Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

Background Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. Methods We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. Results LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. Conclusions Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions

Coulomb dissociation of O-16 into He-4 and C-12

We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4

Variable Threshold Algorithm for Division of Labor Analyzed as a Dynamical System

Division of labor is a widely studied aspect of colony behavior of social insects. Division of labor models indicate how individuals distribute themselves in order to perform different tasks simultaneously. However, models that study division of labor from a dynamical system point of view cannot be found in the literature. In this paper, we define a division of labor model as a discrete-time dynamical system, in order to study the equilibrium points and their properties related to convergence and stability. By making use of this analytical model, an adaptive algorithm based on division of labor can be designed to satisfy dynamic criteria. In this way, we have designed and tested an algorithm that varies the response thresholds in order to modify the dynamic behavior of the system. This behavior modification allows the system to adapt to specific environmental and collective situations, making the algorithm a good candidate for distributed control applications. The variable threshold algorithm is based on specialization mechanisms. It is able to achieve an asymptotically stable behavior of the system in different environments and independently of the number of individuals. The algorithm has been successfully tested under several initial conditions and number of individuals

Multi-Konstellations-GBAS für gekrümmte Steilanflüge

Moderne Satellitennavigation erlaubt die freie Positionierung von Wegpunkten im Raum. Darüber hinaus ermöglicht die erreichbare Genauigkeit und Integrität durch den Einsatz eines Ground Based Augmentation Systems (GBAS) Präzisionsanflüge sogar bei schlechten Sichtbedingungen. Dies bildet die Grundlage für lärmarme und lärmvermeidende Anflugverfahren, die ein gekrümmtes und/oder steileres Profil als Standardanflüge aufweisen. In dieser Arbeit wird auf die Fliegbarkeit solcher Anflugverfahren und technische Aspekte auf der Empfängerseite bei diesen Verfahren eingegangen. Bei einem GBAS werden Korrektursignale für alle aktuell an dem jeweiligen Flughafen sichtbaren Satelliten vom Boden an die Luftfahrzeuge im Empfangsbereich verschickt. Mit diesen Korrektursignalen können die Luftfahrzeuge ihre Position sehr genau und verlässlich bestimmen. Außerdem wird über ein GBAS der Sollanflugweg (oder mehrere mögliche Anflugwege) an die Luftfahrzeuge verschickt. Diese Kombination erlaubt komplexe Anflugverfahren, die durch gekrümmte Anflugwege bewohnte Gebiete im Flughafennahbereich vermeiden oder durch leicht steilere Profile ein längeres Fliegen in größerer Höhe ermöglichen und so den Abstand zum Boden vergrößern, was eine Verringerung des Wahrgenommenen Lärms am Boden zur Folge hat. Um zu gewährleisen, dass ein höchstes Maß an betrieblicher Sicherheit bei solch komplexen Verfahren gewährleistet werden kann, wurde in dieser Arbeit zunächst die Durchführbarkeit solcher Verfahren untersucht. Daneben wurden einige technische Aspekte der Satellitennavigation bei diesen Verfahren beleuchtet. Ein Problem, welches bei gekrümmten Anflügen auftreten kann, besteht im möglichen Verlust von Satelliten niedriger Elevationen. Durch die in den Kurven auftretenden Rollwinkel wird die Wahrscheinlichkeit, dass der Kontakt zu einem Navigationssatelliten verloren geht gegenüber geraden Anflugpfaden deutlich erhöht. Dies ist einerseits bedingt durch die Änderung der Satellitenelevation in Bezug auf die Antenne selbst, andererseits treten insbesondere durch die Tragflächen auch Abschattungen auf, welche zu Signalverlusten oder Cycle-Slips führen können. Auch nach erfolgreicher Reakquise der Navigationssignale steht ein Satellit erst nach der Konvergenz der Smoothing-Filter zur Verfügung. Bei dynamischen Anflugverfahren ist deshalb von einer Degradation der Satellitengeometrie auszugehen, während gleichzeitig die höchsten Anforderungen bezüglich Genauigkeit und Integrität an das Navigationssystem gestellt werden. Aus diesem Grund ist in diesem Fall die Verwendung einer zweiten Konstellation von Navigationssatelliten besonders hilfreich. In dieser Arbeit stellen wir die Ergebnisse aus Flugversuchen zu GBAS-basierten gekrümmten Anflügen dar und zeigen beispielhaft die Vorteile der Verwendung einer Kombination von GPS und Galileo Satelliten. Durch die deutlich größere Anzahl an zur Verfügung stehenden Navigationssignalen lassen sich deutlich höhere Elevationsmasken realisieren, sodass die Auswirkungen von Rollwinkeln im Anflug deutlich reduziert werden können. Aufgrund der typischerweise größeren Messfehler bei Satelliten niedriger Elevation lassen sich zusätzlich auch noch Mehrwegeeffekte reduzieren, sodass in dieser kritischen Flugphase stets die strikten Anforderungen an die Genauigkeit und Zuverlässigkeit der Navigation erfüllt werden können

The Effects of Two Different Concurrent Training Configurations on Markers of Metabolic Syndrome and Fitness in Women With Severe/Morbid Obesity: A Randomised Controlled Trial

Concurrent training (CT), characterised by combining both aerobic and resistance training modalities within the same session, is recognised to improve metabolic syndrome (MetS) markers, but little is known about the effects of different configurations (i.e., order) of these exercise modalities on MetS markers and the interindividual responses. The purpose of the present study was to describe the effects, and the interindividual variability, of 20 weeks of two CT configurations (i.e., high intensity interval training (HIIT) plus resistance training (RT), compared with RT plus HIIT) in women with severe/morbid obesity. Overall, 26 women with severe/morbid obesity were assigned either to HIIT + RT [n = 14, mean and 95%CI, 45.79 (40.74; 50.83) or RT + HIIT (n = 12), 33.6 (25.30; 41.79) years]. MetS-related outcomes were waist circumference (WC, cm), systolic (SBP, mmHg) and diastolic (DBP, mmHg) blood pressure, high-density lipoprotein cholesterol (HDL-c), triglycerides (Tg), and fasting plasma glucose (FPG). Secondary outcomes were other anthropometrics, body composition, lipids, muscle strength, and the six-minute walk test (6Mwt). There were significant differences in the prevalence of nonresponders (NRs) only for WC comparing HIIT + RT 2 (18.1%) vs. RT + HIIT group 5 (50.0%), p 0.05. Additionally, the RT + HIIT group showed significant reductions in WC (Delta -3.84 cm, p = 0.015), SBP (Delta -8.46 mmHg, p = 0.040), whereas the HIIT+RT group elicited significant reductions only in SBP (Delta -8.43 mmHg, p = 0.022). The HIIT + RT promoted a lower prevalence of NRs than the RT + HIIT configuration on WC, and overall, there were slightly more beneficial training-induced effects on markers of MetS in the RT + HIIT group compared to the HIIT + RT group

Experiences and methodology in a multidisciplinary energy and architecture competition: Solar Decathlon Europe 2012

Solar Decathlon Europe is an international competition among universities which promotes interdisciplinary learning in engineering and architecture. Students from different disciplines participate in teams guided by several professors during a 29 month preparation period plus five weeks of on-site contest. The educational project involves designing, building and testing a solar energy house connected to the electrical grid with the strategy of maximizing self-consumption, supported by bioclimatic technologies and maintaining a low environmental footprint. It culminates in a on-site contest in which teams must assembly the house themselves, test it with ordinary real life tasks and finally disassembly it. The event has also a divulgative aim, trying to make students and visitors get interested in discovering the problems presented by real engineering and architecture applications. In addition, SDE covers R&D aspects in different fields such as energy efficiency, solar energy and bioclimatic architecture. This article presents the methodology followed during the SDE 2012 edition, in which more than 850 students participated. The obtained results show that the educational competition was a success according to the technical and professional ambitions of the students, most of them considering that their knowledge had increased in areas related to technical and multidisciplinary aspects. (C) 2014 Elsevier B.V. All rights reserved

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

J.R.-B. has received honoraria for educational activities from Roche; honoraria for consultancies from Boehringer Ingelheim; institutional research funding from Roche; and travel, accommodations, expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Ipsen, PharmaMar, Merck, Pfizer, and Roche. E.B.-V. has received honoraria for consultancies from Leo, and Rovi; and travel, accommodations, expenses from Servier, Merck, Sanofi, Roche, Pierre Fabre, and Amgen. Y.V.-I. has received honoraria for consultancies from PharmaMar. F.V.-R. has received honoraria for consultancies from Roche, Eisai, and Servier; and travel, accommodations, expenses from Lilly, Merck, and Pierre Fabre. S.C.-F. has received honoraria for educational activities from Servier, and Pierre Fabre; and travel, accommodations, expenses from Lilly, and Merck. R.L.-L. has received honoraria for participation in Advisory Boards from Roche, AstraZeneca, Merck, Merck Sharp & Dohme, Bayer, Bristol-Myers Squibb, Novartis, Janssen, Lilly, Pfizer, and Leo; travel, accommodations, and expenses from PharmaMar, Roche, Bristol-Myers Squibb, and Pierre Fabre; research funding from Roche and Merck; and is co-founder and shareholder in Nasasbiotech, S.L., Mtrap Inc. A.R.-C., A.B.C., R.L.-L. and A.D.-L. are inventors in one patent application over these results licensed to Advanced Marker Discovery, S.L. (Amadix). L.C., A.C.M. and R.A. are employees of Advanced Marker Discovery, S.L. (Amadix). The rest of the authors declare no potential conflicts of interest.This research was co-funded by the ISCIII (PI18/00307) and the European Regional Development Fund (FEDER), PRIS3 grant from ACIS and Xunta de Galicia, 2015 Merck Serono research grant, all donors who participated in the Liquid Biopsy Crowdfunding campaign in 2017, and Advanced Marker Discovery S.L. (Amadix). J.R.-B. was supported by a Río Hortega fellowship from ISCIII (CM19/00087) and is supported by a Juan Rodés contract (JR21/00019) and a 2020 TTD Research Grant from the Spanish Cooperative Group for the Treatment of Digestive Tumors. A.R.-C. is supported by the Roche-Chus Joint Unit (IN853B 2018/03) funded by GAIN, "Consellería de Economía, Emprego e Industria." N.C.-F. is funded by a predoctoral contract from "Xunta de Galicia" (IN606A-2020/004). A.B.-C. is funded by a predoctoral contract PFIS from ISCIII (FI19/00240) co-funded by "Fondo Social Europeo" (FSE). L.M.-R. is supported by the AECC. ABC is a Miguel Servet researcher (ISCIII; CP17/0008). A.G. is funded by CA181572, CA184792, CA202797 and CA214254 grants from the National Cancer Institute, National Institutes of Health. A.D.-L. is funded by a contract Juan Rodés from ISCIII (JR17/00016). V.M. is funded by the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds-a way to build Europe-grants PI17-0009, and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE.Background: Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. Methods: We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. Results: LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. Conclusions: Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions