Abstract
Background
Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the ...inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.
Methods
We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.
Results
We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10−5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein–coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.
Conclusion
Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
Guillain‐Barré syndrome (GBS) is a postinfectious immune‐mediated polyneuroradiculopathy in which host factors influence disease susceptibility and clinical course. Single‐nucleotide polymorphisms ...(SNPs) in the glucocorticoid receptor (GR) gene influence the sensitivity to glucocorticoids and are related to both microbial colonization and susceptibility to develop auto‐immune disease. This genetic variation may therefore also influence the chance to develop GBS. In this study, we genotyped 318 GBS patients and 210 control subjects for five known SNPs in the GR gene. We could distinguish six different GR haplotypes of which two carried the BclI polymorphism: haplotype 1, which consists of the minor allele of BclI in combination with the common variant of TthIIII and haplotype 2, which carries the minor allele of BclI as well as the minor allele of TthIIII. The GR haplotypes were not related to susceptibility to develop GBS. Carriers of haplotype 2 had more frequently preceding diarrhea, serum antibodies to GM1 and GD1a, and more severe muscle weakness at entry. Haplotype 1 carriers had a significantly better prognosis. In conclusion, GR haplotypes are not a susceptibility factor for GBS. However, haplotypes carrying the minor allele of the BclI polymorphism were related to the phenotype and outcome of GBS.
Rapid deceleration during sporting activities, such as landing from a jump, has been identified as a common mechanism of acute knee injury. Research into the role of potential sex differences in hip ...abductor function with lower extremity kinematics when landing from a jump is limited.
To evaluate sex differences in hip abductor function in relation to lower extremity landing kinematics.
2 x 2 mixed-model factorial design using a between-subjects factor (sex) and a repeated factor (test).
University laboratory.
A sample of convenience consisting of 30 healthy adults (15 women, 15 men) with no history of lower extremity surgery and no lower extremity injuries within 6 months of testing.
Landing kinematics were assessed as subjects performed 3 pre-exercise landing trials that required them to hop from 2 legs and land on a single leg. Isometric peak torque (PT) of the hip abductors was measured, followed by an endurance test during which subjects maintained 50% of their PT to the limits of endurance. After a 15-minute rest period, subjects completed a 30-second bout of isometric hip abduction, from which we calculated the percentage of endurance capacity (%E). Immediately after exercise, subjects completed 3 postexercise landing trials.
PT, %E, and peak joint displacement (PJD) of the hip and knee in all 3 planes of motion.
Women demonstrated lower PT values (5.8 +/- 1.2% normalized to body weight and height) than did their male counterparts (7.2 +/- 1.5% normalized to body weight and height, P = .009). However, no sex differences were seen in %E. Women also demonstrated larger knee valgus PJD (7.26 degrees +/- 6.61 degrees) than did men (3.29 degrees +/- 3.54 degrees, P = .04). Women's PT was moderately correlated with hip flexion, adduction, and knee valgus PJD; however, PT did not significantly correlate with men's landing kinematics. Regardless of sex, hip flexion (P = .002) and hip adduction (P = .001) were significantly increased following the 30-second bout of exercise.
Women demonstrated lower hip abductor PT and increased knee valgus PJD when landing from a jump, potentially increasing the risk of acute knee injury. Furthermore, correlations between hip abductor strength and landing kinematics were generally larger for women than for men, suggesting that hip abductor strength may play a more important role in neuromuscular control of the knee for women.
A complete understanding of fluid mechanics in Fontan physiology includes knowledge of the caval contributions to right (RPA) and left (LPA) pulmonary arterial blood flow, total systemic venous ...return, and relative blood flow to each lung.
Ten Fontan patients underwent cine MRI. Three cine scans of the pulmonary arteries were performed: (1) no presaturation pulse, (2) a presaturation pulse labeling inferior vena cava (IVC) blood (signal void), and (3) a presaturation pulse labeling superior vena cava (SVC) blood. The relative signal decrease is proportional to the amount of blood originating from the labeled vena cava. This method was validated in a phantom. Whereas 60+/-6% of SVC blood flowed into the RPA, 67+/-12% of IVC blood flowed toward the LPA. Of the blood in the LPA and RPA, 48+/-14% and 31+/-17%, respectively, came from the IVC. IVC blood contributed 40+/-16% to total systemic venous return. The distributions of blood to each lung were nearly equal (RPA/LPA blood=0.94+/-11).
In Fontan patients with total cavopulmonary connection, SVC blood is directed toward the RPA and IVC blood is directed toward the LPA. Although the right lung volume is larger than the left, an equal amount of blood flow went to both lungs. LPA blood is composed of equal amounts of IVC and SVC blood because IVC contribution to total systemic venous return is smaller than that of the SVC. This technique and these findings can help to evaluate design changes of the systemic venous pathway to improve Fontan hemodynamics.
Knowledge of surface pressure is essential for calculating column-averaged dry-air mole fractions of trace gases, such as CO2 (XCO2). In the NASA Orbiting Carbon Observatory 2 (OCO-2) Atmospheric ...Carbon Observations from Space (ACOS) retrieval algorithm, the retrieved surface pressures have been found to have unacceptable errors, warranting a parametric bias correction. This correction depends on the difference between retrieved and a priori surface pressures, which are derived from a meteorological model that is hypsometrically adjusted to the surface elevation using a digital elevation model (DEM). As a result, the effectiveness of the OCO-2 bias correction is contingent upon the accuracy of the referenced DEM. Here, we investigate several different DEM datasets for use in the OCO-2 ACOS retrieval algorithm: the OCODEM used in ACOS v10 and previous versions, the NASADEM+ (a composite of SRTMv4, ASTER GDEMv3, GIMP, and RAMPv2 DEMs) used in ACOS v11, the Copernicus GLO-90 DEM (GLO-90 DEM), and two polar regional DEMs (ArcticDEM and REMA). We find that the NASADEM+ (ASTER GDEMv3) has a persistent negative bias on the order of 10 to 20 m across most regions north of 60° N latitude, relative to all the other DEMs considered (OCODEM, ArcticDEM, and GLO-90 DEM). Variations of 10 m in DEM elevations lead to variations in XCO2 of approximately 0.4 ppm, meaning that the XCO2 from OCO-2 ACOS v11 retrievals tends to be 0.4 to 0.8 ppm lower across regions north of 60° N than XCO2 from OCO-2 ACOS v10. Our analysis also suggests that the GLO-90 DEM has superior global continuity and accuracy compared to the other DEMs, motivating a post-processing update from OCO-2 v11 Lite files (which used NASADEM+) to OCO-2 v11.1 by substituting the GLO-90 DEM globally. We find that OCO-2 v11.1 improves accuracy and spatial continuity in the bias-corrected XCO2 product relative to both v10 and v11 in high-latitude regions while resulting in marginal or no change in most regions within ± 60° latitude. In addition, OCO-2 v11.1 provides increased data throughput after quality control filtering in most regions, partly due to the change in DEM but mostly due to other corrections to quality control parameters. Given large-scale differences north of 60° N between the OCODEM and NASADEM+, we find that replacing the OCODEM with NASADEM+ yields a ∼ 100 TgC shift in inferred carbon uptake for the zones spanning 30 to 60° N and 60 to 90° N, which is on the order of 5 % to 7 % of the estimated pan-Arctic land sink. Changes in inferred fluxes from replacing the OCODEM with the GLO-90 DEM are smaller, and given the evidence for improved accuracies from this DEM, this suggests that large changes in inferred fluxes from the NASADEM+ are likely erroneous.
After utilizing separate congenital databases in the early 1990s, the Society of Thoracic Surgeons (STS) and the European Association for Cardio-Thoracic Surgery (EACTS) collaborated on several joint ...database initiatives.
In 1998, the joint EACTS-STS International Congenital Heart Surgery Nomenclature and Database Project Committee was created and a common nomenclature and common core minimum database dataset were adopted and published by the STS and the EACTS. In 1999, the joint EACTS-STS Aristotle Committee was created and the Aristotle Score was adopted and published as a method to provide complexity adjustment for congenital heart surgery. Collaborative efforts involving the EACTS and STS are underway to develop mechanisms to verify data completeness and accuracy.
Since 1998, this nomenclature, database, and methodology of complexity adjustment have been used by both the STS and EACTS to analyze outcomes of over 40,000 patients. A huge amount of data have been generated which allow comparison of practice patterns and outcomes analysis between Europe and North America. The aggregate data from the first 5 years of data collection not only make for interesting comparison but also allow examination of regional difference in practice patterns. For example, in the EACTS, out of 4,273 neonates, 885 (20.7%) underwent arterial switch procedures and 297 (6.95%) underwent Norwood stage 1 procedures. In the STS, out of 3,988 neonates, 472 (11.8%) underwent arterial switch procedures and 575 (14.4%) underwent Norwood stage 1 procedures.
This analysis of the EACTS-STS multi-institutional outcomes database confirms that in both Europe and North America, case complexity and mortality is highest among neonates, then infants, and then children. Regional differences in practice patterns are demonstrated, with the overall goal being the continued upgrade in the quality of surgery for congenital heart disease worldwide.
White Etch Cracking (WEC) is a severe and unpredictable failure mode that has been frequently observed in, among others, bearings for wind energy applications. In this work a novel, patented, WEC ...resistant bearing steel solution is developed through high temperature solution nitriding, followed by a custom heat treatment. Conventional medium carbon, 13 wt% Cr martensitic stainless steels were subjected to the novel process to obtain a nitrogen-rich case. A series of soft annealing, austenitization, cryogenic and tempering treatments converted the nitrogen-rich region into a fine-grained case containing nano-sized precipitates. Test bearings and tribometer specimens were treated with the same sequence of treatments. These specimens were tested under two different accelerated WEC failure promoting conditions. In contrast to standard through-hardened bearing steel the nitrided specimens showed no WEC formation, not even after prolonged testing.
•A high temperature nitriding process was developed for bearing steel.•An ultrafine microstructure was obtained in stainless steel after nitriding.•Laboratory tests indicated the nitrided steel was immune to white etch cracking.•This replicates the performance of expensive high-nitrogen steels.
The purpose of this study was to determine whether the expression of cytochrome P450 (CYP) enzyme mRNAs, other drug-metabolizing enzyme mRNAs, and transporter mRNAs can be detected using DNA arrays. ...Total RNA was isolated from peripheral blood mononuclear cells of 10 multiple sclerosis patients and 10 age- and sex-matched controls. The mRNA was reverse transcribed to radiolabeled cDNA, and the resultant cDNA was used to probe a DNA array containing several thousand known human genes. The signals corresponding to several CYPs, drug-metabolizing, and transporter mRNAs was substantially above background. The results demonstrate that the DNA array technique has the sensitivity and the selectivity for applications in the pharmaceutical sciences. The mean values for mRNAs of specific CYPs and drug-metabolizing enzymes in peripheral blood cells were compared with reported values for liver. The capabilities of DNA arrays may prove useful for characterizing CYP expression in a variety of clinical samples.
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