Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

International audienceBACKGROUND: The von Hippel-Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC. METHODS: A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC. CONCLUSION: Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy

Native and foreign born as predictors of pediatric asthma in an Asian immigrant population: a cross sectional survey

<p>Abstract</p> <p>Background</p> <p>Asthma prevalence is lower in less developed countries and among some recent immigrant populations in the US, but the reasons for this are not clear. One possibility is that early childhood infections are protective against asthma.</p> <p>Methods</p> <p>We surveyed Asian immigrant children (n = 204; age 4–18) to assess the relationship between asthma and native or foreign place of birth. We included questions about environmental exposures, demographic variables and family history of asthma to test whether they might explain effects of place of birth on asthma.</p> <p>Results</p> <p>The native and foreign born groups were similar in most respects. Analysis of association with diagnosed asthma for all ages together resulted in two logistic regression models. Both retained born in the US (ORs were 3.2 and 4.3; p < 0.01) and family history of asthma (ORs were 6.4 and 7.2; p < 0.001). One model retained living near heavy motor traffic (OR = 2.6; p = 0.012). The other retained language (OR = 3.2; p = 0.003). However, for older children (11–18 years of age) being born in the US lost some of its predictive power.</p> <p>Conclusion</p> <p>Our findings are consistent with early childhood infections that are prevalent outside the US protecting against asthma.</p

Statistics for Fission-Track Thermochronology

This chapter introduces statistical tools to extract geologically meaningful information from fission-track (FT) data using both the external detector and LA-ICP-MS methods. The spontaneous fission of 238U is a Poisson process resulting in large single-grain age uncertainties. To overcome this imprecision, it is nearly always necessary to analyse multiple grains per sample. The degree to which the analytical uncertainties can explain the observed scatter of the single-grain data can be visually assessed on a radial plot and objectively quantified by a chi-square test. For sufficiently low values of the chi-square statistic (or sufficiently high p values), the pooled age of all the grains gives a suitable description of the underlying ‘true’ age population. Samples may fail the chi-square test for several reasons. A first possibility is that the true age population does not consist of a single discrete age component, but is characterised by a continuous range of ages. In this case, a ‘random effects’ model can constrain the true age distribution using two parameters: the ‘central age’ and the ‘(over)dispersion’. A second reason why FT data sets might fail the chi-square test is if they are underlain by multimodal age distributions. Such distributions may consist of discrete age components, continuous age distributions, or a combination of the two. Formalised statistical tests such as chi-square can be useful in preventing overfitting of relatively small data sets. However, they should be used with caution when applied to large data sets (including length measurements) which generate sufficient statistical ‘power’ to reject any simple yet geologically plausible hypothesis

Protracted timescales of lower crustal growth at the fast-spreading East Pacific Rise

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 5 (2012): 275-278, doi:10.1038/ngeo1378.Formation of the oceanic crust at mid-ocean ridges is a fundamental component of plate tectonics. A majority of the crust at many ridges is composed of plutonic rocks that form by crystallization of mantle-derived magmas within the crust. Recent application of U/Pb dating to samples from in-situ oceanic crust has begun to provide exciting new insight into the timing, duration and distribution of magmatism during formation of the plutonic crust1-4. Previous studies have focused on samples from slow-spreading ridges, however, the time scales and processes of crustal growth are expected to vary with plate spreading rate. Here we present the first high-precision dates from plutonic crust formed at the fast-spreading East Pacific Rise (EPR). Individual zircon minerals yielded dates from 1.420–1.271 million years ago, with uncertainties of ± 0.006–0.081 million years. Within individual samples, zircons record a range of dates of up to ~0.124 million years, consistent with protracted crystallization or assimilation of older zircons from adjacent rocks. The variability in dates is comparable to data from the Vema lithospheric section on the Mid-Atlantic Ridge (MAR)3, suggesting that time scales of magmatic processes in the lower crust may be similar at slow- and fast-spreading ridges.This research was partially funded by NSF grant OCE-0727914 (SAB), a Cardiff University International Collaboration Award (CJL) and NERC grant NE/C509023/1 (CJM).2012-07-2

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Sample Reproducibility of Genetic Association Using Different Multimarker TDTs in Genome-Wide Association Studies: Characterization and a New Approach

Multimarker Transmission/Disequilibrium Tests (TDTs) are very robust association tests to population admixture and structure which may be used to identify susceptibility loci in genome-wide association studies. Multimarker TDTs using several markers may increase power by capturing high-degree associations. However, there is also a risk of spurious associations and power reduction due to the increase in degrees of freedom. In this study we show that associations found by tests built on simple null hypotheses are highly reproducible in a second independent data set regardless the number of markers. As a test exhibiting this feature to its maximum, we introduce the multimarker -Groups TDT (), a test which under the hypothesis of no linkage, asymptotically follows a distribution with degree of freedom regardless the number of markers. The statistic requires the division of parental haplotypes into two groups: disease susceptibility and disease protective haplotype groups. We assessed the test behavior by performing an extensive simulation study as well as a real-data study using several data sets of two complex diseases. We show that test is highly efficient and it achieves the highest power among all the tests used, even when the null hypothesis is tested in a second independent data set. Therefore, turns out to be a very promising multimarker TDT to perform genome-wide searches for disease susceptibility loci that may be used as a preprocessing step in the construction of more accurate genetic models to predict individual susceptibility to complex diseases

Malaria vectors and transmission dynamics in Goulmoun, a rural city in south-western Chad

<p>Abstract</p> <p>Background</p> <p>Knowledge of some baseline entomological data such as Entomological Inoculation Rates (EIR) is crucially needed to assess the epidemiological impact of malaria control activities directed either against parasites or vectors. In Chad, most published surveys date back to the 1960's. In this study, anopheline species composition and their relation to malaria transmission were investigated in a dry Sudanian savannas area of Chad.</p> <p>Methods</p> <p>A 12-month longitudinal survey was conducted in the irrigated rice-fields area of Goulmoun in south western Chad. Human landing catches were performed each month from July 2006 to June 2007 in three compounds (indoors and outdoors) and pyrethrum spray collections were conducted in July, August and October 2006 in 10 randomly selected rooms. Mosquitoes belonging to the <it>Anopheles gambiae </it>complex and to the <it>An. funestus </it>group were identified by molecular diagnostic tools. <it>Plasmodium falciparum </it>infection and blood meal sources were detected by ELISA.</p> <p>Results</p> <p>Nine anopheline species were collected by the two sampling methods. The most aggressive species were <it>An. arabiensis </it>(51 bites/human/night), <it>An. pharoensis </it>(12.5 b/h/n), <it>An. funestus </it>(1.5 b/h/n) and <it>An. ziemanni </it>(1.3 b/h/n). The circumsporozoite protein rate was 1.4% for <it>An. arabiensis</it>, 1.4% for <it>An. funestus</it>, 0.8% for <it>An. pharoensis </it>and 0.5% for <it>An. ziemanni</it>. Malaria transmission is seasonal, lasting from April to December. However, more than 80% of the total EIR was concentrated in the period from August to October. The overall annual EIR was estimated at 311 bites of infected anophelines/human/year, contributed mostly by <it>An. arabiensis </it>(84.5%) and <it>An. pharoensis </it>(12.2%). <it>Anopheles funestus </it>and <it>An. ziemanni </it>played a minor role. Parasite inoculation occurred mostly after 22:00 hours but around 20% of bites of infected anophelines were distributed earlier in the evening.</p> <p>Conclusion</p> <p>The present study revealed the implication of <it>An. pharoensis </it>in malaria transmission in the irrigated rice fields of Goulmoun, complementing the major role played by <it>An. arabiensis</it>. The transmission period did not depend upon irrigation. Correct use of insecticide treated nets in this area may be effective for vector control although additional protective measures are needed to prevent pre-bedtime exposure to the bites of infected anophelines.</p

A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8×10−11, GWA scan; P = 1.8×10−30, replication; P = 1.8×10−39, combined; U.K. PSA: P = 6.9×10−11). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13×10−26 in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4×10−4; U.K. PSA: P = 8.0×10−4; IL12B:rs6887695, U.S. PS, P = 5×10−5 and U.K. PSA, P = 1.3×10−3) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2×10−6 for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2×10−5 for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9×10−5 for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis)