Multiple myeloma primary cells show a highly rearranged unbalanced genome with amplifications and homozygous deletions irrespective of the presence of immunoglobulin-related chromosome translocations

Background and Objectives Multiple myeloma (MM) is a malignant plasma cell neoplasia in which genetic studies have shown that genomic changes may affect almost all chromosomes, as shown by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Our objective was the genomic characterization of CD 138 positive primary MM samples by means of a high resolution array CGH platform. Design and Methods For the first time, a high resolution array CGH with more than 40,000 probes, has been used to analyze 26 primary MM samples after the enrichment of CD138-positive plasma cells. Results This approach identified copy number imbalances in all cases. Bioinformatics strategies were optimized to perform data analysis allowing the segregation of hyperdiploid and non-hyperdiploid cases by array CGH. Additional analysis showed that structural chromosome rearrangements were more frequently seen in hyperdiploid cases. We also identified the same Xq21 duplication in nearly 20% of the cases, which originated through unbalanced chromosome translocations. High level amplifications and homozygous deletions were recurrently observed in our series and involved genes with meaningful function in cancer biology. Interpretation and Conclusions High resolution array CGH allowed us to identify copy number changes in 100% of the primary MM samples. We segregated different MM subgroups based on their genomic profiles which made it possible to identify homozygous deletions and amplifications of great genetic relevance in MM

An estimate of the total catch in the Spanish Mediterranean Sea and Gulf of Cadiz regions (1950-2010)

The underestimation of fisheries removals is a global issue that spans countries from different continents and different socio-economic situations. Underestimation of catches is especially important in countries where fishing fleets are highly diversified, the enforcement of fishing management is low, data availability is poor, and there is high demand for fish products in local markets. This is the case for Mediterranean countries. Here, we estimated total removals of marine resources by Spain from 1950 to 2010 for the Spanish Mediterranean Sea and Gulf of Cadiz regions following a catch-reconstruction approach. We first collected information from scientific publications, grey literature and secondary sources of information (i.e., personal communications, interviews with managers and fishers) to complement officially reported catch data, which are publicly available from FAO databases and from national and regional statistics. A literature search and fishers interviews provided assessments of missing catch sectors that are time-point estimates. These were used as anchor points of reliable data upon which we then estimated total catch using interpolation to fill in the periods for which quantitative data were missing. Overall, the reconstructed catch was 70% larger than the nationally reported data for the same time period. Results illustrated that unreported removals and discards represent important portions of total removals in the study area. Unreported landings and discards accounted for, on average, 42% of total removals between 1950s and 2010, and were composed of black market sales, subsistence fishing, artisanal fishing, recreational fishing and illegal catch, in addition to discarding. By the late 2000s, recreational fishing was the most important sector for unreported landings (~36%), followed by black market sales (~32%), subsistence fishing (~17%), unreported artisanal fishing (~12%) and illegal catch (~2%). While FAO landings data showed an increase of landings from 1950 to the mid-1960s and a decline from the mid-1970s to 2010, a different trend emerged after accounting for all fisheries removals. Reconstructed total catches revealed an earlier maximum of total removals in the late 1950s, a plateau being reached during the 1960s and 1970s, and a decline from the early 1980s to 2010. Our estimates of total fisheries catches represent an improvement over official catch data, and suggest a different historical trend of marine resource use

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

The t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies

DT/T beyond linear theory

The major contribution to the anisotropy of the temperature of the Cosmic Microwave Background (CMB) radiation is believed to come from the interaction of linear density perturbations with the radiation previous to the decoupling time. Assuming a standard thermal history for the gas after recombination, only the gravitational field produced by the linear density perturbations present on a $\Omega\neq 1$ universe can generate anisotropies at low z (these anisotropies would manifest on large angular scales). However, secondary anisotropies are inevitably produced during the nonlinear evolution of matter at late times even in a universe with a standard thermal history. Two effects associated to this nonlinear phase can give rise to new anisotropies: the time-varying gravitational potential of nonlinear structures (Rees-Sciama RS effect) and the inverse Compton scattering of the microwave photons with hot electrons in clusters of galaxies (Sunyaev-Zeldovich SZ effect). These two effects can produce distinct imprints on the CMB temperature anisotropy. We discuss the amplitude of the anisotropies expected and the relevant angular scales in different cosmological scenarios. Future sensitive experiments will be able to probe the CMB anisotropies beyong the first order primary contribution.Comment: plain tex, 16 pages, 3 figures. Proceedings of the Laredo Advance School on Astrophysics "The universe at high-z, large-scale structure and the cosmic microwave background". To be publised by Springer-Verla

Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas

Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis. However, amplification of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers and has been associated with poor outcome and resistance to treatment. In this article are descriptions of two cases of germinal-center-derived B-cell lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case contained a IGH/MYC complicon in double minutes, whereas the second case showed a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular cytogenetic and mutation analyses revealed that the first case also contained a chromosomal translocation affecting the BCL6 oncogene and a biallelic inactivation of TP53. The second case harbored a duplication of REL and acquired a translocation affecting IGL and a biallelic inactivation of TP53 during progression. Complicons affecting Igh/Myc have been reported previously in lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this is the first time that IGH/MYC complicons have been reported in human lymphomas. Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously

Mapping cardiac remodeling in chronic kidney disease

Patients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia-related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified notable changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed toward endothelin-1 and methylglyoxal being involved in capillary dysfunction and TNFα driving cardiomyocyte hypertrophy in CKD, which was validated in vitro and in vivo. TNFα inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFα, hold promise to ameliorate cardiac remodeling in CKD.</p

Multidisciplinary approach to reconstructing local pastoral activities: an example from the Pyrenean Mountains (Pays Basque)

International audienceIn this study archaeology, history and palaeoecology (modern and fossil data sets of pollen and nonpollen palynomorphs) were used to reconstruct small-scale pastoral activities in the Pyrenees Mountains during the last two millennia. Modern pollen assemblages from the major vegetation units (both natural andanthropogenic) are studied on one restricted watershed area. A correlative model (RDA) of 61 modern pollen spectra and 35 external variables distinguishes two groups of taxa, providing information on the nature and spatial extent of human impact on the landscape. The first pool indicates local pastoral activities, and the second one implies regional input from outside the studied watershed, and is not characteristic of a specific land use. These pools are described as 'Local Pastoral Pollen Indicators' (LPPI) for this particular mountain region on crystalline bedrock and 'Regional Human Activities Pollen Indicators' (RHAPI). The modern data set is used to aid interpretation of the local pollen sequence of Sourzay that covers the last 2000 calendar years BP, using RDA reconstructions, and best modern analogues as a means of comparing modern and fossil spectra. The study also demonstrates agreement between the independent interpretations of two fossil proxies, LPPI and coprophilous fungi

Down-Regulation of hsa-miR-10a in Chronic Myeloid Leukemia CD34+ Cells Increases USF2-Mediated Cell Growth

MicroRNAs (miRNA) are small noncoding, single-stranded RNAs that inhibit gene expression at a posttranscriptional level, whose abnormal expression has been described in different tumors. The aim of our study was to identify miRNAs potentially implicated in chronic myeloid leukemia (CML). We detected an abnormal miRNA expression profile in mononuclear and CD34+ cells from patients with CML compared with healthy controls. Of 157 miRNAs tested, hsa-miR-10a, hsa-miR-150, and hsa-miR-151 were down-regulated, whereas hsa-miR-96 was up-regulated in CML cells. Down-regulation of hsa-miR-10a was not dependent on BCR-ABL1 activity and contributed to the increased cell growth of CML cells. We identified the upstream stimulatory factor 2 (USF2) as a potential target of hsa-miR-10a and showed that overexpression of USF2 also increases cell growth. The clinical relevance of these findings was shown in a group of 85 newly diagnosed patients with CML in which expression of hsa-miR-10a was down-regulated in 71% of the patients, whereas expression of USF2 was up-regulated in 60% of the CML patients, with overexpression of USF2 being significantly associated with decreased expression of hsa-miR-10a (P = 0.004). Our results indicate that down-regulation of hsa-miR-10a may increase USF2 and contribute to the increase in cell proliferation of CML implicating a miRNA in the abnormal behavior of CML