1. |
- Waszak, S. M., et al.
(författare)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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2. |
- Stewart, A. J., et al.
(författare)
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LOFAR MSSS : detection of a low-frequency radio transient in 400 h of monitoring of the North Celestial Pole
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 456:3, s. 2321-2342
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Tidskriftsartikel (refereegranskat)abstract
- We present the results of a four-month campaign searching for low-frequency radio transients near the North Celestial Pole with the Low-Frequency Array (LOFAR), as part of the Multifrequency Snapshot Sky Survey (MSSS). The data were recorded between 2011 December and 2012 April and comprised 2149 11-min snapshots, each covering 175 deg2. We have found one convincing candidate astrophysical transient, with a duration of a few minutes and a flux density at 60 MHz of 15–25 Jy. The transient does not repeat and has no obvious optical or high-energy counterpart, as a result of which its nature is unclear. The detection of this event implies a transient rate at 60 MHz of 3.9−3.7+14.7×10−4" style="position: relative;" tabindex="0" id="MathJax-Element-1-Frame" class="MathJax">3.9+14.7−3.7×10−4 d−1 deg−2, and a transient surface density of 1.5 × 10−5 deg−2, at a 7.9-Jy limiting flux density and ∼10-min time-scale. The campaign data were also searched for transients at a range of other time-scales, from 0.5 to 297 min, which allowed us to place a range of limits on transient rates at 60 MHz as a function of observation duration.
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4. |
- Buitink, S., et al.
(författare)
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A large light-mass component of cosmic rays at 1017–1017.5 electronvolts from radio observations
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 531:7592, s. 70-73
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Tidskriftsartikel (refereegranskat)abstract
- Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 1017–1018 electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal1 comes from accelerators capable of producing cosmic rays of these energies2. Cosmic rays initiate air showers—cascades of secondary particles in the atmosphere—and their masses can be inferred from measurements of the atmospheric depth of the shower maximum3 (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground4. Current measurements5 have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays6, 7, 8 is a rapidly developing technique9 for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front6, 12. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 1017–1017.5 electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 1017.5 electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 1017–1017.5 electronvolt range.
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5. |
- Heald, G. H., et al.
(författare)
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The LOFAR Multifrequency Snapshot Sky Survey (MSSS) : I. Survey description and first results
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 582, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- We present the Multifrequency Snapshot Sky Survey (MSSS), the first northern-sky Low Frequency Array (LOFAR) imaging survey. In this introductory paper, we first describe in detail the motivation and design of the survey. Compared to previous radio surveys, MSSS is exceptional due to its intrinsic multifrequency nature providing information about the spectral properties of the detected sources over more than two octaves (from 30 to 160 MHz). The broadband frequency coverage, together with the fast survey speed generated by LOFAR’s multibeaming capabilities, make MSSS the first survey of the sort anticipated to be carried out with the forthcoming Square Kilometre Array (SKA). Two of the sixteen frequency bands included in the survey were chosen to exactly overlap the frequency coverage of large-area Very Large Array (VLA) and Giant Metrewave Radio Telescope (GMRT) surveys at 74 MHz and 151 MHz respectively. The survey performance is illustrated within the MSSS Verification Field (MVF), a region of 100 square degrees centered at (α,δ)J2000 = (15h,69°). The MSSS results from the MVF are compared with previous radio survey catalogs. We assess the flux and astrometric uncertainties in the catalog, as well as the completeness and reliability considering our source finding strategy. We determine the 90% completeness levels within the MVF to be 100 mJy at 135 MHz with 108″ resolution, and 550 mJy at 50 MHz with 166″ resolution. Images and catalogs for the full survey, expected to contain 150 000–200 000 sources, will be released to a public web server. We outline the plans for the ongoing production of the final survey products, and the ultimate public release of images and source catalogs.
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6. |
- Sobey, C., et al.
(författare)
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LOFAR discovery of a quiet emission mode in PSR B0823+26
- 2015
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 451, s. 2493-2506
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Tidskriftsartikel (refereegranskat)abstract
- PSR B0823+26, a 0.53-s radio pulsar, displays a host of emission phenomena over time-scales of seconds to (at least) hours, including nulling, subpulse drifting, and mode-changing. Studying pulsars like PSR B0823+26 provides further insight into the relationship between these various emission phenomena and what they might teach us about pulsar magnetospheres. Here we report on the LOFAR (Low-Frequency Array) discovery that PSR B0823+26 has a weak and sporadically emitting ‘quiet’ (Q) emission mode that is over 100 times weaker (on average) and has a nulling fraction forty-times greater than that of the more regularly-emitting ‘bright’ (B) mode. Previously, the pulsar has been undetected in the Q mode, and was assumed to be nulling continuously. PSR B0823+26 shows a further decrease in average flux just before the transition into the B mode, and perhaps truly turns off completely at these times. Furthermore, simultaneous observations taken with the LOFAR, Westerbork, Lovell, and Effelsberg telescopes between 110 MHz and 2.7 GHz demonstrate that the transition between the Q mode and B mode occurs within one single rotation of the neutron star, and that it is concurrent across the range of frequencies observed.
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7. |
- Moldón, J., et al.
(författare)
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The LOFAR long baseline snapshot calibrator survey
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 574
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Tidskriftsartikel (refereegranskat)abstract
- Aims. An efficient means of locating calibrator sources for international LOw Frequency ARray (LOFAR) is developed and used to determine the average density of usable calibrator sources on the sky for subarcsecond observations at 140 MHz.Methods. We used the multi-beaming capability of LOFAR to conduct a fast and computationally inexpensive survey with the full international LOFAR array. Sources were preselected on the basis of 325 MHz arcminute-scale flux density using existing catalogues. By observing 30 different sources in each of the 12 sets of pointings per hour, we were able to inspect 630 sources in two hours to determine if they possess a sufficiently bright compact component to be usable as LOFAR delay calibrators.Results. More than 40% of the observed sources are detected on multiple baselines between international stations and 86 are classified as satisfactory calibrators. We show that a flat low-frequency spectrum (from 74 to 325 MHz) is the best predictor of compactness at 140 MHz. We extrapolate from our sample to show that the sky density of calibrators that are sufficiently bright to calibrate dispersive and non-dispersive delays for the international LOFAR using existing methods is 1.0 per square degree.Conclusions. The observed density of satisfactory delay calibrator sources means that observations with international LOFAR should be possible at virtually any point in the sky provided that a fast and efficient search, using the methodology described here, is conducted prior to the observation to identify the best calibrator.
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8. |
- Morris, John A, et al.
(författare)
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An atlas of genetic influences on osteoporosis in humans and mice.
- 2019
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51, s. 258-266
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR)=58, P=1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P<0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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9. |
- Pilia, M., et al.
(författare)
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Wide-band, low-frequency pulse profiles of 100 radio pulsars with LOFAR
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 586
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Tidskriftsartikel (refereegranskat)abstract
- Context. LOFAR offers the unique capability of observing pulsars across the 10−240 MHz frequency range with a fractional bandwidth of roughly 50%. This spectral range is well suited for studying the frequency evolution of pulse profile morphology caused by both intrinsic and extrinsic effects such as changing emission altitude in the pulsar magnetosphere or scatter broadening by the interstellar medium, respectively.Aims. The magnitude of most of these effects increases rapidly towards low frequencies. LOFAR can thus address a number of open questions about the nature of radio pulsar emission and its propagation through the interstellar medium.Methods. We present the average pulse profiles of 100 pulsars observed in the two LOFAR frequency bands: high band (120–167 MHz, 100 profiles) and low band (15–62 MHz, 26 profiles). We compare them with Westerbork Synthesis Radio Telescope (WSRT) and Lovell Telescope observations at higher frequencies (350 and 1400 MHz) to study the profile evolution. The profiles were aligned in absolute phase by folding with a new set of timing solutions from the Lovell Telescope, which we present along with precise dispersion measures obtained with LOFAR.Results. We find that the profile evolution with decreasing radio frequency does not follow a specific trend; depending on the geometry of the pulsar, new components can enter into or be hidden from view. Nonetheless, in general our observations confirm the widening of pulsar profiles at low frequencies, as expected from radius-to-frequency mapping or birefringence theories.
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10. |
- Garsden, H., et al.
(författare)
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LOFAR sparse image reconstruction
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 575:A90
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Tidskriftsartikel (refereegranskat)abstract
- Context. The LOw Frequency ARray (LOFAR) radio telescope is a giant digital phased array interferometer with multiple antennas distributed in Europe. It provides discrete sets of Fourier components of the sky brightness. Recovering the original brightness distribution with aperture synthesis forms an inverse problem that can be solved by various deconvolution and minimization methods.Aims. Recent papers have established a clear link between the discrete nature of radio interferometry measurement and the “compressed sensing” (CS) theory, which supports sparse reconstruction methods to form an image from the measured visibilities. Empowered by proximal theory, CS offers a sound framework for efficient global minimization and sparse data representation using fast algorithms. Combined with instrumental direction-dependent effects (DDE) in the scope of a real instrument, we developed and validated a new method based on this framework.Methods. We implemented a sparse reconstruction method in the standard LOFAR imaging tool and compared the photometric and resolution performance of this new imager with that of CLEAN-based methods (CLEAN and MS-CLEAN) with simulated and real LOFAR data.Results. We show that i) sparse reconstruction performs as well as CLEAN in recovering the flux of point sources; ii) performs much better on extended objects (the root mean square error is reduced by a factor of up to 10); and iii) provides a solution with an effective angular resolution 2−3 times better than the CLEAN images.Conclusions. Sparse recovery gives a correct photometry on high dynamic and wide-field images and improved realistic structures of extended sources (of simulated and real LOFAR datasets). This sparse reconstruction method is compatible with modern interferometric imagers that handle DDE corrections (A- and W-projections) required for current and future instruments such as LOFAR and SKA.
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11. |
- Hoffman, Lindsey M., et al.
(författare)
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Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG) : A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries
- 2018
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Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 36:19, s. 1963-1972
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Tidskriftsartikel (refereegranskat)abstract
- PurposeDiffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs).Materials and MethodsData abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia.ResultsAmong 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration (P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002).ConclusionWe report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
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12. |
- Nelles, A., et al.
(författare)
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Measuring a Cherenkov ring in the radio emission from air showers at 110-190 MHz with LOFAR
- 2015
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 65, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- Measuring radio emission from air showers offers a novel way to determine properties of the primary cosmic rays such as their mass and energy. Theory predicts that relativistic time compression effects lead to a ring of amplified emission which starts to dominate the emission pattern for frequencies above ∼100∼100 MHz. In this article we present the first detailed measurements of this structure. Ring structures in the radio emission of air showers are measured with the LOFAR radio telescope in the frequency range of 110–190 MHz. These data are well described by CoREAS simulations. They clearly confirm the importance of including the index of refraction of air as a function of height. Furthermore, the presence of the Cherenkov ring offers the possibility for a geometrical measurement of the depth of shower maximum, which in turn depends on the mass of the primary particle.
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13. |
- Vedantham, H. K., et al.
(författare)
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Lunar occultation of the diffuse radio sky : LOFAR measurements between 35 and 80 MHz
- 2015
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 450, s. 2291-2305
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Tidskriftsartikel (refereegranskat)abstract
- We present radio observations of the Moon between 35 and 80 MHz to demonstrate a novel technique of interferometrically measuring large-scale diffuse emission extending far beyond the primary beam (global signal) for the first time. In particular, we show that (i) the Moon appears as a negative-flux source at frequencies 35 < ν < 80 MHz since it is ‘colder’ than the diffuse Galactic background it occults, (ii) using the (negative) flux of the lunar disc, we can reconstruct the spectrum of the diffuse Galactic emission with the lunar thermal emission as a reference, and (iii) that reflected RFI (radio-frequency interference) is concentrated at the centre of the lunar disc due to specular nature of reflection, and can be independently measured. Our RFI measurements show that (i) Moon-based Cosmic Dawn experiments must design for an Earth-isolation of better than 80 dB to achieve an RFI temperature <1 mK, (ii) Moon-reflected RFI contributes to a dipole temperature less than 20 mK for Earth-based Cosmic Dawn experiments, (iii) man-made satellite-reflected RFI temperature exceeds 20 mK if the aggregate scattering cross-section of visible satellites exceeds 175 m2 at 800 km height, or 15 m2 at 400 km height. Currently, our diffuse background spectrum is limited by sidelobe confusion on short baselines (10–15 per cent level). Further refinement of our technique may yield constraints on the redshifted global 21 cm signal from Cosmic Dawn (40 > z > 12) and the Epoch of Reionization (12 > z > 5).
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