1. |
- Bosch Campos, Ana, et al.
(författare)
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PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:283, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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2. |
- Brown, A. G. A., et al.
(författare)
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Gaia Data Release 1 Summary of the astrometric, photometric, and survey properties
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595
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Tidskriftsartikel (refereegranskat)abstract
- Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues - a realisation of the Tycho-Gaia Astrometric Solution (TGAS) - and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of similar to 3000 Cepheid and RR Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr(-1) for the proper motions. A systematic component of similar to 0.3 mas should be added to the parallax uncertainties. For the subset of similar to 94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr(-1). For the secondary astrometric data set, the typical uncertainty of the positions is similar to 10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to similar to 0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data.
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3. |
- Clementini, G., et al.
(författare)
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Testing parallaxes with local Cepheids and RR Lyrae stars
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 605
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Tidskriftsartikel (refereegranskat)abstract
- Context. Parallaxes for 331 classical Cepheids, 31 Type II Cepheids, and 364 RR Lyrae stars in common between Gaia and the HIPPARCOS and Tycho-2 catalogues are published in Gaia Data Release 1 (DR1) as part of the Tycho-Gaia Astrometric Solution (TGAS). Aims. In order to test these first parallax measurements of the primary standard candles of the cosmological distance ladder, which involve astrometry collected by Gaia during the initial 14 months of science operation, we compared them with literature estimates and derived new period-luminosity (PL), period-Wesenheit (PW) relations for classical and Type II Cepheids and infrared PL, PL-metallicity (PLZ), and optical luminosity-metallicity (MV-[Fe/H]) relations for the RR Lyrae stars, with zero points based on TGAS.Methods. Classical Cepheids were carefully selected in order to discard known or suspected binary systems. The final sample comprises 102 fundamental mode pulsators with periods ranging from 1.68 to 51.66 days (of which 33 with sigma(omega)/omega < 0 : 5). The Type II Cepheids include a total of 26 W Virginis and BL Herculis stars spanning the period range from 1.16 to 30.00 days (of which only 7 with sigma(omega)/omega 0 : 5). The RR Lyrae stars include 200 sources with pulsation period ranging from 0.27 to 0.80 days (of which 112 with sigma(omega)/omega < 0 : 5). The new relations were computed using multi- band (V; I; J; K-s) photometry and spectroscopic metal abundances available in the literature, and by applying three alternative approaches: (i) linear least-squares fitting of the absolute magnitudes inferred from direct transformation of the TGAS parallaxes; (ii) adopting astrometry-based luminosities; and (iii) using a Bayesian fitting approach. The last two methods work in parallax space where parallaxes are used directly, thus maintaining symmetrical errors and allowing negative parallaxes to be used. The TGAS-based PL; PW; PLZ, and MV [Fe/H] relations are discussed by comparing the distance to the Large Magellanic Cloud provided by different types of pulsating stars and alternative fitting methods.Results. Good agreement is found from direct comparison of the parallaxes of RR Lyrae stars for which both TGAS and HST measurements are available. Similarly, very good agreement is found between the TGAS values and the parallaxes inferred from the absolute magnitudes of Cepheids and RR Lyrae stars analysed with the Baade-Wesselink method. TGAS values also compare favourably with the parallaxes inferred by theoretical model fitting of the multi-band light curves for two of the three classical Cepheids and one RR Lyrae star, which were analysed with this technique in our samples. The K-band PL relations show the significant improvement of the TGAS parallaxes for Cepheids and RR Lyrae stars with respect to the HIPPARCOS measurements. This is particularly true for the RR Lyrae stars for which improvement in quality and statistics is impressive.Conclusions. TGAS parallaxes bring a significant added value to the previous HIPPARCOS estimates. The relations presented in this paper represent the first Gaia-calibrated relations and form a work-in-progress milestone report in the wait for Gaia-only parallaxes of which a first solution will become available with Gaia Data Release 2 (DR2) in 2018.
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4. |
- Khaliq, Muhammad Waqas, et al.
(författare)
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GHz sample excitation at the ALBA-PEEM
- 2023
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Ingår i: Ultramicroscopy. - 0304-3991. ; 250
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Tidskriftsartikel (refereegranskat)abstract
- We describe a setup that is used for high-frequency electrical sample excitation in a cathode lens electron microscope with the sample stage at high voltage as used in many synchrotron light sources. Electrical signals are transmitted by dedicated high-frequency components to the printed circuit board supporting the sample. Sub-miniature push-on connectors (SMP) are used to realize the connection in the ultra-high vacuum chamber, bypassing the standard feedthrough. A bandwidth up to 4 GHz with -6 dB attenuation was measured at the sample position, which allows to apply sub-nanosecond pulses. We describe different electronic sample excitation schemes and demonstrate a spatial resolution of 56 nm employing the new setup.
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5. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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6. |
- Prusti, T., et al.
(författare)
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The Gaia mission
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595
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Tidskriftsartikel (refereegranskat)abstract
- Gaia is a cornerstone mission in the science programme of the European Space Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page.
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7. |
- van Leeuwen, F., et al.
(författare)
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Gaia Data Release 1 : Open cluster astrometry: Performance, limitations, and future prospects
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 601
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Tidskriftsartikel (refereegranskat)abstract
- Context. The first Gaia Data Release contains the Tycho-Gaia Astrometric Solution (TGAS). This is a subset of about 2 million stars for which, besides the position and photometry, the proper motion and parallax are calculated using Hipparcos and Tycho-2 positions in 1991.25 as prior information. Aims. We investigate the scientific potential and limitations of the TGAS component by means of the astrometric data for open clusters. Methods. Mean cluster parallax and proper motion values are derived taking into account the error correlations within the astrometric solutions for individual stars, an estimate of the internal velocity dispersion in the cluster, and, where relevant, the effects of the depth of the cluster along the line of sight. Internal consistency of the TGAS data is assessed. Results. Values given for standard uncertainties are still inaccurate and may lead to unrealistic unit-weight standard deviations of least squares solutions for cluster parameters. Reconstructed mean cluster parallax and proper motion values are generally in very good agreement with earlier Hipparcos-based determination, although the Gaia mean parallax for the Pleiades is a significant exception. We have no current explanation for that discrepancy. Most clusters are observed to extend to nearly 15 pc from the cluster centre, and it will be up to future Gaia releases to establish whether those potential cluster-member stars are still dynamically bound to the clusters. Conclusions. The Gaia DR1 provides the means to examine open clusters far beyond their more easily visible cores, and can provide membership assessments based on proper motions and parallaxes. A combined HR diagram shows the same features as observed before using the Hipparcos data, with clearly increased luminosities for older A and F dwarfs.
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