Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors

<p>Abstract</p> <p>Background</p> <p>Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, <it>SOSTDC1 </it>and <it>MEOX2</it>, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.</p> <p>Methods</p> <p>To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of <it>SOSTDC1 </it>in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of <it>SOSTDC1 </it>genetic aberrations on SOSTDC1 protein levels and signaling.</p> <p>Results</p> <p>Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected <it>SOSTDC1</it>. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected <it>SOSTDC1</it>. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of <it>SOSTDC1 </it>LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.</p> <p>Conclusions</p> <p>This study shows that genetic aberrations near <it>SOSTDC1 </it>are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of <it>SOSTDC1 </it>LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of <it>SOSTDC1 </it>may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.</p

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

The Relationship Between Large Scale Thermospheric Density Enhancements and the Spatial Distribution of Poynting Flux

Large thermospheric neutral density enhancements in the cusp region have been examined for many years. The Challenging Minisatellite Payload (CHAMP) satellite for example has enabled many observations of the perturbation, showing that it is mesoscale in size and exists statistically over solar cycle timescales. Further studies examining the relationship with magnetospheric energy input have shown that fine‐scale Poynting fluxes are associated with the density perturbations on a case‐by‐case basis, whilst others have found that mesoscale downward fluxes also exist in the cusp region statistically. In this study, we use nearly 8 years of the overlapping Super Dual Auroral Radar Network and Active Magnetosphere and Planetary Electrodynamics Response Experiment datasets to generate global‐scale patterns of the high‐latitude and height‐integrated Poynting flux into the ionosphere, with a time resolution of 2 min. From these, average patterns are generated based on the interplanetary magnetic field orientation. We show the cusp is indeed an important feature in the Poynting flux maps, but the magnitude does not correlate well with statistical neutral mass density perturbations observed by the CHAMP satellite on similar spatial scales. Importantly, the lack of correlation between mesoscale height‐integrated Poynting fluxes and the cusp neutral mass density enhancement gives possible insight into other processes that may account for the discrepancy, such as energy deposition at finer scale sizes or at higher altitudes than captured

A comparison of small-scale magnetic fluctuations in the Region 1 and 2 field-aligned current systems

By determining the location and size of the Region 1 (R1) and Region 2 (R2) large‐scale field‐aligned currents (FACs) from Active Magnetosphere and Planetary Electrodynamics Response Experiment data, we are able to study the small‐scale magnetic fluctuations observed by the Swarm satellites embedded within the large‐scale FACs. A statistical comparison of R1 and R2 high‐frequency fluctuations is presented in terms of different solar wind conditions and geomagnetic activities. We find that (1) the amplitude of high‐frequency fluctuations in both R1 and R2 increases as the large‐scale R1 and R2 FACs intensify; (2) high‐frequency fluctuations in R1 peak near dayside dawn and dusk, while those in R2 peak around noon; (3) the location of the largest high‐frequency fluctuations in R1 shifts in local time in response to IMF By, indicating a connection between the R1 fluctuation and the driving solar wind most likely explained by magnetic reconnection; and (4) high‐frequency fluctuations in R2 are enhanced in a small region near local noon and respond clearly to nightside drivers, as characterized by the auroral electrojet index. Our analysis shows that the intensity of R1 and R2 high‐frequency magnetic fluctuations is directly connected to the intensity of FACs, which implies that the magnetic fluctuations are closely related to the magnetospheric processes that drive them. © 2017 American Geophysical Unio