| 1. |
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| 2. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 3. |
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| 4. |
- Orsini, S., et al.
(författare)
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Inner southern magnetosphere observation of Mercury via SERENA ion sensors in BepiColombo mission
- 2022
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mercury’s southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury’s magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.
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| 5. |
- Kangas, T., et al.
(författare)
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Supernova 2013fc in a circumnuclear ring of a luminous infrared galaxy : the big brother of SN 1998S
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 456:1, s. 323-346
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Tidskriftsartikel (refereegranskat)abstract
- We present photometric and spectroscopic observations of SN 2013fc, a bright type II supernova (SN) in a circumnuclear star-forming ring in the luminous infrared galaxy ESO 154-G010, observed as part of the Public ESO Spectroscopic Survey of Transient Objects. SN 2013fc is both photometrically and spectroscopically similar to the well-studied type IIn SN 1998S and to the bright type II-L SN 1979C. It exhibits an initial linear decline, followed by a short plateau phase and a tail phase with a decline too fast for Co-56 decay with full. gamma-ray trapping. Initially, the spectrum was blue and featureless. Later on, a strong broad (similar to 8000 km s(-1)) H alpha emission profile became prominent. We apply a STARLIGHT stellar population model fit to the SN location (observed when the SN had faded) to estimate a high extinction of A(V) = 2.9 +/- 0.2 mag and an age of 10(+ 3) (- 2) Myr for the underlying cluster. We compare the SN to SNe 1998S and 1979C and discuss its possible progenitor star considering the similarities to these events. With a peak brightness of B = - 20.46 +/- 0.21 mag, SN 2013fc is 0.9 mag brighter than SN 1998S and of comparable brightness to SN 1979C. We suggest that SN 2013fc was consistent with a massive red supergiant (RSG) progenitor. Recent mass loss probably due to a strong RSG wind created the circumstellar matter illuminated through its interaction with the SN ejecta. We also observe a near- infrared excess, possibly due to newly condensed dust.
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| 6. |
- Margutti, R., et al.
(författare)
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A PANCHROMATIC VIEW OF THE RESTLESS SN 2009ip REVEALS THE EXPLOSIVE EJECTION OF A MASSIVE STAR ENVELOPE
- 2014
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 780:1
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Tidskriftsartikel (refereegranskat)abstract
- The double explosion of SN 2009ip in 2012 raises questions about our understanding of the late stages of massive star evolution. Here we present a comprehensive study of SN 2009ip during its remarkable rebrightenings. High-cadence photometric and spectroscopic observations from the GeV to the radio band obtained from a variety of ground-based and space facilities (including the Very Large Array, Swift, Fermi, Hubble Space Telescope, and XMM) constrain SN 2009ip to be a low energy (E similar to 1050 erg for an ejecta mass similar to 0.5 M-circle dot) and asymmetric explosion in a complex medium shaped by multiple eruptions of the restless progenitor star. Most of the energy is radiated as a result of the shock breaking out through a dense shell of material located at similar to 5 x 10(14) cm with M similar to 0.1 M-circle dot, ejected by the precursor outburst similar to 40 days before the major explosion. We interpret the NIR excess of emission as signature of material located further out, the origin of which has to be connected with documented mass-loss episodes in the previous years. Our modeling predicts bright neutrino emission associated with the shock break-out if the cosmic-ray energy is comparable to the radiated energy. We connect this phenomenology with the explosive ejection of the outer layers of the massive progenitor star, which later interacted with material deposited in the surroundings by previous eruptions. Future observations will reveal if the massive luminous progenitor star survived. Irrespective of whether the explosion was terminal, SN 2009ip brought to light the existence of new channels for sustained episodic mass loss, the physical origin of which has yet to be identified.
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| 7. |
- Appleton, O, et al.
(författare)
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The next-generation ARC middleware
- 2010
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Ingår i: ANNALS OF TELECOMMUNICATIONS-ANNALES DES TELECOMMUNICATIONS. - : Presses Polytechniques Romandes. - 0003-4347 .- 1958-9395. ; 65:11-12, s. 771-776
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced Resource Connector (ARC) is a light-weight, non-intrusive, simple yet powerful Grid middleware capable of connecting highly heterogeneous computing and storage resources. ARC aims at providing general purpose, flexible, collaborative computing environments suitable for a range of uses, both in science and business. The server side offers the fundamental job execution management, information and data capabilities required for a Grid. Users are provided with an easy to install and use client which provides a basic toolbox for job- and data management. The KnowARC project developed the next-generation ARC middleware, implemented as Web Services with the aim of standard-compliant interoperability.
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| 8. |
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| 9. |
- Farzan, N, et al.
(författare)
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Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium
- 2017
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 18:10, s. 931-943
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Tidskriftsartikel (refereegranskat)abstract
- Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.
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| 10. |
- Fox, Ori D., et al.
(författare)
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The slow demise of the long-lived SN 2005ip
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 498:1, s. 517-531
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Tidskriftsartikel (refereegranskat)abstract
- The Type IIn supernova (SN IIn) 2005ip is one of the most well-studied and long-lasting examples of an SN interacting with its circumstellar environment. The optical light curve plateaued at a nearly constant level for more than five years, suggesting ongoing shock interaction with an extended and clumpy circumstellar medium (CSM). Here, we present continued observations of the SN from ∼1000 to 5000 d post-explosion at all wavelengths, including X-ray, ultraviolet, near-infrared (NIR), and mid-infrared. The UV spectra probe the pre-explosion mass loss and show evidence for CNO processing. From the bolometric light curve, we find that the total radiated energy is in excess of 1050 erg, the progenitor star’s pre-explosion mass-loss rate was ≳1×10−2M⊙ yr−1, and the total mass lost shortly before explosion was ≳1M⊙, though the mass lost could have been considerably larger depending on the efficiency for the conversion of kinetic energy to radiation. The ultraviolet through NIR spectrum is characterized by two high-density components, one with narrow high-ionization lines, and one with broader low-ionization H i, He i, [O i], Mg ii, and Fe ii lines. The rich Fe ii spectrum is strongly affected by Lyα fluorescence, consistent with spectral modelling. Both the Balmer and He i lines indicate a decreasing CSM density during the late interaction period. We find similarities to SN 1988Z, which shows a comparable change in spectrum at around the same time during its very slow decline. These results suggest that, at long last, the shock interaction in SN 2005ip may finally be on the decline.
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| 11. |
- Haak-Frendscho, M, et al.
(författare)
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Histidine decarboxylase expression in human melanoma.
- 2000
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 115:3, s. 345-52
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Tidskriftsartikel (refereegranskat)abstract
- Histamine has been implicated as one of the mediators involved in regulation of proliferation in both normal and neoplastic tissues. Histidine decarboxylase, the only enzyme that catalyzes the formation of histamine from L-histidine, is an essential regulator of histamine levels. In this study, we investigated the gene and protein expression of histidine decarboxylase in melanoma. Reverse transcriptase polymerase chain reaction and in situ hybridization studies of WM-35, WM-983/B, HT-168, and M1 human melanoma cell lines both resulted in positive signals for histidine decarboxylase messenger RNA. A polyclonal chicken antibody was developed against human histidine decarboxylase and protein expression was confirmed by western blot analysis of the cell lysates, revealing a predominant immunoreactive band at approximately 54 kDa corresponding to monomeric histidine decarboxylase. Protein expression of histidine decarboxylase was also shown by flow cytometric analysis and strong punctate cytoplasmic staining of melanoma cell lines. Moreover, both primary and metastatic human melanoma tissues were brightly stained for histidine decarboxylase. When compared with the very weak or no reactions on cultivated human melanocytes both western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells. These findings suggest that expression of histidine decarboxylase is elevated in human melanoma.
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| 12. |
- Shahbandeh, Melissa, et al.
(författare)
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JWST observations of dust reservoirs in type IIP supernovae 2004et and 2017eaw
- 2023
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Ingår i: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 523:4, s. 6048-6060
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Tidskriftsartikel (refereegranskat)abstract
- Supernova (SN) explosions have been sought for decades as a possible source of dust in the Universe, providing the seeds of galaxies, stars, and planetary systems. SN 1987A offers one of the most promising examples of significant SN dust formation, but until the James Webb Space Telescope (JWST), instruments have traditionally lacked the sensitivity at both late times (>1 yr post-explosion) and longer wavelengths (i.e. >10 μm) to detect analogous dust reservoirs. Here we present JWST/MIRI observations of two historic Type IIP SNe, 2004et and SN 2017eaw, at nearly 18 and 5 yr post-explosion, respectively. We fit the spectral energy distributions as functions of dust mass and temperature, from which we are able to constrain the dust geometry, origin, and heating mechanism. We place a 90 per cent confidence lower limit on the dust masses for SNe 2004et and 2017eaw of >0.014 and >4 × 10−4 M⊙, respectively. More dust may exist at even colder temperatures or may be obscured by high optical depths. We conclude dust formation in the ejecta to be the most plausible and consistent scenario. The observed dust is radiatively heated to ∼100–150 K by ongoing shock interaction with the circumstellar medium. Regardless of the best fit or heating mechanism adopted, the inferred dust mass for SN 2004et is the second highest (next to SN 1987A) mid-infrared inferred dust mass in extragalactic SNe thus far, promoting the prospect of SNe as potential significant sources of dust in the Universe.
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| 13. |
- Szalai, Alan M., et al.
(författare)
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A fluorescence nanoscopy marker for corticotropin-releasing hormone type 1 receptor : computer design, synthesis, signaling effects, super-resolved fluorescence imaging, and in situ affinity constant in cells
- 2018
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 10:46, s. 29212-29220
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Tidskriftsartikel (refereegranskat)abstract
- Class B G protein-coupled receptors (GPCRs) are involved in a variety of human pathophysiological states. These groups of membrane receptors are less studied than class A GPCRs due to the lack of structural information, delayed small molecule drug discovery, and scarce fluorescence detection tools available. The class B corticotropin-releasing hormone type 1 receptor (CRHR1) is a key player in the stress response whose dysregulation is critically involved in stress-related disorders: psychiatric conditions (i.e. depression, anxiety, and addictions), neuroendocrinological alterations, and neurodegenerative diseases. Here, we present a strategy to label GPCRs with a small fluorescent antagonist that permits the observation of the receptor in live cells through stochastic optical reconstruction microscopy (STORM) with 23 nm resolution. The marker, an aza-BODIPY derivative, was designed based on computational docking studies, then synthesized, and finally tested in biological cells. Experiments on hippocampal neurons demonstrate antagonist effects in similar concentrations as the well-established antagonist CP-376395. A quantitative analysis of two color STORM images enabled the determination of the binding affinity of the new marker in the cellular environment.
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| 14. |
- Szalai, Tamás, et al.
(författare)
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Spitzer's Last Look at Extragalactic Explosions : Long-term Evolution of Interacting Supernovae
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 919:1
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Tidskriftsartikel (refereegranskat)abstract
- Here we present new, yet final, mid-infrared (mid-IR) data for supernovae (SNe) based on measurements with the Spitzer Space Telescope. Comparing our recent 3.6 and 4.5 mu m photometry with previously published mid-IR and further multiwavelength data sets, we were able to draw some conclusions about the origin and heating mechanism of the dust in these SNe or in their environments, as well as about possible connection with circumstellar matter (CSM) originating from pre-explosion mass-loss events in the progenitor stars. We also present new results regarding both certain SN classes and single objects. We highlight the mid-IR homogeneity of SNe Ia-CSM, which may be a hint of their common progenitor type and of their basically uniform circumstellar environments. Regarding single objects, it is worth highlighting the late-time interacting Type Ib SNe 2003gk and 2004dk, for which we present the first-ever mid-IR data, which seem to be consistent with clues of ongoing CSM interaction detected in other wavelength ranges. Our current study suggests that long-term mid-IR follow-up observations play a key role in a better understanding of both pre- and post-explosion processes in SNe and their environments. While Spitzer is not available anymore, the expected unique data from the James Webb Space Telescope, as well as long-term near-IR follow-up observations of dusty SNe, can bring us closer to the hidden details of this topic.
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| 15. |
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| 16. |
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| 17. |
- Uner, OE, et al.
(författare)
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Estimation of the timing of BAP1 mutation in uveal melanoma progression
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 8923-
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Tidskriftsartikel (refereegranskat)abstract
- Uveal melanoma is the most common primary intraocular malignancy. A vast majority of metastasizing tumors have mutations in the BAP1 gene. Here, we investigate the spatiotemporal timing of these mutations. The size of 177 uveal melanomas and 8.3 million individual tumor cells was measured. BAP1 sequencing results and BAP1 IHC were available and for 76 (43%) and 101 (57%) of these, respectively. Tumors with a BAP1 mutation had significantly larger volume (2109 vs. 1552 mm3, p = 0.025). Similarly, tumor cells with loss of BAP1 protein expression had significantly larger volume (2657 vs. 1593 μm3, p = 0.027). Using observations of the time elapsed between mitoses, the BAP1 mutation was calculated to occur when the primary tumor had a size of a few malignant cells to 6 mm3, 0.5 to 4.6 years after tumor initiation and at least 9 years before diagnosis. We conclude that BAP1 mutations occur early in the growth of uveal melanoma, well before the average tumor is diagnosed. Its timing coincides with the seeding of micrometastases.
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| 18. |
- Zsíros, Szanna, et al.
(författare)
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Serendipitous detection of the dusty Type IIL SN 1980K with JWST/MIRI
- 2024
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Ingår i: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 529:1, s. 155-168
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Tidskriftsartikel (refereegranskat)abstract
- We present mid-infrared (mid-IR) imaging of the Type IIL supernova (SN) 1980K with the JWST more than 40 yr post-explosion. SN 1980K, located in the nearby (D ≈ 7 Mpc) ‘SN factory’ galaxy NGC 6946, was serendipitously captured in JWST/MIRI images taken of the field of SN 2004et in the same galaxy. SN 1980K serves as a promising candidate for studying the transitional phase between young SNe and older SN remnants and also provides a great opportunity to investigate its the close environment. SN 1980K can be identified as a clear and bright point source in all eight MIRI filters from F560W up to F2550W. We fit analytical dust models to the mid-IR spectral energy distribution that reveal a large amount (Md ≈ 0.002 M⊙) of Si-dominated dust at Tdust≈150 K (accompanied by a hotter dust/gas component), and also computed numerical SED dust models. Radiative transfer modelling of a late-time optical spectrum obtained recently with Keck discloses that an even larger (∼0.24–0.58 M⊙) amount of dust is needed in order for selective extinction to explain the asymmetric line profile shapes observed in SN 1980K. As a conclusion, with JWST, we may see i) pre-existing circumstellar dust heated collisionally (or, partly radiatively), analogous to the equatorial ring of SN 1987A, or ii) the mid-IR component of the presumed newly-formed dust, accompanied by much more colder dust present in the ejecta (as suggested by the late-time the optical spectra).
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