Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10−8). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT

Flexible fibre optic vs digital ureteroscopy and enhanced vs unenhanced imaging for diagnosis and treatment of upper tract urothelial carcinoma (UTUC): results from the Clinical Research Office of the Endourology Society (CROES)‐UTUC registry

Objectives To compare the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) undergoing kidney-sparing surgery (KSS) with fibre-optic (FO) vs digital (D) ureteroscopy (URS). To evaluate the oncological impact of image-enhancement technologies such as narrow-band imaging (NBI) and Image1-S in patients with UTUC. Patients and Methods The Clinical Research Office of the Endourology Society (CROES)-UTUC registry is an international, multicentre, cohort study prospectively collecting data on patients with UTUC. Patients undergoing flexible FO- or D-URS for diagnostic or diagnostic and treatment purposes were included. Differences between groups in terms of overall survival (OS) and disease-free survival (DFS) were evaluated. Results The CROES registry included 2380 patients from 101 centres and 37 countries, of whom 401 patients underwent URS (FO-URS 186 and D-URS 215). FO-URS were performed more frequently for diagnostic purposes, while D-URS was peformed when a combined diagnostic and treatment strategy was planned. Intra- and postoperative complications did not differ between the groups. The 5-year OS and DFS rates were 91.5% and 66.4%, respectively. The mean OS was 42 months for patients receiving FO-URS and 39 months for those undergoing D-URS (P = 0.9); the mean DFS was 28 months in the FO-URS group and 21 months in the D-URS group (P < 0.001). In patients who received URS with treatment purposes, there were no differences in OS (P = 0.9) and DFS (P = 0.7). NBI and Image1-S technologies did not improve OS or DFS over D-URS. Conclusions D-URS did not provide any oncological advantage over FO-URS. Similarly, no differences in terms of OS and DFS were found when image-enhancement technologies were compared to D-URS. These findings underline the importance of surgeon skills and experience, and reinforce the need for the centralisation of UTUC care

Managing bridge scour risk using structural health monitoring

Scour is the leading cause of bridge failures worldwide. In the United States, 22 bridges fail every year, whereas in the UK scour contributed significantly to the 138 bridge collapses recorded in the last century. In Scotland, there are around 2,000 bridges susceptible to scour. Scour assessments are currently based on visual inspections, which are expensive, time-consuming, and the information collected is qualitative. However, monitoring an entire infrastructure network against scour is not economically feasible. A way to overcome this limitation is to install monitoring systems at critical locations, and then extend the pieces of information gained to the entire asset through a probabilistic approach. This paper proposes a Decision Support System (DSS) for bridge scour management that exploits information from a limited number of scour monitoring systems to achieve a more confined estimate of the scour risk for a bridge network. A Bayesian network (BN) is used to describe conditional dependencies among the involved random variables. The BN allows estimating, and updating, the scour depth distributions using information from monitoring of scour depth and river flow characteristics. Data collected by the monitoring system and BN's outcomes are then used to inform a decision model and thus support transport agencies’ decision frameworks. A case study consisting of several road bridges in Scotland is considered to demonstrate the functioning of the DSS. The BN is found to estimate accurately the scour depth at unmonitored bridges, and the decision model provides higher values of scour thresholds compared to the ones implicitly chosen by the transport agencies

Reduction of pluripotent gene expression in murine embryonic stem cells exposed to mechanical loading or Cyclo RGD peptide

Abstract Background Self-renewal and differentiation of embryonic stem cells (ESCs) is directed by biological and/or physical cues that regulate multiple signaling cascades. We have previously shown that mESCs seeded in a type I collagen matrix demonstrate a loss of pluripotent marker expression and differentiate towards an osteogenic lineage. In this study, we examined if this effect was mediated in part through Arginylglycylaspartic acid (RGD) dependent integrin activity and/or mechano-transduction. Results The results from this study suggest that mESC interaction with the local microenvironment through RGD dependent integrins play a role in the regulation of mESC core transcription factors (TF), Oct-4, Sox 2 and Nanog. Disruption of this interaction with a cyclic RGD peptide (cRGDfC) was sufficient to mimic the effect of a mechanical stimulus in terms of pluripotent gene expression, specifically, we observed that supplementation with cRGDfC, or mechanical stimulus, significantly influenced mESC pluripotency by down-regulating core transcription factors. Moreover, our results indicated that the presence of the cRGDfC peptide inhibited integrin expression and up-regulated early lineage markers (mesoderm and ectoderm) in a Leukemia inhibitory factor (LIF) dependent manner. When cRGDfC treated mESCs were injected in Severe combined immunodeficiency (SCID) mice, no tissue growth and/or teratoma formation was observed, suggesting that the process of mESC tumor formation in vivo is potentially dependent on integrin interaction. Conclusions Overall, the disruption of cell-integrin interaction via cRGDfC peptide can mimic the effect of mechanical stimulation on mESC pluripotency gene expression and also inhibit the tumorigenic potential of mESCs in vivo