imunológica , Sangue Fetal/citologia , Sangue Fetal/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
15.
Br J Haematol ; 120(6): 1037-46, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12648074

RESUMO

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.


Assuntos
Anemia/terapia , Técnicas de Apoio para a Decisão , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Síndromes Mielodisplásicas/terapia , Qualidade de Vida , Idoso , Anemia Refratária/terapia , Anemia Refratária com Excesso de Blastos/terapia , Anemia Sideroblástica/terapia , Transfusão de Sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Resultado do Tratamento
16.
Blood ; 102(1): 118-26, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12637333

RESUMO

The Fas receptor and its ligand have been implicated in mediating the bone marrow (BM) suppression observed in graft-versus-host disease and a number of other BM-failure syndromes. However, previous studies have suggested that Fas is probably not expressed on human hematopoietic stem cells (HSCs), but up-regulated as a consequence of their commitment and differentiation, suggesting that progenitors or differentiated blood cells, rather than HSCs, are the targets of Fas-mediated suppression. The present studies confirm that candidate HSCs in human cord blood and BM lack constitutive expression of Fas, but demonstrate that Fas expression on CD34+ progenitor and stem cells is correlated to their cell cycle and activation status. With the use of recently developed in vitro conditions promoting HSC self-renewing divisions, Fas was up-regulated on virtually all HSCs capable of multilineage reconstituting nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice in vivo, as well as on long-term culture-initiating cells (LTC-ICs). Similarly, in vivo cycling of NOD-SCID repopulating cells upon transplantation, resulted in up-regulation of Fas expression. However, repopulating HSCs expressing high levels of Fas remained highly resistant to Fas-mediated suppression, and HSC function was compromised only upon coactivation with tumor necrosis factor. Thus, reconstituting human HSCs up-regulate Fas expression upon active cycling, demonstrating that HSCs could be targets for Fas-mediated BM suppression.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Regulação para Cima , Receptor fas/análise , Receptor fas/fisiologia , Animais , Células da Medula Óssea , Ciclo Celular , Divisão Celular , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Citocinas/farmacologia , Sangue Fetal , Citometria de Fluxo , Humanos , Camundongos , Camundongos SCID , Células-Tronco Multipotentes , Transplante Heterólogo
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