| 1. |
|
|
| 2. |
- Campbell, PJ, et al.
(author)
-
Pan-cancer analysis of whole genomes
- 2020
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
-
Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
|
|
| 3. |
- Sherratt, K., et al.
(author)
-
Predictive performance of multi-model ensemble forecasts of COVID-19 across European nations
- 2023
-
In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
-
Journal article (peer-reviewed)abstract
- Methods: We used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported by a standardised source for 32 countries over the next 1–4 weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models’ predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models’ forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models’ past predictive performance.Results: Over 52 weeks, we collected forecasts from 48 unique models. We evaluated 29 models’ forecast scores in comparison to the ensemble model. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 83% of participating models’ forecasts of incident cases (with a total N=886 predictions from 23 unique models), and 91% of participating models’ forecasts of deaths (N=763 predictions from 20 models). Across a 1–4 week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over 4 weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models.Conclusions: Our results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than 2 weeks.
|
|
| 4. |
- Dankiewicz, Josef, et al.
(author)
-
Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
- 2021
-
In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294
-
Journal article (peer-reviewed)abstract
- Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
|
|
| 5. |
- Hussein, A. E., et al.
(author)
-
Laser-wakefield accelerators for high-resolution X-ray imaging of complex microstructures
- 2019
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Journal article (peer-reviewed)abstract
- Laser-wakefield accelerators (LWFAs) are high acceleration-gradient plasma-based particle accelerators capable of producing ultra-relativistic electron beams. Within the strong focusing fields of the wakefield, accelerated electrons undergo betatron oscillations, emitting a bright pulse of X-rays with a micrometer-scale source size that may be used for imaging applications. Non-destructive X-ray phase contrast imaging and tomography of heterogeneous materials can provide insight into their processing, structure, and performance. To demonstrate the imaging capability of X-rays from an LWFA we have examined an irregular eutectic in the aluminum-silicon (Al-Si) system. The lamellar spacing of the Al-Si eutectic microstructure is on the order of a few micrometers, thus requiring high spatial resolution. We present comparisons between the sharpness and spatial resolution in phase contrast images of this eutectic alloy obtained via X-ray phase contrast imaging at the Swiss Light Source (SLS) synchrotron and X-ray projection microscopy via an LWFA source. An upper bound on the resolving power of 2.7 ± 0.3 μm of the LWFA source in this experiment was measured. These results indicate that betatron X-rays from laser wakefield acceleration can provide an alternative to conventional synchrotron sources for high resolution imaging of eutectics and, more broadly, complex microstructures.
|
|
| 6. |
- Smid, Marcel, et al.
(author)
-
Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.
|
|
| 7. |
- Smid, Marcel, et al.
(author)
-
The circular RNome of primary breast cancer
- 2019
-
In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 29:3, s. 356-366
-
Journal article (peer-reviewed)abstract
- Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R <0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.
|
|
| 8. |
- Maitrallain, A., et al.
(author)
-
Parametric study of high-energy ring-shaped electron beams from a laser wakefield accelerator
- 2022
-
In: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 24:1
-
Journal article (peer-reviewed)abstract
- Laser wakefield accelerators commonly produce on-axis, low-divergence, high-energy electron beams. However, a high charge, annular shaped beam can be trapped outside the bubble and accelerated to high energies. Here we present a parametric study on the production of low-energy-spread, ultra-relativistic electron ring beams in a two-stage gas cell. Ring-shaped beams with energies higher than 750 MeV are observed simultaneously with on axis, continuously injected electrons. Often multiple ring shaped beams with different energies are produced and parametric studies to control the generation and properties of these structures were conducted. Particle tracking and particle-in-cell simulations are used to determine properties of these beams and investigate how they are formed and trapped outside the bubble by the wake produced by on-axis injected electrons. These unusual femtosecond duration, high-charge, high-energy, ring electron beams may find use in beam driven plasma wakefield accelerators and radiation sources.
|
|
| 9. |
- Spesyvtsev, R., et al.
(author)
-
Generation of electron high energy beams with a ring-like structure by a dual stage laser wakefield accelerator
- 2019
-
In: Relativistic Plasma Waves and Particle Beams as Coherent and Incoherent Radiation Sources III. - : SPIE. - 9781510627383 ; 11036
-
Conference paper (peer-reviewed)abstract
- The laser wake-field accelerator (LWFA) traditionally produces high brightness, quasi-monoenergetic electron beams with Gaussian-like spatial and angular distributions. In the present work we investigate the generation of ultra-relativistic beams with ring-like structures in the blowout regime of the LWFA using a dual stage accelerator. A density down-ramp triggers injection after the first stage and is used to produce ring-like electron spectra in the 300 - 600 MeV energy range. These well defined, annular beams are observed simultaneously with the on-axis, high energy electron beams, with a divergence of a few milliradians. The rings have quasi-monoenergetic energy spectra with an RMS spread estimated to be less than 5%. Particle-in-cell simulations confirm that off-axis injection provides the electrons with the initial transverse momentum necessary to undertake distinct betatron oscillations within the plasma bubble during their acceleration process.
|
|
| 10. |
- Streeter, M. J.V., et al.
(author)
-
Characterization of laser wakefield acceleration efficiency with octave spanning near-IR spectrum measurements
- 2022
-
In: Physical Review Accelerators and Beams. - 2469-9888. ; 25:10
-
Journal article (peer-reviewed)abstract
- We report on experimental measurements of energy transfer efficiencies in a GeV-class laser wakefield accelerator. Both the transfer of energy from the laser to the plasma wakefield and from the plasma to the accelerated electron beam was diagnosed by simultaneous measurement of the deceleration of laser photons and the acceleration of electrons as a function of plasma length. The extraction efficiency, which we define as the ratio of the energy gained by the electron beam to the energy lost by the self-guided laser mode, was maximized at 19±3% by tuning the plasma density and length. The additional information provided by the octave-spanning laser spectrum measurement allows for independent optimization of the plasma efficiency terms, which is required for the key goal of improving the overall efficiency of laser wakefield accelerators.
|
|
| 11. |
- De Ferrari, G. M., et al.
(author)
-
Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure
- 2011
-
In: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 32:7, s. 847-855
-
Journal article (peer-reviewed)abstract
- AIMS: In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular (LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy. METHODS AND RESULTS: This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients [age 56 +/- 11 years, LV ejection fraction (LVEF) 23 +/- 8%]. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 +/- 76 to 471 +/- 111 m), LVEF (from 22 +/- 7 to 29 +/- 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year. CONCLUSIONS: This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.
|
|
| 12. |
- de Witte, H H, et al.
(author)
-
Prognostic significance of TP53 accumulation in human primary breast cancer : comparison between a rapid quantitative immunoassay and SSCP analysis.
- 1996
-
In: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 69:2, s. 125-130
-
Journal article (peer-reviewed)abstract
- TP53 accumulation in human primary breast carcinomas was studied by a quantitative luminometric immunoassay (LIA), and TP53 gene alterations, exons 5-8, were examined by single-strand conformation polymorphism (SSCP) analysis. In 48 of 142 breast tumor samples, a TP53 gene alteration was identified. In tumor samples without a TP53 gene alteration, the median cytosolic TP53 protein level, as determined by LIA, was 0.4 ng/mg protein (range 0-70.8 ng/mg protein), whereas the median TP53 protein level for tumor samples with a TP53 gene alteration was 10 times higher, i.e., 4.1 ng/mg protein (range 0.1-176.0 ng/mg protein). Despite a significant correlation between the outcome of LIA and SSCP, a disagreement was found in 22% of cases analyzed. Significant correlations were found between TP53 protein accumulation and low estrogen receptor content, and with a shorter relapse-free as well as overall survival, with a median duration of follow-up of 100 months. Due to its rapid and easy performance on routinely prepared cytosols, the LIA for TP53 protein may be useful in evaluating the prognostic impact of TP53 protein accumulation in human primary breast cancer.
|
|
| 13. |
- Kettle, B., et al.
(author)
-
Single-Shot Multi-keV X-Ray Absorption Spectroscopy Using an Ultrashort Laser-Wakefield Accelerator Source
- 2019
-
In: Physical Review Letters. - 0031-9007. ; 123:25
-
Journal article (peer-reviewed)abstract
- Single-shot absorption measurements have been performed using the multi-keV x rays generated by a laser-wakefield accelerator. A 200 TW laser was used to drive a laser-wakefield accelerator in a mode which produced broadband electron beams with a maximum energy above 1 GeV and a broad divergence of ≈15 mrad FWHM. Betatron oscillations of these electrons generated 1.2±0.2×106 photons/eV in the 5 keV region, with a signal-to-noise ratio of approximately 300 1. This was sufficient to allow high-resolution x-ray absorption near-edge structure measurements at the K edge of a titanium sample in a single shot. We demonstrate that this source is capable of single-shot, simultaneous measurements of both the electron and ion distributions in matter heated to eV temperatures by comparison with density functional theory simulations. The unique combination of a high-flux, large bandwidth, few femtosecond duration x-ray pulse synchronized to a high-power laser will enable key advances in the study of ultrafast energetic processes such as electron-ion equilibration.
|
|
| 14. |
- Nik-Zainal, Serena, et al.
(author)
-
Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
-
Journal article (peer-reviewed)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
|
|
| 15. |
- van Hoek, A. H. A. M., et al.
(author)
-
A quantitative approach towards a better understanding of the dynamics of Salmonella spp. in a pork slaughter-line
- 2012
-
In: International Journal of Food Microbiology. - : Elsevier BV. - 0168-1605 .- 1879-3460. ; 153:1-2, s. 45-52
-
Journal article (peer-reviewed)abstract
- Pork contributes significantly to the public health disease burden caused by Salmonella infections. During the slaughter process pig carcasses can become contaminated with Salmonella. Contamination at the slaughter-line is initiated by pigs carrying Salmonella on their skin or in their faeces. Another contamination route could be resident flora present on the slaughter equipment. To unravel the contribution of these two potential sources of Salmonella a quantitative study was conducted. Process equipment (belly openers and carcass splitters), faeces and carcasses (skin and cutting surfaces) along the slaughter-line were sampled at 11 sampling days spanning a period of 4. months.Most samples taken directly after killing were positive for Salmonella. On 96.6% of the skin samples Salmonella was identified, whereas a lower number of animals tested positive in their rectum (62.5%). The prevalence of Salmonella clearly declined on the carcasses at the re-work station, either on the cut section or on the skin of the carcass or both (35.9%). Throughout the sampling period of the slaughter-line the total number of Salmonella per animal was almost 2log lower at the re-work station in comparison to directly after slaughter.Seven different serovars were identified during the study with S. Derby (41%) and S. Typhimurium (29%) as the most prominent types. A recurring S. Rissen contamination of one of the carcass splitters indicated the presence of an endemic 'house flora' in the slaughterhouse studied. On many instances several serotypes per individual sample were found.The enumeration of Salmonella and the genotyping data gave unique insight in the dynamics of transmission of this pathogen in a slaughter-line. The data of the presented study support the hypothesis that resident flora on slaughter equipment was a relevant source for contamination of pork. © 2011 Elsevier B.V.
|
|
| 16. |
- de Graan, Anne-Joy M., et al.
(author)
-
A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform
- 2013
-
In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:18, s. 5210-5217
-
Journal article (peer-reviewed)abstract
- Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training-and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance.
|
|
| 17. |
|
|
| 18. |
- Glodzik, Dominik, et al.
(author)
-
A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers
- 2017
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 341-348
-
Journal article (peer-reviewed)abstract
- Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
|
|
| 19. |
- Melin, Tomas, et al.
(author)
-
Investigating active vortex generators as a novel high lift device
- 2006
-
In: ICAS-Secretariat - 25th Congress of the International Council of the Aeronautical Sciences 2006. - : Curran Associates, Inc.. ; , s. 1472-1483
-
Conference paper (peer-reviewed)abstract
- Within the framework of the HELIX programme [1], a study using experimental and numerical tools was employed to simulate the aerodynamic behavior of a transport aircraft wing profile when equipped with deployable Active Vortex Generators (AVGs). The geometry of the investigated concept consists of a single row array of delta wings positioned above the main airfoil, close to the leading edge, see figure 1. The operational hypothesis of this concept is that the vortex pair generated by the shear layer roll-up at the leading edge of the delta wing will translate downwards. Previous wind tunnel results, obtained for a different wing profile, were promising [5], indicating a possible gain in maximum lift coefficient CLmax of about 0.3 with only small increment in drag and beneficiary stall characteristics. The numerical simulations performed were divided into three different cases: cruise, takeoff and landing configurations. The numerical simulation set-up was a 2.5 dimensional workspace, extruding the profile to a width of one vortex generator. An experimental validation was performed at VZLU:s three meter open low speed tunnel facility. The wind tunnel measurements were performed at a Reynold's number of 1.65.106: The results of the investigation showed that the baseline profile, without the AVGs mounted, produced a higher CLmax and a lower drag than the concept investigated. Possibly, the stall behavior of the AVG concept could be said to have better characteristics than the baseline. The conclusion is that the AVG cannot replace the slat on a late generation wing profile.
|
|
| 20. |
|
|
| 21. |
- Brinkman, Arie B., et al.
(author)
-
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
- 2019
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
-
Journal article (peer-reviewed)abstract
- Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
|
|
| 22. |
- Burkhard, Benjamin, et al.
(author)
-
Mapping and assessing ecosystem services in the EU - Lessons learned from the ESMERALDA approach of integration
- 2018
-
In: One Ecosystem. - : Pensoft Publishers. - 2367-8194. ; 3
-
Journal article (peer-reviewed)abstract
- The European Union (EU) Horizon 2020 Coordination and Support Action ESMERALDA aimed at developing guidance and a flexible methodology for Mapping and Assessment of Ecosystems and their Services (MAES) to support the EU member states in the implementation of the EU Biodiversity Strategy’s Target 2 Action 5. ESMERALDA’s key tasks included network creation, stakeholder engagement, enhancing ecosystem services mapping and assessment methods across various spatial scales and value domains, work in case studies and support of EU member states in MAES implementation. Thus ESMERALDA aimed at integrating various project outcomes around four major strands: i) Networking, ii) Policy, iii) Research and iv) Application. The objective was to provide guidance for integrated ecosystem service mapping and assessment that can be used for sustainable decision-making in policy, business, society, practice and science at EU, national and regional levels. This article presents the overall ESMERALDA approach of integrating the above-mentioned project components and outcomes and provides an overview of how the enhanced methods were applied and how they can be used to support MAES implementation in the EU member states. Experiences with implementing such a large pan-European Coordination and Support Action in the context of EU policy are discussed and recommendations for future actions are given.
|
|
| 23. |
- Debono, Bertrand, et al.
(author)
-
Consensus statement for perioperative care in lumbar spinal fusion : Enhanced Recovery After Surgery (ERAS®) Society recommendations
- 2021
-
In: The spine journal. - : Elsevier. - 1529-9430 .- 1878-1632. ; 21:5, s. 729-752
-
Research review (peer-reviewed)abstract
- BACKGROUND: Enhanced Recovery After Surgery (ERAS) evidence-based protocols for perioperative care have led to improvements in outcomes in numerous surgical areas, through multimodal optimization of patient pathway, reduction of complications, improved patient experience and reduction in the length of stay. ERAS represent a relatively new paradigm in spine surgery.PURPOSE: This multidisciplinary consensus review summarizes the literature and proposes recommendations for the perioperative care of patients undergoing lumbar fusion surgery with an ERAS program.STUDY DESIGN: This is a review article.METHODS: Under the impetus of the ERAS (R) society, a multidisciplinary guideline development group was constituted by bringing together international experts involved in the practice of ERAS and spine surgery. This group identified 22 ERAS items for lumbar fusion. A systematic search in the English language was performed in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Systematic reviews, randomized controlled trials, and cohort studies were included, and the evidence was graded according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Consensus recommendation was reached by the group after a critical appraisal of the literature.RESULTS: Two hundred fifty-six articles were included to develop the consensus statements for 22 ERAS items; one ERAS item (prehabilitation) was excluded from the final summary due to very poor quality and conflicting evidence in lumbar spinal fusion. From these remaining 21 ERAS items, 28 recommendations were included. All recommendations on ERAS protocol items are based on the best available evidence. These included nine preoperative, eleven intraoperative, and six postoperative recommendations. They span topics from preoperative patient education and nutritional evaluation, intraoperative anesthetic and surgical techniques, and postoperative multi-modal analgesic strategies. The level of evidence for the use of each recommendation is presented.CONCLUSION: Based on the best evidence available for each ERAS item within the multidisciplinary perioperative care pathways, the ERAS (R) Society presents this comprehensive consensus review for perioperative care in lumbar fusion.
|
|
| 24. |
- Gudmundsson, J, et al.
(author)
-
Approximate distance oracles revisited
- 2002
-
In: Algorithms and Computation, Proceedings / Lecture Notes in Computer Science. - 0302-9743 .- 1611-3349. ; 2518, s. 357-368
-
Conference paper (peer-reviewed)abstract
- Let G be a geometric t-spanner in E-d with n vertices and m edges, where t is a constant. We show that G can be preprocessed in O(m log n) time, such that (1 + epsilon)-approximate shortest-path queries in G can be answered in O(1) time. The data structure uses O(n log n) space.
|
|
| 25. |
- Holgersson, Johan, et al.
(author)
-
Hypothermic versus Normothermic Temperature Control after Cardiac Arrest
- 2022
-
In: NEJM Evidence. - 2766-5526. ; 1:11, s. 1-13
-
Journal article (peer-reviewed)abstract
- BACKGROUNDThe evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics.METHODSAn individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence).RESULTSThe primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups.CONCLUSIONSHypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)
|
|
| 26. |
- Höpe, Andreas, et al.
(author)
-
"Multidimensional reflectometry for industry" (xD-Reflect) an European research project
- 2014
-
In: Proceedings of SPIE - The International Society for Optical Engineering 2014. - : SPIE.
-
Conference paper (peer-reviewed)abstract
- The European Metrology Research Program (EMRP) is a metrology-focused program of coordinated Research and Development (RD) funded by the European Commission and participating countries within the European Association of National Metrology Institutes (EURAMET). It supports and ensures research collaboration between them by launching and managing different types of project calls. Within the EMRP Call 2012 "Metrology for Industry", the joint research project (JRP) entitled "Multidimensional Reflectometry for Industry" (xD-Reflect) was submitted by a consortium of 8 National Metrology Institutes (NMIs) and 2 universities and was subsequently funded. The general objective of xD-Reflect is to meet the demands from industry to describe the overall macroscopic appearance of modern surfaces by developing and improving methods for optical measurements which correlate with the visual sensation being evoked. In particular, the project deals with the "Goniochromatism", "Gloss" and "Fluorescence" properties of dedicated artifacts, which will be investigated in three main work packages (WP). Two additional transversal WP reinforce the structure: "Modelling and Data Analysis" with the objective to give an irreducible set of calibration schemes and handling methods and "Visual Perception", which will produce perception scales for the different visual attributes. Multidimensional reflectometry involves the enhancement of spectral and spatial resolution of reference gonioreflectometers for BRDF measurements using modern detectors, conoscopic optical designs, CCD cameras, line scan cameras, and modern light sources in order to describe new effects like sparkle and graininess/coarseness. More information and updated news concerning the project can be found on the xD-Reflect website http://www.xdreflect.eu/.
|
|
| 27. |
- Levcopoulos, Christos, et al.
(author)
-
Improved algorithms for constructing fault-tolerant spanners
- 2002
-
In: Algorithmica. - 0178-4617. ; 32:1, s. 144-156
-
Journal article (peer-reviewed)abstract
- Let S be a set of n points in a metric space, and let k be a positive integer. Algorithms are given that construct k-fault-tolerant spanners for S. If in such a spanner at most k vertices and/or edges are removed, then each pair of points in the remaining graph is still connected by a "short" path. First, an algorithm is given that transforms an arbitrary spanner into a k-fault-tolerant spanner. For the Euclidean metric in Rd, this leads to an O (n log n + c(k) n)-time algorithm that constructs a k-fault-tolerant spanner of degree O(c(k)), whose total edge length is O(c(k)) times the weight of a minimum spanning tree of S, for some constant c. For constant values of k, this result is optimal, In the second part of the paper, algorithms are presented for the Euclidean metric in Rd. These algorithms construct (i) in O(n log n + k(2)n) time, a k-fault-tolerant spanner with O (k(2)n) edges, and (ii) in O(kn log n) time, such a spanner with O(kn log n) edges.
|
|
| 28. |
|
|
| 29. |
- Meijer, J. E. M., et al.
(author)
-
The resilience of Jewish communities living in the diaspora : a scoping review
- 2023
-
In: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 14
-
Research review (peer-reviewed)abstract
- Introduction: Throughout history, Jewish communities have been exposed to collectively experienced traumatic events. Little is known about the role that the community plays in the impact of these traumatic events on Jewish diaspora people. This scoping review aims to map the concepts of the resilience of Jewish communities in the diaspora and to identify factors that influence this resilience. Methods: We followed the Joanna Briggs Institute (JBI) methodology. Database searches yielded 2,564 articles. Sixteen met all inclusion criteria. The analysis was guided by eight review questions. Results: Community resilience of the Jewish diaspora was often described in terms of coping with disaster and struggling with acculturation. A clear definition of community resilience of the Jewish diaspora was lacking. Social and religious factors, strong organizations, education, and communication increased community resilience. Barriers to the resilience of Jewish communities in the diaspora included the interaction with the hosting country and other communities, characteristics of the community itself, and psychological and cultural issues. Discussion: Key gaps in the literature included the absence of quantitative measures of community resilience and the lack of descriptions of how community resilience affects individuals’ health-related quality of life. Future studies on the interaction between community resilience and health-related individual resilience are warranted.
|
|
| 30. |
|
|
| 31. |
- Šmíd, M., et al.
(author)
-
Highly efficient angularly resolving x-ray spectrometer optimized for absorption measurements with collimated sources
- 2017
-
In: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 88:6
-
Journal article (peer-reviewed)abstract
- Highly collimated betatron radiation from a laser wakefield accelerator is a promising tool for spectroscopic measurements. Therefore, there is a requirement to create spectrometers suited to the unique properties of such a source. We demonstrate a spectrometer which achieves an energy resolution of <5 eV at 9 keV (E/Delta;E>1800) and is angularly resolving the x-ray emission allowing the reference and spectrum to be recorded at the same time. The single photon analysis is used to significantly reduce the background noise. Theoretical performance of various configurations of the spectrometer is calculated by a ray-tracing algorithm. The properties and performance of the spectrometer including the angular and spectral resolution are demonstrated experimentally on absorption above the K-edge of a Cu foil backlit by a laser-produced betatron radiation x-ray beam.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
- Tucker, Catherine M., et al.
(author)
-
Governance of interdependent ecosystem services and common-pool resources
- 2023
-
In: Land use policy. - : Elsevier. - 0264-8377 .- 1873-5754. ; 127
-
Journal article (peer-reviewed)abstract
- Environmental governance is recognized as a key issue in many natural and social sciences. It is highly relevant for ecosystem services and common-pool resources as well. Both fields overlap yet have typically been studied separately. Therefore, this study aimed a) to examine the emerging body of literature that incorporates concepts from both fields of research and considers governance challenges, and b) to identify policy tools and recommendations presented for addressing those challenges. The analysis of thirty-nine selected peer-review papers revealed the multiplicity of interacting governance challenges with three major categories: environmental, socioeconomic, and problems of governance itself. Governance is impeded by institutional mismatches, exclusion of local actors, corruption, and perverse policies. The proposed policy recommendations most often suggest changes in institutional arrangements and increasing scientific understanding. Meeting human needs, and increasing social equity and justice were recognized broadly as integral for improving governance, yet correlations among governance problems and solutions appear elusive. These findings extend theoretical reasoning, while carrying practical implications for policy, governance and environmental stewardship. The analysis implies that policies to improve human conditions will be key for improved environmental governance, but more research is needed to learn which types of policy recommendations prove successful given diverse local contexts.
|
|
