Abstract
Motivation
Genome-wide association studies (GWAS) are a powerful method to detect even weak associations between variants and phenotypes; however, many of the identified associated variants ...are in non-coding regions, and presumably influence gene expression regulation. Identifying potential drug targets, i.e. causal protein-coding genes, therefore, requires crossing the genetics results with functional data.
Results
We present a novel data integration pipeline that analyses GWAS results in the light of experimental epigenetic and cis-regulatory datasets, such as ChIP-Seq, Promoter-Capture Hi-C or eQTL, and presents them in a single report, which can be used for inferring likely causal genes. This pipeline was then fed into an interactive data resource.
Availability and implementation
The analysis code is available at www.github.com/Ensembl/postgap and the interactive data browser at postgwas.opentargets.io.
Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. ...However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring.
We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously.
Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP.
Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397.
This paper presents the layout and results of a three-year follow-up of a national intercomparison campaign organized on a voluntary basis among the Spanish Laboratories in charge of environmental ...monitoring at and in the vicinity of Spanish nuclear installations. The dosemeters were exposed in the field at an environmental reference station with a known ambient dose equivalent, and controlled meteorological parameters. The study aimed at verifying the consistency of the different laboratories in estimating the ambient dose equivalent in realistic fields and to evaluate the influence of two different procedures to estimate the transit dose during the transfer of the dosemeters both from and to the dosimetric laboratory and the monitored site. All the results were within 20% of the reference doses for all the dosemeters tested, and in most cases they were within 10%.
We describe a trackway (LH-Mg-10-16) occurring in laminated carbonated limestones of the Las Hoyas locality, Serranía de Cuenca, Spain. It is unmistakably a large theropod dinosaur trackway ...encompassing two unusual aspects, namely, wide-steps, and a set of equally deformed left footprints (with a dislocated digit). The layer also preserves other vertebrate trails (fish Undichna) and different impressions in the sediment. To address these complex settings, we devised a multidisciplinary approach, including the ichnological and taphonomical descriptions, characterisation of the rock lithofacies using thin-sections, 3D structured-light digitalisation with a high precision of 200-400 μm, and a geometric morphometric comparison with a large sample of bipedal dinosaur trackways. Sedimentary analyses showed that the trackway was produced in a humid, benthonic microbial mat, the consistency and plasticity of which enabled the preservation of the details of the movement of the animal. The results of the geometric analysis indicate that the "wide-steps" of the trackway is not unusual compared to other trackways, providing evidence that it was made by a single individual with an estimated hip height approximately 2 m. Analogous pathologies in extant archosaurs that yield the combination of wide steps and deformed digits in the same trackway were considered. All results mutually support the hypothesis that a large theropod dinosaur, with a pathological foot, generated the trackway as it crossed an area of shallow water while slowly walking towards the main water source, thus stepping steadily over the benthonic mat over which multiple fish were swimming.
X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors ...contributing to hypertension in XLH patients have yet to be identified. A multicenter cross-sectional study of adult patients diagnosed with XLH. Metabolomic analysis was performed using ultra-performance liquid chromatography (UPLC) coupled to a high-resolution mass spectrometer. Twenty subjects were included, of which nine (45%) had hypertension. The median age was 44 years. Out of the total, seven (35%) subjects had a family history of hypertension. No statistically significant differences were found between both groups for nephrocalcinosis or hyperparathyroidism. Those with hypertension exhibited significantly higher levels of creatinine (1.08 ± 0.31 mg/dL vs. 0.78 ± 0.19 mg/dL;
= 0.01) and LDL-C (133.33 ± 21.92 mg/dL vs. 107.27 ± 20.12 mg/dL,
= 0.01). A total of 106 metabolites were identified. Acetylcarnitine (
= 0.03), pyruvate
= (0.04), ethanolamine (
= 0.03), and butyric acid (
= 0.001) were significantly different between both groups. This study is the first to examine the metabolomics of hypertension in patients with XLH. We have identified significant changes in specific metabolites that shed new light on the potential mechanisms of hypertension in XLH patients. These findings could lead to new studies identifying associated biomarkers and developing new diagnostic approaches for XLH patients.
Abstract
The Ensembl project (https://www.ensembl.org) makes key genomic data sets available to the entire scientific community without restrictions. Ensembl seeks to be a fundamental resource ...driving scientific progress by creating, maintaining and updating reference genome annotation and comparative genomics resources. This year we describe our new and expanded gene, variant and comparative annotation capabilities, which led to a 50% increase in the number of vertebrate genomes we support. We have also doubled the number of available human variants and added regulatory regions for many mouse cell types and developmental stages. Our data sets and tools are available via the Ensembl website as well as a through a RESTful webservice, Perl application programming interface and as data files for download.
Abstract
Patients on peritoneal dialysis (PD) have an increased risk of cardiovascular disease (CVD) and an atherogenic lipid profile generated by exposure to high glucose dialysis solutions. In the ...general population, the reduction of classic lipids biomarkers is associated with improved clinical outcomes; however, the same results have not been seen in PD population, a lack of data this study aims to fulfill. Single-center prospective observational study of a cohort of CKD patients who started renal replacement therapy with continuous ambulatory peritoneal dialysis. The differences in the lipid profile and analytical variables before and 6 months after the start of peritoneal dialysis were analyzed. Samples were analyzed on an Ultra-Performance Liquid Chromatography system. Thirty-nine patients were enrolled in this study. Their mean age was 57.9 ± 16.3 years. A total of 157 endogenous lipid species of 11 lipid subclasses were identified. There were significant increases in total free fatty acids (p < 0.05), diacylglycerides (p < 0.01), triacylglycerides, (p < 0.01), phosphatidylcholines (p < 0.01), phosphatidylethanolamines (p < 0.01), ceramides (p < 0.01), sphingomyelins (p < 0.01), and cholesterol esters (p < 0.01) from baseline to 6 months. However, there were no differences in the classical lipid markers, neither lysophosphatidylcholines, monoacylglycerides, and sphingosine levels. 6 months after the start of the technique, PD patients present changes in the lipidomic profile beyond the classic markers of dyslipidemia.
Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is ...considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN‐positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN‐associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto‐oncogene c‐Src (SRC) inhibitor dasatinib due to activation of the Yes‐associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer‐derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.
Previous efforts trying to find a therapeutic strategy using chromosomal instability (CIN) as a biomarker did not yield promising results. We screened a drug library using breast cancer cells overexpressing individual genes, closely associated with CIN, in an inducible manner. We found that overexpression of the CIN‐associated gene TPX2 provides sensitivity to the SRC inhibitor dasatinib, due to an increase in YAP/TAZ transcriptional signaling.
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising ...clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3′UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.
•A wide range of sensitivity to abemaciclib is observed among Rb+ tumor cells•CDKN2A mutant cancers show only intermediate sensitivity to CDK4/6 inhibition•D-cyclin activating features are associated with highly sensitive cells•About 5% of endometrial cancers bear a stabilizing mutation in the CCND1 3′UTR
Gong et al. identify a subset of cancers highly sensitive to CDK4/6 inhibition, which are characterized by various genomic aberrations known to elevate D-cyclin levels but not by CDKN2A mutations. They also identify a recurrent CCND1 3′UTR mutation associated with increased CCND1 expression in endometrial cancer.
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