An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia [version 1; referees: 2 approved]

Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA

The use of next-generation sequencing in the diagnosis of rare inherited anaemias: A Joint BSH/EHA Good Practice Paper

Next-generation sequencing; Rare anemiaSecuenciación de nueva generación; Anemia raraSeqüenciació de nova generació; Anèmia rar

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies

Axe eAtlasudoe: penetration d’internet dans les foyers une analyse comparative des régions d’Aragon, de Lisbonne et de Midi-Pyrénées

En 2004, la moitié des européens affirment avoir utilisé Internet. Les moins de 24 ans semblent être les plus adeptes, avec 75% d’entre eux qui naviguent régulièrement plus ou moin sur la toile. En 2005, environ un foyer européen sur deux possède une connexion Internet. Au cours des vingt dernières années, l’informatique et l’Internet ont bouleversé l’économie, la recherche scientifique et l’administration au niveau mondial. Les réseaux informatiques maillent progressivement l’ensemble des territoires. Les politiques publiques centrées sur la Société de l’Information ont un rôle à jouer dans ce domaine. Les TIC représentent un des moyens de lutter contre l’exclusion sociale. Afin de mieux observer la diffusion des nouvelles technologies, le programme européen eAtlasudoe a pour objectif de transmettre aux chercheurs et aux acteurs publics des informations sur l’évolution des usages des TIC. Une équipe, formée de trois universités et de trois observatoires régionaux, a choisi de constituer une communauté de travail pour rendre compte de l’émergence de la Société de l’Information sur les territoires du Sud-Ouest européen. Les membres du projet sont répartis sur trois territoires : - Midi-Pyrénées, en France - Aragon, en EspagneRégion de Lisbonne, au Portugal1 Un des enjeux du partenariat est d’analyser les différenciations territoriales afin de déceler « les bonnes pratiques », les points positifs de ces trois régions dans le domaine des TIC, et les freins des non-utilisateurs. Parmi six axes de travail étudiés par l’ensemble des partenaires, les observatoires se sont engagés à mettre en commun des indicateurs sur un thème précis : la pénétration d’Internet au sein des foyers. Cet axe vise à s’interroger sur l’évolution des usages Internet des ménages, la connexion haut débit, etc. En terme de méthodologie, des interrogations restent en suspend, notamment concernant la structure de l’échantillon, le panel : qu’entend-on par foyers ? Interroge t’on un foyer au complet ou un individu au sein d’un foyer ? Ce dossier rassemble le travail qui a été réalisé sur les TIC dans les foyers par les trois observatoires régionaux. En première partie, nous découvrirons un panorama général sur l’utilisation d’Internet au niveau européen et national. La seconde partie concerne l’étude réalisée par le biais du partenariat eAtlasudoe, rassemblant des données chiffrées des trois territoires.N/

Lugares de Acceso Publico à Internet: una comparación entre las Regiones de Aragón, de Lisboa Y Valle del Tajo e de Midi-Pyrénées

Disponíveis versões do relatório em Espanhol e FrancêsO presente eixo de análise tem como principal objectivo avaliar a importância das políticas destinadas à implementação de postos públicos de acesso à Internet nas três regiões em estudo, nomeadamente avaliando a sua importância ao nível dos utilizadores. O trabalho que a seguir se apresenta está estruturado em 4 partes. Na primeira parte apresentam-se e comparam-se os conceitos de “posto público de acesso à internet” considerados na análise das três regiões. Na segunda parte, é feita uma análise comparativa das políticas desenvolvidas nos três países e regiões neste domínio. A terceira parte desenvolve-se com base num inquérito realizado aos utilizadores destes espaços nas regiões de Lisboa e Vale do tejo e de Midi-Pyrénées. Na quarta parte são apresentadas as principais conclusões.info:eu-repo/semantics/publishedVersio

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts

Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia

Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to "ribosomal stress" with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA

Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project

Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mild dengue fever, to severe forms, including dengue hemorrhagic fever. Currently no specific vaccine or antiviral drugs are available. We carried out a prospective clinical study in South-East Asia and Latin America, of virologically confirmed dengue-infected patients attending the hospital, and members of their households. Among 215 febrile dengue subjects, 177 agreed to household investigation. Based on our data, we estimated the proportion of dengue-infected household members to be about 45%. At the time of the home visit, almost three quarters of (29/39) presented an inapparent dengue infection. The proportion of inapparent dengue infection was higher in South-East Asia than in Latin America. These findings confirm the complexity of dengue disease in humans and the need to strengthen multidisciplinary research efforts to improve our understanding of virus transmission and host responses to dengue virus in various human populations

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04–71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58–96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96–61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43–60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies