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1.
J Leukoc Biol ; 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31302947

RESUMO

PSGL-1 is a mucin-like glycoprotein that supports, in mammals, leukocyte rolling on selectins. However, we have limited knowledge whether its function is conserved in non-mammals and how its structure adapted during evolution. To identify conserved amino acid sequences required for selectin binding, we performed multiple alignments of PSGL-1 sequences from 18 mammals, 4 birds, 3 reptiles, 1 amphibian, and 15 fishes. The amino-terminal T[D/E]PP[D/E] motif, which identifies in mammals a core-2 O-glycosylated threonine required for selectin-binding, is partially conserved in some fishes (e.g., T. rubripes) and birds (e.g., G. gallus), however, most non-mammals do not display it. The sulfated tyrosine residues of human PSGL-1, which bind L- and P-selectin, are not observed in non-mammals, suggesting that they are dispensable for selectin-binding or that other amino acids play their role. A mucin-like domain is present in all species. Interestingly, the alignment of cytoplasmic sequences of non-mammals reveals the conservation of ezrin/radixin/moesin binding site and two new motifs (M1 and M2). To examine the conservation of PSGL-1 function, we cloned PSGL-1 cDNA sequences of zebrafish and fugu, and established their cross-reactivity with human selectins under flow conditions. Importantly, deleting the well-conserved M1 motif strongly decreased PSGL-1 expression at leukocyte surface and induced retention of the precursor molecule in the endoplasmic reticulum, indicating that M1 motif provides a signal required to export PSGL-1 precursors to the Golgi complex. These data show for the first time the conservation of PSGL-1 function from fishes to mammals and reveal the function of a new motif.

2.
Br J Haematol ; 184(6): 969-973, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592029

RESUMO

Acute leukaemia is a life-threatening disease that needs treatment without delay. Fertility preservation is recommended, but often not possible because of the necessity to start treatment as soon as possible. The present study is a retrospective single-centre analysis of 459 patients diagnosed with acute leukaemia between 2002 and 2012. Sperm or oocyte preservation was successfully performed in only 29 (6%) patients. Of the 150 children, no paediatric patient sample was taken. The collected samples enabled the conception of 2 children by in vitro fertilisation; in addition, 3 spontaneous, non-assisted births in partners of male patients were observed. Fertility preservation is important but difficult to accomplish in patients with acute leukaemia; more efforts are clearly needed to preserve fertility in long-term survivors of acute leukaemia.

4.
Haematologica ; 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026341

RESUMO

In standard risk acute promyelocytic leukemia, recent results have shown that ATRA + Arsenic trioxide combinations were at least as effective as classical ATRA + anthracycline based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher risk acute promyelocytic leukemia, and access to arsenic remains limited for frontline treatment of standard risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared for consolidation treatment (after ATRA-Chemotherapy induction treatment) arsenic, ATRA and the classical AraC in standard risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher risk APL. Newly diagnosed acute promyelocytic leukemia patients with white blood cells < 10 G/L, after an induction treatment consisting of ATRA plus Idarubicin-AraC, received consolidation chemotherapy with Idarubicin and AraC, arsenic or ATRA. Patients with white blood cells >10G received consolidation chemotherapy with arsenic or without arsenic.795 acute promyelocytic leukemia patients were enrolled in this trial. In Standard risk APL (n= 581), 5-year EFS from randomization was 88.7%, 95.7% and 85.4% in the AraC, arsenic and ATRA consolidation groups, respectively (p=0.0067) and 5 year cumulative incidence of relapse (CIR) was 5.5%, 0% and 8.2%. (p=0.001). In higher risk APL (n=214), 5-year EFS was 85.5% vs 92.1% (p=0.38) in the chemotherapy and chemotherapy+ arsenic groups, respectively and 5-year CIR of 4.6% and 3.5% (p= 0.99) in the chemotherapy and chemotherapy+ arsenic groups. Due to prolonged myelosuppression in the chemotherapy+ arsenic arm, an amendment excluded AraC during consolidation cycles in the chemotherapy+ arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation where we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).

7.
Cancer Epidemiol ; 52: 55-62, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29223104

RESUMO

Acute Myeloid Leukaemia (AML) is a rare and heterogeneous haematological malignancy with increasing incidence in the elderly. We performed a population-based, observational analysis of AML cases reported to the Cantonal Cancer Registries in Switzerland. Data was aggregated by the National Institute for Epidemiology and Cancer Registration and stratified for the two time periods 2001-2007 and 2008-2013. Overall, 2351 new AML cases were registered with a stable age-standardised incidence rate (3.0 [95 CI: 2.8-3.2] per 100,000 person-years). This indicates that our observed raise of annual AML cases (+10.9%) is mainly related to demographic ageing and not to an increase of age-specific risks. The fraction of non-classifiable AML cases decreased over time (54.6% to 41.8%) but remained high in elderly patients (65-74yrs: 44%; 75-84yrs: 54.2%, 85+yrs: 59.1%), suggesting less accurate diagnostics and reporting with increasing age. 5yrs relative survival (RS) correlated with AML risk class (favorable: 61.7%-68.4%; adverse risk: 11.4%-21.9%) and age (<65yrs: 42.6-43.3%; 75-84yrs: 2.0-3.0%), but improved only modestly overall (19.2% to 23.3%). Interestingly, we identified a significant improvement of RS in patients aged 65-74yrs (5yrs: 5.2% to 13.5%; p<0.001). As surrogate for changes in management, we found an increase of allogeneic haematopoietic stem cell transplantations (1.4 to 7%) and clinical trial activities (25 to 29%) for elderly AML patients during the observation period. Our analysis indicates that recent progress made in management of elderly AML patients results in an improvement of survival on a population-based level in Switzerland and that therapeutic nihilism is not justifiable.

8.
Clin Case Rep ; 5(8): 1320-1322, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28781850

RESUMO

We report here the clinical course of a Ph+ ALL patient who was treated with ponatinib 15 mg/day, as maintenance therapy, and developed a BCR-ABL T315I mutation leading to ALL relapse. This clonal evolution was reversed, without adverse effects, by increasing ponatinib to 45 mg/day. To our knowledge, we have been confronted with the first clinical case of a T315I clonal selection of ALL caused by subeffective therapeutic level of the drug. This single patient experience highlights the risk of T315I clone selection in Ph+ ALL treated with reduced dose ponatinib.

10.
Blood ; 129(12): 1636-1645, 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28049642

RESUMO

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

11.
J Emerg Med ; 50(1): 55-60, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26281812

RESUMO

BACKGROUND: Wild garlic and related plants are increasingly sought after by fans of natural products. They can be confused with other plants containing colchicine and cause potentially fatal intoxications. CASE REPORT: We report a case of accidental poisoning by Colchicum autumnale, which was mistaken for wild garlic (Allium ursinum). The patient initially presented with mild gastrointestinal symptoms, but progressed rapidly to agranulocytosis, paraparesis, and delirium before the causative agent was identified. The laboratory tests revealed rhabdomyolysis, coagulopathy, alteration of liver tests, and prerenal azotemia. Botanical examination confirmed the incriminated plant (Colchicum autumnale). Serum and urine analysis confirmed the presence of colchicine. The patient required intensive support therapy, and she fully recovered within 8 weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Colchicine poisoning should be considered in the differential diagnosis of patients presenting with gastroenteritis after ingestion of wild garlic.


Assuntos
Colchicum/envenenamento , Insuficiência de Múltiplos Órgãos/etiologia , Extratos Vegetais/envenenamento , Allium , Feminino , Humanos , Pessoa de Meia-Idade
12.
Cancer ; 121(14): 2393-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25845577

RESUMO

BACKGROUND: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL. METHODS: The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL. RESULTS: In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months. CONCLUSIONS: Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/epidemiologia , Leucemia Promielocítica Aguda/terapia , Adulto , Idoso , Antraciclinas/administração & dosagem , Bélgica/epidemiologia , Quimiorradioterapia , Feminino , França/epidemiologia , Humanos , Incidência , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Estudos Prospectivos , Recidiva , Suíça/epidemiologia
13.
PLoS One ; 7(11): e49010, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23152841

RESUMO

BACKGROUND: The diagnosis of malignant hematologic diseases has become increasingly complex during the last decade. It is based on the interpretation of results from different laboratory analyses, which range from microscopy to gene expression profiling. Recently, a method for the analysis of RNA phenotypes has been developed, the nCounter technology (Nanostring® Technologies), which allows for simultaneous quantification of hundreds of RNA molecules in biological samples. We evaluated this technique in a Swiss multi-center study on eighty-six samples from acute leukemia patients. METHODS: mRNA and protein profiles were established for normal peripheral blood and bone marrow samples. Signal intensities of the various tested antigens with surface expression were similar to those found in previously performed Affymetrix microarray analyses. Acute leukemia samples were analyzed for a set of twenty-two validated antigens and the Pearson Correlation Coefficient for nCounter and flow cytometry results was calculated. RESULTS: Highly significant values between 0.40 and 0.97 were found for the twenty-two antigens tested. A second correlation analysis performed on a per sample basis resulted in concordant results between flow cytometry and nCounter in 44-100% of the antigens tested (mean = 76%), depending on the number of blasts present in a sample, the homogeneity of the blast population, and the type of leukemia (AML or ALL). CONCLUSIONS: The nCounter technology allows for fast and easy depiction of a mRNA profile from hematologic samples. This technology has the potential to become a valuable tool for the diagnosis of acute leukemias, in addition to multi-color flow cytometry.


Assuntos
Leucemia/genética , Leucemia/metabolismo , Proteoma , Transcriptoma , Antígenos CD/genética , Antígenos CD/metabolismo , Células Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Citometria de Fluxo/métodos , Genômica/métodos , Humanos , Imunofenotipagem , Leucemia/diagnóstico , Proteômica/métodos
15.
Anticancer Res ; 32(8): 3015-27, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22843869

RESUMO

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2ß isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2ß was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2ß or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2ß also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2ß contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células , Isoenzimas/metabolismo , Leucemia Mieloide Aguda/patologia , Tumores Neuroendócrinos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Taxa de Sobrevida , Animais , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/antagonistas & inibidores
16.
J Biol Chem ; 287(13): 10693-702, 2012 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-22311979

RESUMO

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the capture (tethering) of free-flowing leukocytes and subsequent rolling on selectins. PSGL-1 interactions with endothelial selectins activate Src kinases and spleen tyrosine kinase (Syk), leading to α(L)ß(2) integrin-dependent leukocyte slow rolling, which promotes leukocyte recruitment into tissues. In addition, but through a distinct pathway, PSGL-1 engagement activates ERK. Because ezrin, radixin and moesin proteins (ERMs) link PSGL-1 to actin cytoskeleton and because they serve as adaptor molecules between PSGL-1 and Syk, we examined the role of PSGL-1 ERM-binding sequence (EBS) on cell capture, rolling, and signaling through Syk and MAPK pathways. We carried out mutational analysis and observed that deletion of EBS severely reduced 32D leukocyte tethering and rolling on L-, P-, and E-selectin and slightly increased rolling velocity. Alanine substitution of Arg-337 and Lys-338 showed that these residues play a key role in supporting leukocyte tethering and rolling on selectins. Importantly, EBS deletion or Arg-337 and Lys-338 mutations abrogated PSGL-1-induced ERK activation, whereas they did not prevent Syk phosphorylation or E-selectin-induced leukocyte slow rolling. These studies demonstrate that PSGL-1 EBS plays a critical role in recruiting leukocytes on selectins and in activating the MAPK pathway, whereas it is dispensable to phosphorylate Syk and to lead to α(L)ß(2)-dependent leukocyte slow rolling.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Migração e Rolagem de Leucócitos/fisiologia , Leucócitos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Glicoproteínas de Membrana/metabolismo , Selectinas/metabolismo , Animais , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Ativação Enzimática/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucócitos/citologia , Antígeno-1 Associado à Função Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fosforilação/fisiologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Selectinas/genética , Deleção de Sequência , Quinase Syk , Quinases da Família src/genética , Quinases da Família src/metabolismo
19.
J Biol Chem ; 283(42): 28536-45, 2008 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-18713749

RESUMO

P-selectin glycoprotein ligand-1 (PSGL-1) interacts with selectins to support leukocyte rolling along vascular wall. L- and P-selectin bind to N-terminal tyrosine sulfate residues and to core-2 O-glycans attached to Thr-57, whereas tyrosine sulfation is not required for E-selectin binding. PSGL-1 extracellular domain contains decameric repeats, which extend L- and P-selectin binding sites far above the plasma membrane. We hypothesized that decamers may play a role in regulating PSGL-1 interactions with selectins. Chinese hamster ovary cells expressing wild-type PSGL-1 or PSGL-1 molecules exhibiting deletion or substitution of decamers with the tandem repeats of platelet glycoprotein Ibalpha were compared in their ability to roll on selectins and to bind soluble L- or P-selectin. Deletion of decamers abrogated soluble L-selectin binding and cell rolling on L-selectin, whereas their substitution partially reversed these diminutions. P-selectin-dependent interactions with PSGL-1 were less affected by decamer deletion. Videomicroscopy analysis showed that decamers are required to stabilize L-selectin-dependent rolling. Importantly, adhesion assays performed on recombinant decamers demonstrated that they directly bind to E-selectin and promote slow rolling. Our results indicate that the role of decamers is to extend PSGL-1 N terminus far above the cell surface to support and stabilize leukocyte rolling on L- or P-selectin. In addition, they function as a cell adhesion receptor, which supports approximately 80% of E-selectin-dependent rolling.


Assuntos
Glicoproteínas de Membrana/fisiologia , Selectinas/química , Animais , Células CHO , Adesão Celular , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Humanos , Células K562 , Migração e Rolagem de Leucócitos , Glicoproteínas de Membrana/metabolismo , Microscopia de Vídeo , Modelos Biológicos , Estrutura Terciária de Proteína , Tirosina/análogos & derivados , Tirosina/química
20.
BMC Evol Biol ; 7: 166, 2007 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-17868453

RESUMO

BACKGROUND: P-selectin glycoprotein ligand-1 (PSGL-1) plays a critical role in recruiting leukocytes in inflammatory lesions by mediating leukocyte rolling on selectins. Core-2 O-glycosylation of a N-terminal threonine and sulfation of at least one tyrosine residue of PSGL-1 are required for L- and P-selectin binding. Little information is available on the intra- and inter-species evolution of PSGL-1 primary structure. In addition, the evolutionary conservation of selectin binding site on PSGL-1 has not been previously examined in detail. Therefore, we performed multiple sequence alignment of PSGL-1 amino acid sequences of 14 mammals (human, chimpanzee, rhesus monkey, bovine, pig, rat, tree-shrew, bushbaby, mouse, bat, horse, cat, sheep and dog) and examined mammalian PSGL-1 interactions with human selectins. RESULTS: A signal peptide was predicted in each sequence and a propeptide cleavage site was found in 9/14 species. PSGL-1 N-terminus is poorly conserved. However, each species exhibits at least one tyrosine sulfation site and, except in horse and dog, a T [D/E]PP [D/E] motif associated to the core-2 O-glycosylation of a N-terminal threonine. A mucin-like domain of 250-280 amino acids long was disclosed in all studied species. It lies between the conserved N-terminal O-glycosylated threonine (Thr-57 in human) and the transmembrane domain, and contains a central region exhibiting a variable number of decameric repeats (DR). Interspecies and intraspecies polymorphisms were observed. Transmembrane and cytoplasmic domain sequences are well conserved. The moesin binding residues that serve as adaptor between PSGL-1 and Syk, and are involved in regulating PSGL-1-dependent rolling on P-selectin are perfectly conserved in all analyzed mammalian sequences. Despite a poor conservation of PSGL-1 N-terminal sequence, CHO cells co-expressing human glycosyltransferases and human, bovine, pig or rat PSGL-1 efficiently rolled on human L- or P-selectin. By contrast, pig or rat neutrophils were much less efficiently recruited than human or bovine neutrophils on human selectins. Horse PSGL-1, glycosylated by human or equine glycosyltransferases, did not interact with P-selectin. In all five species, tyrosine sulfation of PSGL-1 was required for selectin binding. CONCLUSION: These observations show that PSGL-1 amino acid sequence of the transmembrane and cytoplasmic domains are well conserved and that, despite a poor conservation of PSGL-1 N-terminus, L- and P-selectin binding sites are evolutionary conserved. Functional assays reveal a critical role for post-translational modifications in regulating mammalian PSGL-1 interactions with selectins.


Assuntos
Evolução Molecular , Glicoproteínas de Membrana/genética , Infiltração de Neutrófilos/genética , Sequência de Aminoácidos , Animais , Células CHO , Bovinos , Adesão Celular , Cricetinae , Cricetulus , Citometria de Fluxo , Furina/genética , Cavalos , Humanos , Imunofenotipagem , Camundongos , Ratos , Especificidade da Espécie , Suínos , Transfecção
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