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Le Touquet – Paris-Plage, France

Devlin E.E.,Genetics and Molecular Biology Branch | DaCosta L.,French Institute of Health and Medical Research | DaCosta L.,Hematology Laboratory | DaCosta L.,University Paris Diderot | And 3 more authors.
Blood | Year: 2010

Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBAby haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation. Source


Urrechaga E.,Hematology Laboratory | Borque L.,University of Zaragoza | Escanero J.F.,University of Zaragoza
International Journal of Laboratory Hematology | Year: 2011

The reticulocyte hemoglobin equivalent (Ret He) represents an indirect measure of the functional iron available for erythropoiesis over the previous 2-3 days. Only the analyzers of a single manufacturer, Sysmex (Sysmex Corporation, Kobe, Japan), include Ret He. Red blood cell size factor (RSf) is a new parameter provided by Beckman Coulter, which joins together the volume of the erythrocytes and the volume of reticulocytes. The aims of the study were to investigate the clinical usefulness of RSf in the study of erythropoiesis status and to assess its concordance with Ret He values. Samples from 417 patients were run on both LH 780 (Beckman Coulter) and Sysmex XE 5000 analyzers. Independent samples t-test, Pearson correlation, receiver operating characteristic (ROC) analysis and inter-rater reliability (Κ index) were applied. Good correlation between RSf and Ret He was observed, r = 0.8184. Significant differences (P< 0.001) were detected when groups with inefficient erythropoiesis were compared with patients undergoing therapy and healthy subjects. ROC analysis for RSf in the diagnosis of inefficient erythropoiesis, cutoff 91.1%fl, area under curve 0.963, sensitivity 91.7%, specificity 88.5%. Concordance between RSf and Ret He Κ = 0.68. RSf and Ret He are suitable parameters for the assessment of erythropoiesis status. © 2010 Blackwell Publishing Ltd. Source


Urrechaga E.,Hematology Laboratory | Borque L.,University of Zaragoza | Escanero J.F.,University of Zaragoza
International Journal of Laboratory Hematology | Year: 2011

Cell counter-based formulae have been used in the differential diagnosis of microcytic anemia. The measurement of new red cell parameters is now available on the Sysmex XE 5000 analyzer. Derived from the percentages of microcytic and hypochromic red cells, the authors describe the new formula %microcytic-%hypochromic, M-H index. The aim of this study was to assess the discriminant value of this new index in the differential diagnosis of microcytic anemia and thalassemia screening compared to the published indices. Receiver operating characteristic curves, sensitivity, specificity and Youden index were calculated for a set of 170 iron-deficiency anemia patients and 200 β thalassemia carriers. % microcytic-% hypochromic index showed the best area under the curve (area under curve AUC, 0.994) and Youden index (93.9%), among considered indices; 98% sensitivity, 95.9% specificity, at a cutoff value >11.5; Green and King index ranked second (AUC 0.99, Youden index 90.8%). Because of high sensitivity and specificity, the new index %microcytic-%hypochromic was the most reliable index evaluated. M-H index could be a useful tool in the differential diagnosis of microcytic anemia, and samples with M-H> 11.5 can be chosen for further analysis to confirm the diagnosis of thalassemia. © 2010 Blackwell Publishing Ltd. Source


Jordheim L.P.,French Institute of Health and Medical Research | Jordheim L.P.,University of Lyon | Seve P.,French Institute of Health and Medical Research | Seve P.,University of Lyon | And 5 more authors.
The Lancet Oncology | Year: 2011

The large subunit of human ribonucleotide reductase, RRM1, is involved in the regulation of cell proliferation, cell migration, tumour and metastasis development, and the synthesis of deoxyribonucleotides for DNA synthesis. It is also a cellular target for the chemotherapeutic agent, gemcitabine. RRM1 has been studied in a large number of patients with different types of cancer, such as non-small-cell lung cancer, pancreatic cancer, breast cancer, and biliary tract cancer, to establish its prognostic or predictive value when patients were treated with gemcitabine, and mRNA expression and genetic variants as determined by genotyping have in some cases been associated with clinical outcome of patients with cancer. Here, we review preclinical and clinical studies of RRM1 assessment and discuss the further steps in the development of this clinically pertinent biomarker. © 2011 Elsevier Ltd. Source


Urrechaga E.,Hematology Laboratory | Borque L.,University of Zaragoza | Escanero J.F.,University of Zaragoza
American Journal of Clinical Pathology | Year: 2011

Cell counter-based formulas have been used in the differential diagnosis of microcytic anemia. The measurement of RBC subpopulations is now available on the Sysmex XE 5000 analyzer (Sysmex, Kobe, Japan). We describe the new formulas: % microcytic - % hypochromic; and % microcytic - % hypochromic - red cell distribution width (RDW), derived from the percentages of microcytic and hypochromic RBCs. The present study aimed to prospectively evaluate the reliability of these new formulas in the differential diagnosis of microcytosis and β-thalassemia screening compared with already published indices. The indices were calculated for a set of 250 iron-deficient patients and 270 β-thalassemia carriers. Independent samples t test and receiver-operating characteristics analysis were applied. The % microcytic - % hypochromic - RDW, % microcytic - % hypochromic, and Green and King indices provided higher areas under the curve. The % microcytic - % hypochromic - RDW was the most reliable index evaluated, with 100% sensitivity and 92.6% specificity. This index can be used to efficiently screen patients with microcytosis for further hematologic studies to confirm β-thalassemia. © American Society for Clinical Pathology. Source

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