Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Construction and biological testing of artificial implants for peripheral nerve repair

In this thesis I documented the development of an artificial nerve conduit and subsequent biological testing within an animal model of peripheral nerve injury. The focus for the development of the conduit lied in the utilization of electrospun microfibers to serve as a guidance structure for Schwann cells and axons during regeneration. Through the incorporation of such a guidance structure into the lumen of a conventional hollow nerve conduit, Schwann cell migration and axonal elongation across artificial nerve conduits was supposed to be facilitated, thereby expanding the applicability of artificial nerve conduits to the repair of larger nerve gaps.To achieve this I initially established a procedure to produce three-dimensional arrays of aligned microfibers. Through embedding of these arrays into a biocompatible hydrogel I created a scaffold with an integrated guidance structure, which can be incorporated into a conventional nerve conduit. This scaffold was then used to confirm in vitro, whether the guidance properties, the fibers exerted under two-dimensional conditions, are preserved in a three dimensional environment. Since the hydrogel (e.g. collagen) could potentially compete with the fibers for the interaction with cells due to its fibrillary structure.Subsequently the new implants were assembled through incorporation of the scaffold into conventional conduits and the benefit of the integrated structure was then evaluated in comparison to the autologous nerve graft and the conventional hollow conduit by using an animal model of peripheral nerve injury. For this, a sciatic nerve lesion was performed in rats (Rattus norvegicus), which was subsequently repaired by insertion of the respective im-/transplant. Assessment of recovery by means of immunohistological investigation of the regenerated nerve, electromyography, determination of muscle weight as well as different behavioral tests, revealed an advantage of the internally structured conduit over the conventional hollow conduit, particularly when the integrated fibers contained proteins derived from the extracellular matrix. Thus, even though the autologous nerve graft still performed considerably better than the other implants tested, the new structured design offers several possibilities for further optimization and thus presents a promising approach to narrow the gap between autologous nerve grafts and their artificial alternatives

Influence of backpressure during ECAP on the monotonic and cyclic deformation behavior of AA5754 and Cu99.5

Ultrafine-grained (UFG) metals produced by equal channel angular pressing (ECAP) exhibit outstanding mechanical properties. They show high strength under monotonic loading as well as strongly enhanced fatigue lives in the W&ouml;hler S-N-plot compared to their coarse grained (CG) counterparts. It could be shown that the fatigue lives can be significantly enhanced further by applying backpressure during ECAP. Besides the positive effect of backpressure on the processability of hard to deform materials via ECAP, the hydrostatic stress induced by backpressure also influences the mechanical properties under monotonic and cyclic loading. Therefore the influence of backpressure on ECAPed Cu99.5 and on the ECAPed aluminum alloy AA5754 was investigated. It is shown that backpressure has no effect on the hardness and grain size in Cu99.5 but changes the grain boundary misorientation to higher fractions of low angle grain boundaries. Also the temperature dependency of the yield strength as well as the hardening behavior under monotonic compression is affected. The cyclic deformation behavior of Cu99.5 is not strongly influenced by backpressure, but the mean stress level changes drastically. The fatigue life increases with the application of backpressure at low plastic amplitudes due to a change in the crack initiation and propagation. Aim of this work is the investigation of the influence of backpressure during equal channel angular pressing (ECAP) on the mechanical properties under monotonic and cyclic loading. Therefore we performed hardness measurements, compression, and fatigue tests on ECAPed Cu99.5 and AA5754. The results are discussed in terms of microstructure and relevant deformation and damage mechanisms

First report of Klebsiella pneumonia carbapenemase-producing Pseudomonas aeruginosa isolated from burn patients in Iran: phenotypic and genotypic methods

[english] Wound infection associated with carbapenem-resistant in burn patients is a growing problem. One of the main mechanisms of resistance to carbapenem antibiotics is the ability of to produce carbapenemase enzymes. carbapemenase (KPC) is an important type of carbapenemase which can hydrolyze carbapenem antibiotics. The Modified Hodge Test (MHT) and boronic acid as a KPC inhibitor are two phenotypic methods used for detection of carbapenemase. The sensitivity and specificity of these two phenotypic tests for the identification of KPC can be measured by PCR.In this study, 241 strains were isolated from wounds of hospitalized burn patients. Carbapenem-resistant isolates were determined by the disk diffusion method. KPC-producing carbapenem-resistant strains were examined using the Modified Hodge Test, followed by boronic acid. Further, strains with positive responses to MHT and boronic acid tests were analyzed with the PCR molecular method. One hundred eighty-six of 241 isolates were resistant to carbapenems and 75 were positive in the MHT. Three exhibited an at least 5-mm diameter difference when meropenem was combined with boronic acid vs meropenem alone in the boronic acid test. Two strains had a specific band with primer No.1 after gel electrophoresis. This study showed that MHT, despite excellent sensitivity, has variable specificity independent of bacterial species. Further, the use of KPC inhibitors such as boronic acid did not yield favorable sensitivity and specificity among the specimens from Iranian patients. Thus, it seems that sequencing after PCR should be considered the gold standard for the detection of KPC-producing