| 1. |
- Schuette, Moritz, et al.
(författare)
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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
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| 2. |
- Wild, Philipp S., et al.
(författare)
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A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
- 2011
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Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association/Lippincott, Williams & Wilkins. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
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Tidskriftsartikel (refereegranskat)abstract
- Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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| 3. |
- Alagöz, Ibrahim, et al.
(författare)
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Validating Test Cases for Safety Relevant ECUs using Simulation Models
- 2017
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Ingår i: 4th International Symposium on Future Active Safety Technology towards Zero-Traffic-Accidents (FAST-zero).
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Konferensbidrag (refereegranskat)abstract
- Software Components responsible for active safety require extensive testing using multiple steps from unit level to integration level. As the hardware involved in this process is costly and limited, it is important that test cases used in this environment are valid. In this study, we present a novel approach towards validating test cases for active safety software components in vehicles. Simulation models from the integration testing step are re-used for validating test cases early in the process. The approach builds upon the SimTAny framework that conducts a test-driven agile simulation. However, simulation models are available in their Matlab/Simulink simulation environment. Thus a distributed simulation of the test and the system model is required. Accordingly, an extended framework for distributed simulation is created using the high- level architecture / run-time infrastructure standard. We validate the approach by applying it to a test for reversible belt tensioning and the respective simulation model. We were able to reuse an existing simulation model and validate connected test cases. We show that the framework has the potential to save valuable time on expensive hardware resources and time to review test results.
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| 4. |
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| 5. |
- Auffray, Charles, et al.
(författare)
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Making sense of big data in health research: Towards an EU action plan
- 2016
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Ingår i: Genome Medicine. - : BIOMED CENTRAL LTD. - 1756-994X .- 1756-994X. ; 8:71
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Tidskriftsartikel (refereegranskat)abstract
- Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health arid healthcare for all Europearis.
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| 6. |
- Backes, Claudia, et al.
(författare)
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Production and processing of graphene and related materials
- 2020
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Ingår i: 2D Materials. - : IOP Publishing. - 2053-1583. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- We present an overview of the main techniques for production and processing of graphene and related materials (GRMs), as well as the key characterization procedures. We adopt a 'hands-on' approach, providing practical details and procedures as derived from literature as well as from the authors' experience, in order to enable the reader to reproduce the results. Section I is devoted to 'bottom up' approaches, whereby individual constituents are pieced together into more complex structures. We consider graphene nanoribbons (GNRs) produced either by solution processing or by on-surface synthesis in ultra high vacuum (UHV), as well carbon nanomembranes (CNM). Production of a variety of GNRs with tailored band gaps and edge shapes is now possible. CNMs can be tuned in terms of porosity, crystallinity and electronic behaviour. Section II covers 'top down' techniques. These rely on breaking down of a layered precursor, in the graphene case usually natural crystals like graphite or artificially synthesized materials, such as highly oriented pyrolythic graphite, monolayers or few layers (FL) flakes. The main focus of this section is on various exfoliation techniques in a liquid media, either intercalation or liquid phase exfoliation (LPE). The choice of precursor, exfoliation method, medium as well as the control of parameters such as time or temperature are crucial. A definite choice of parameters and conditions yields a particular material with specific properties that makes it more suitable for a targeted application. We cover protocols for the graphitic precursors to graphene oxide (GO). This is an important material for a range of applications in biomedicine, energy storage, nanocomposites, etc. Hummers' and modified Hummers' methods are used to make GO that subsequently can be reduced to obtain reduced graphene oxide (RGO) with a variety of strategies. GO flakes are also employed to prepare three-dimensional (3d) low density structures, such as sponges, foams, hydro- or aerogels. The assembly of flakes into 3d structures can provide improved mechanical properties. Aerogels with a highly open structure, with interconnected hierarchical pores, can enhance the accessibility to the whole surface area, as relevant for a number of applications, such as energy storage. The main recipes to yield graphite intercalation compounds (GICs) are also discussed. GICs are suitable precursors for covalent functionalization of graphene, but can also be used for the synthesis of uncharged graphene in solution. Degradation of the molecules intercalated in GICs can be triggered by high temperature treatment or microwave irradiation, creating a gas pressure surge in graphite and exfoliation. Electrochemical exfoliation by applying a voltage in an electrolyte to a graphite electrode can be tuned by varying precursors, electrolytes and potential. Graphite electrodes can be either negatively or positively intercalated to obtain GICs that are subsequently exfoliated. We also discuss the materials that can be amenable to exfoliation, by employing a theoretical data-mining approach. The exfoliation of LMs usually results in a heterogeneous dispersion of flakes with different lateral size and thickness. This is a critical bottleneck for applications, and hinders the full exploitation of GRMs produced by solution processing. The establishment of procedures to control the morphological properties of exfoliated GRMs, which also need to be industrially scalable, is one of the key needs. Section III deals with the processing of flakes. (Ultra)centrifugation techniques have thus far been the most investigated to sort GRMs following ultrasonication, shear mixing, ball milling, microfluidization, and wet-jet milling. It allows sorting by size and thickness. Inks formulated from GRM dispersions can be printed using a number of processes, from inkjet to screen printing. Each technique has specific rheological requirements, as well as geometrical constraints. The solvent choice is critical, not only for the GRM stability, but also in terms of optimizing printing on different substrates, such as glass, Si, plastic, paper, etc, all with different surface energies. Chemical modifications of such substrates is also a key step. Sections IV-VII are devoted to the growth of GRMs on various substrates and their processing after growth to place them on the surface of choice for specific applications. The substrate for graphene growth is a key determinant of the nature and quality of the resultant film. The lattice mismatch between graphene and substrate influences the resulting crystallinity. Growth on insulators, such as SiO2, typically results in films with small crystallites, whereas growth on the close-packed surfaces of metals yields highly crystalline films. Section IV outlines the growth of graphene on SiC substrates. This satisfies the requirements for electronic applications, with well-defined graphene-substrate interface, low trapped impurities and no need for transfer. It also allows graphene structures and devices to be measured directly on the growth substrate. The flatness of the substrate results in graphene with minimal strain and ripples on large areas, allowing spectroscopies and surface science to be performed. We also discuss the surface engineering by intercalation of the resulting graphene, its integration with Si-wafers and the production of nanostructures with the desired shape, with no need for patterning. Section V deals with chemical vapour deposition (CVD) onto various transition metals and on insulators. Growth on Ni results in graphitized polycrystalline films. While the thickness of these films can be optimized by controlling the deposition parameters, such as the type of hydrocarbon precursor and temperature, it is difficult to attain single layer graphene (SLG) across large areas, owing to the simultaneous nucleation/growth and solution/precipitation mechanisms. The differing characteristics of polycrystalline Ni films facilitate the growth of graphitic layers at different rates, resulting in regions with differing numbers of graphitic layers. High-quality films can be grown on Cu. Cu is available in a variety of shapes and forms, such as foils, bulks, foams, thin films on other materials and powders, making it attractive for industrial production of large area graphene films. The push to use CVD graphene in applications has also triggered a research line for the direct growth on insulators. The quality of the resulting films is lower than possible to date on metals, but enough, in terms of transmittance and resistivity, for many applications as described in section V. Transfer technologies are the focus of section VI. CVD synthesis of graphene on metals and bottom up molecular approaches require SLG to be transferred to the final target substrates. To have technological impact, the advances in production of high-quality large-area CVD graphene must be commensurate with those on transfer and placement on the final substrates. This is a prerequisite for most applications, such as touch panels, anticorrosion coatings, transparent electrodes and gas sensors etc. New strategies have improved the transferred graphene quality, making CVD graphene a feasible option for CMOS foundries. Methods based on complete etching of the metal substrate in suitable etchants, typically iron chloride, ammonium persulfate, or hydrogen chloride although reliable, are time- and resource-consuming, with damage to graphene and production of metal and etchant residues. Electrochemical delamination in a low-concentration aqueous solution is an alternative. In this case metallic substrates can be reused. Dry transfer is less detrimental for the SLG quality, enabling a deterministic transfer. There is a large range of layered materials (LMs) beyond graphite. Only few of them have been already exfoliated and fully characterized. Section VII deals with the growth of some of these materials. Amongst them, h-BN, transition metal tri- and di-chalcogenides are of paramount importance. The growth of h-BN is at present considered essential for the development of graphene in (opto) electronic applications, as h-BN is ideal as capping layer or substrate. The interesting optical and electronic properties of TMDs also require the development of scalable methods for their production. Large scale growth using chemical/physical vapour deposition or thermal assisted conversion has been thus far limited to a small set, such as h-BN or some TMDs. Heterostructures could also be directly grown. Section VIII discusses advances in GRM functionalization. A broad range of organic molecules can be anchored to the sp(2) basal plane by reductive functionalization. Negatively charged graphene can be prepared in liquid phase (e.g. via intercalation chemistry or electrochemically) and can react with electrophiles. This can be achieved both in dispersion or on substrate. The functional groups of GO can be further derivatized. Graphene can also be noncovalently functionalized, in particular with polycyclic aromatic hydrocarbons that assemble on the sp(2) carbon network by pi-pi stacking. In the liquid phase, this can enhance the colloidal stability of SLG/FLG. Approaches to achieve noncovalent on-substrate functionalization are also discussed, which can chemically dope graphene. Research efforts to derivatize CNMs are also summarized, as well as novel routes to selectively address defect sites. In dispersion, edges are the most dominant defects and can be covalently modified. This enhances colloidal stability without modifying the graphene basal plane. Basal plane point defects can also be modified, passivated and healed in ultra-high vacuum. The decoration of graphene with metal nanoparticles (NPs) has also received considerable attention, as it allows to exploit synergistic effects between NPs and graphene. Decoration can be either achieved chemically or in the gas phase. All LMs,
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| 7. |
- Campa, Daniele, et al.
(författare)
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Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study
- 2010
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Ingår i: BMC Gastroenterology. - 1471-230X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. Methods: We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. Results: We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. Conclusion: A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (P-trend = 0.004).
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| 8. |
- Carrai, Maura, et al.
(författare)
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Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99-1.67; P-value = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06-1.75; P-value = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12-1.61; P-value = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin.
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| 9. |
- Hämmerle, Christoph H F, et al.
(författare)
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Biology of soft tissue wound healing and regeneration : consensus report of group 1 of the 10th European workshop on periodontology
- 2014
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Ingår i: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 41:s15, s. S1-S5
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND:The scope of this consensus was to review the biological processes of soft tissue wound healing in the oral cavity and to histologically evaluate soft tissue healing in clinical and pre-clinical models. AIMS:To review the current knowledge regarding the biological processes of soft tissue wound healing at teeth, implants and on the edentulous ridge. Furthermore, to review soft tissue wound healing at these sites, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. COLLECTION OF DATA:Searches of the literature with respect to recessions at teeth and soft tissue deficiencies at implants, augmentation of the area of keratinized tissue and soft tissue volume were conducted. The available evidence was collected, categorized and summarized. FUNDAMENTAL PRINCIPLES OF ORAL SOFT TISSUE WOUND HEALING:Oral mucosal and skin wound healing follow a similar pattern of the four phases of haemostasis, inflammation, proliferation and maturation/matrix remodelling. The soft connective tissue determines the characteristics of the overlaying oral epithelium. Within 7-14 days, epithelial healing of surgical wounds at teeth is completed. Soft tissue healing following surgery at implants requires 6-8 weeks for maturation. The resulting tissue resembles scar tissue. Well-designed pre-clinical studies providing histological data have been reported describing soft tissue wound healing, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Few controlled clinical studies with low numbers of patients are available for some of the treatments reviewed at teeth. Whereas, histological new attachment has been demonstrated in pre-clinical studies resulting from some of the treatments reviewed, human histological data commonly report a lack of new attachment but rather long junctional epithelial attachment and connective tissue adhesion. Regarding soft tissue healing at implants human data are very scarce. CONCLUSIONS:Oral soft tissue healing at teeth, implants and the edentulous ridge follows the same phases as skin wound healing. Histological studies in humans have not reported new attachment formation at teeth for the indications studied. Human histological data of soft tissue wound healing at implants are limited. CLINICAL RECOMMENDATIONS:The use of barriers membranes, growth and differentiation factors and soft tissue substitutes for the treatment of localized gingival/mucosal recessions, insufficient amount of keratinized tissue and insufficient soft tissue volume is at a developing stage.
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| 10. |
- Kaufman, Darrell, et al.
(författare)
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A global database of Holocene paleotemperature records
- 2020
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format.
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