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Le Touquet – Paris-Plage, France

Konz T.,University of Oviedo | Montes-Bayon M.,University of Oviedo | Vaulont S.,French Institute of Health and Medical Research | Vaulont S.,French National Center for Scientific Research | And 2 more authors.
Metallomics | Year: 2014

Hepcidin is a 25-amino acid peptide hormone that is produced and secreted predominantly by hepatocytes, circulates in the bloodstream, and is excreted by the kidneys. Since the discovery of hepcidin and the elucidation of its important role in iron homeostasis, hepcidin has been suggested as a promising diagnostic marker for iron-related disorders. In this regard, a number of analytical methods have been developed in order to assess hepcidin concentration in different biological fluids, particularly serum and urine. In this critical review we have tried to address the issues still pending in accurate determination of this peptide by evaluating the available analytical methodologies. Among them, the use of ELISA strategies (in competitive or sandwich formats) and molecular mass spectrometry (MS) including MALDI and/or LC-MS has been critically compared. The use of elemental mass spectrometry (ICP-MS) has also been included as a possible complementary tool to the previous ones. In addition, this manuscript has revised the existing and potentially emerging clinical applications of hepcidin testing for diagnosis. These include the iron disorders such as iron deficiency anemia (IDA, low hepcidin), anemia of chronic disease (ACD, high hepcidin) and the combined state of ACD and IDA or hemochromatosis. Other applications such as using hepcidin in assessing the response to existing therapies in cancer have also been revised in the manuscript. © 2014 The Royal Society of Chemistry.

Oustric V.,French Institute of Health and Medical Research | Manceau H.,French Institute of Health and Medical Research | Ducamp S.,French Institute of Health and Medical Research | Soaid R.,French Institute of Health and Medical Research | And 33 more authors.
American Journal of Human Genetics | Year: 2014

In 90% of people with erythropoietic protoporphyria (EPP), the disease results from the inheritance of a common hypomorphic FECH allele, encoding ferrochelatase, in trans to a private deleterious FECH mutation. The activity of the resulting FECH enzyme falls below the critical threshold of 35%, leading to the accumulation of free protoporphyrin IX (PPIX) in bone marrow erythroblasts and in red cells. The mechanism of low expression involves a biallelic polymorphism (c.315-48T>C) localized in intron 3. The 315-48C allele increases usage of the 3′ cryptic splice site between exons 3 and 4, resulting in the transcription of an unstable mRNA with a premature stop codon, reducing the abundance of wild-type FECH mRNA, and finally reducing FECH activity. Through a candidate-sequence approach and an antisense- oligonucleotide-tiling method, we identified a sequence that, when targeted by an antisense oligonucleotide (ASO-V1), prevented usage of the cryptic splice site. In lymphoblastoid cell lines derived from symptomatic EPP subjects, transfection of ASO-V1 reduced the usage of the cryptic splice site and efficiently redirected the splicing of intron 3 toward the physiological acceptor site, thereby increasing the amount of functional FECH mRNA. Moreover, the administration of ASO-V1 into developing human erythroblasts from an overtly EPP subject markedly increased the production of WT FECH mRNA and reduced the accumulation of PPIX to a level similar to that measured in asymptomatic EPP subjects. Thus, EPP is a paradigmatic Mendelian disease in which the in vivo correction of a common single splicing defect would improve the condition of most affected individuals. © 2014 The American Society of Human Genetics.

Brousse V.,Hopital University Necker Enfants Malades | Brousse V.,University of Paris Descartes | Brousse V.,Laboratory of Excellence GR Ex | Buffet P.,Laboratory of Excellence GR Ex | And 2 more authors.
British Journal of Haematology | Year: 2014

The spleen has a combined function of immune defence and quality control of senescent or altered red cells. It is the first organ injured in sickle cell anaemia (SCA) with evidence of hyposplenism present before 12 months in the majority of children. Repeated splenic vaso-occlusion leads to fibrosis and progressive atrophy of the organ (autosplenectomy), which is generally complete by 5 years in SCA. The precise sequence of pathogenic events leading to hyposplenism is unknown. Splenic injury is generally silent and progressive. It can be clinically overt with acute splenic sequestration of red cells, an unpredictable and life-threatening complication in infants. Splenomegaly, with or without hypersplenism, can also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism indirectly increases the risk of vaso-occlusion or other circulatory complications remains to be determined. © 2014 John Wiley & Sons Ltd.

Olivieri L.,French Institute of Health and Medical Research | Olivieri L.,University of Reunion Island | Olivieri L.,Sanguine | Olivieri L.,Laboratory of Excellence GR Ex | And 4 more authors.
Journal of Molecular Graphics and Modelling | Year: 2014

FKBP12 is an important target in the treatment of transplant rejection and is also a promising target for cancer and neurodegenerative diseases. We determined for two ligands of nanomolar affinity the set of parameters in the CHARMM force field. The fitting procedure was based on reproducing the quantum chemistry data (distances, angles, and energies). Since the dynamical behavior of such ligands strongly depends on the dihedral angles, care was taken to derive the corresponding parameters. Moreover, since each of the central core region of these two ligands is similar to other known ligands or drugs of other proteins, part at least of these parameters could also be useful for these other ligands. © 2014 Elsevier Inc.

Moura D.S.,French Institute of Health and Medical Research | Moura D.S.,University of Paris Pantheon Sorbonne | Moura D.S.,French National Center for Scientific Research | Moura D.S.,Laboratory of Excellence GR Ex | And 10 more authors.
Immunology and Allergy Clinics of North America | Year: 2014

In approximately one-third of cases, patients with mastocytosis can display various disabling general and neuropsychological symptoms. General signs may have a major impact on quality of life. Neurologic symptoms are less frequent. In a majority of cases, the pathophysiology of these symptoms is not known but could be linked to tissular mast cell infiltration, mast cell mediator release, or both. Treatments aiming at reducing mast cell number and/or stabilizating mast cells may be useful. Preliminary results suggest that treatment with kinase inhibitors may improve symptoms of depression and cognitive impairment. © 2014 Elsevier Inc.

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