| 1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
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| 8. |
- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)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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| 9. |
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| 10. |
- Abe, O, et al.
(author)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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In: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Journal article (peer-reviewed)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 11. |
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| 12. |
- Harrison, J.R., et al.
(author)
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Overview of new MAST physics in anticipation of first results from MAST Upgrade
- 2019
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In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 59:11
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Research review (peer-reviewed)abstract
- The mega amp spherical tokamak (MAST) was a low aspect ratio device (R/a = 0.85/0.65 ∼ 1.3) with similar poloidal cross-section to other medium-size tokamaks. The physics programme concentrates on addressing key physics issues for the operation of ITER, design of DEMO and future spherical tokamaks by utilising high resolution diagnostic measurements closely coupled with theory and modelling to significantly advance our understanding. An empirical scaling of the energy confinement time that favours higher power, lower collisionality devices is consistent with gyrokinetic modelling of electron scale turbulence. Measurements of ion scale turbulence with beam emission spectroscopy and gyrokinetic modelling in up-down symmetric plasmas find that the symmetry of the turbulence is broken by flow shear. Near the non-linear stability threshold, flow shear tilts the density fluctuation correlation function and skews the fluctuation amplitude distribution. Results from fast particle physics studies include the observation that sawteeth are found to redistribute passing and trapped fast particles injected from neutral beam injectors in equal measure, suggesting that resonances between the m = 1 perturbation and the fast ion orbits may be playing a dominant role in the fast ion transport. Measured D-D fusion products from a neutron camera and a charged fusion product detector are 40% lower than predictions from TRANSP/NUBEAM, highlighting possible deficiencies in the guiding centre approximation. Modelling of fast ion losses in the presence of resonant magnetic perturbations (RMPs) can reproduce trends observed in experiments when the plasma response and charge-exchange losses are accounted for. Measurements with a neutral particle analyser during merging-compression start-up indicate the acceleration of ions and electrons. Transport at the plasma edge has been improved through reciprocating probe measurements that have characterised a geodesic acoustic mode at the edge of an ohmic L-mode plasma and particle-in-cell modelling has improved the interpretation of plasma potential estimates from ball-pen probes. The application of RMPs leads to a reduction in particle confinement in L-mode and H-mode and an increase in the core ionization source. The ejection of secondary filaments following type-I ELMs correlates with interactions with surfaces near the X-point. Simulations of the interaction between pairs of filaments in the scrape-off layer suggest this results in modest changes to their velocity, and in most cases can be treated as moving independently. A stochastic model of scrape-off layer profile formation based on the superposition of non-interacting filaments is in good agreement with measured time-average profiles. Transport in the divertor has been improved through fast camera imaging, indicating the presence of a quiescent region devoid of filament near the X-point, extending from the separatrix to ψ n ∼ 1.02. Simulations of turbulent transport in the divertor show that the angle between the divertor leg on the curvature vector strongly influences transport into the private flux region via the interchange mechanism. Coherence imaging measurements show counter-streaming flows of impurities due to gas puffing increasing the pressure on field lines where the gas is ionised. MAST Upgrade is based on the original MAST device, with substantially improved capabilities to operate with a Super-X divertor to test extended divertor leg concepts. SOLPS-ITER modelling predicts the detachment threshold will be reduced by more than a factor of 2, in terms of upstream density, in the Super-X compared with a conventional configuration and that the radiation front movement is passively stabilised before it reaches the X-point. 1D fluid modelling reveals the key role of momentum and power loss mechanisms in governing detachment onset and evolution. Analytic modelling indicates that long legs placed at large major radius, or equivalently low at the target compared with the X-point are more amenable to external control. With MAST Upgrade experiments expected in 2019, a thorough characterisation of the sources of the intrinsic error field has been carried out and a mitigation strategy developed.
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| 15. |
- Barragan, O., et al.
(author)
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The young HD 73583 (TOI-560) planetary system: two 10-M-circle plus mini-Neptunes transiting a 500-Myr-old, bright, and active K dwarf
- 2022
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 514:2, s. 1606-1627
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Journal article (peer-reviewed)abstract
- We present the discovery and characterization of two transiting planets observed by TESS in the light curves of the young and bright (V = 9.67) star HD73583 (TOI-560). We perform an intensive spectroscopic and photometric space- and ground-based follow-up in order to confirm and characterize the system. We found that HD73583 is a young (similar to 500 Myr) active star with a rotational period of 12.08 +/- 0.11 d, and a mass and radius of 0.73 +/- 0.02 M-circle dot and 0.65 +/- 0.02 R-circle dot, respectively. HD 73583 b (P-b = 6.3980420(-0.0000062)(+0.0000067 )d) has a mass and radius of 10.2(-3.1)(+3.4) M-circle plus and 2.79 +/- 0.10 R-circle plus, respectively, which gives a density of 2.58(-0.81)(+0.95) g cm(-3). HD 73583 c (P-c = 18.87974(-0.00074)(+0.00086) d) has a mass and radius of 9.7(-1.7)(+1.8) M-circle plus and 2.39(-0.09)(+0.10) R-circle plus, respectively, which translates to a density of 3.88(-0.80)(+0.91) g cm(-3). Both planets are consistent with worlds made of a solid core surrounded by a volatile envelope. Because of their youth and host star brightness, they both are excellent candidates to perform transmission spectroscopy studies. We expect ongoing atmospheric mass-loss for both planets caused by stellar irradiation. We estimate that the detection of evaporating signatures on H and He would be challenging, but doable with present and future instruments.
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| 19. |
- Leleu, A., et al.
(author)
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Six transiting planets and a chain of Laplace resonances in TOI-178
- 2021
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
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Journal article (peer-reviewed)abstract
- Determining the architecture of multi-planetary systems is one of the cornerstones of understanding planet formation and evolution. Resonant systems are especially important as the fragility of their orbital configuration ensures that no significant scattering or collisional event has taken place since the earliest formation phase when the parent protoplanetary disc was still present. In this context, TOI-178 has been the subject of particular attention since the first TESS observations hinted at the possible presence of a near 2:3:3 resonant chain. Here we report the results of observations from CHEOPS, ESPRESSO, NGTS, and SPECULOOS with the aim of deciphering the peculiar orbital architecture of the system. We show that TOI-178 harbours at least six planets in the super-Earth to mini-Neptune regimes, with radii ranging from 1.152 to 2.87 Earth radii and periods of 1.91, 3.24, 6.56, 9.96, 15.23, and 20.71 days. All planets but the innermost one form a 2:4:6:9:12 chain of Laplace resonances, and the planetary densities show important variations from planet to planet, jumping from 1.02 to 0.177 times the Earth's density between planets c and d. Using Bayesian interior structure retrieval models, we show that the amount of gas in the planets does not vary in a monotonous way, contrary to what one would expect from simple formation and evolution models and unlike other known systems in a chain of Laplace resonances. The brightness of TOI-178 (H = 8.76 mag, J = 9.37 mag, V = 11.95 mag) allows for a precise characterisation of its orbital architecture as well as of the physical nature of the six presently known transiting planets it harbours. The peculiar orbital configuration and the diversity in average density among the planets in the system will enable the study of interior planetary structures and atmospheric evolution, providing important clues on the formation of super-Earths and mini-Neptunes. -0.070 -0.13 -0.23 -0.061 +0.073 +0.14 +0.28 +0.055
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| 20. |
- Luque, R., et al.
(author)
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A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067
- 2023
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In: Nature. - 0028-0836 .- 1476-4687. ; 623:7989, s. 932-937
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Journal article (peer-reviewed)abstract
- Planets with radii between that of the Earth and Neptune (hereafter referred to as ‘sub-Neptunes’) are found in close-in orbits around more than half of all Sun-like stars 1,2. However, their composition, formation and evolution remain poorly understood 3. The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R ⊕ to 2.85R ⊕. Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.
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| 21. |
- Nielsen, L. D., et al.
(author)
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Mass determinations of the three mini-Neptunes transiting TOI-125
- 2020
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 492:4, s. 5399-5412
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Journal article (peer-reviewed)abstract
- The Transiting Exoplanet Survey Satellite, TESS, is currently carrying out an all-sky search for small planets transiting bright stars. In the first year of the TESS survey, a steady progress was made in achieving the mission's primary science goal of establishing bulk densities for 50 planets smaller than Neptune. During that year, the TESS's observations were focused on the southern ecliptic hemisphere, resulting in the discovery of three mini-Neptunes orbiting the star T01-125, a V = 11,0 KO dwarf. We present intensive HARPS radial velocity observations, yielding precise mass measurements for TO1-125b, TOI-125c, and TOI-125d. TOI-125b has an orbital period of 4,65 d, a radius of 2,726 + 0,075 RE, a mass of 9,50 0,88 ME, and is near the 2:1 mean motion resonance with TOI-125c at 9.15 d. TOI-125c has a similar radius of 2,759 0.10 RE and a mass of 6,63 + 0,99 ME, being the puffiest of the three planets. T01-125d has an orbital period of 19,98 d and a radius of 2.93 + 0,17 RE and mass 13,6 1,2 ME, For T01-125b and d, we find unusual high eccentricities of 0.19 0.04 and 0.17+(c):(!,(, respectively. Our analysis also provides upper mass limits for the two low-SNR planet candidates in the system; for T01-125.04 (Rp = 1.36 RE, P = 0.53 d), we find a 2a upper mass limit of 1.6 ME, whereas T01-125.05 (RP = 4.2-'2E44 RE, P = 13.28 d) is unlikely a viable planet candidate with an upper mass limit of 2.7 ME. We discuss the internal structure of the three confirmed planets, as well as dynamical stability and system architecture for this intriguing exoplanet system.
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| 22. |
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| 23. |
- Hoyer, S., et al.
(author)
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TOI-220b: a warm sub-Neptune discovered by TESS
- 2021
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 505:3, s. 3361-3379
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Journal article (peer-reviewed)abstract
- In this paper, we report the discovery of TOI-220b, a new sub-Neptune detected by the Transiting Exoplanet Survey Satellite (TESS) and confirmed by radial velocity follow-up observations with the HARPS spectrograph. Based on the combined analysis of TESS transit photometry and high precision radial velocity measurements, we estimate a planetary mass of 13.8 +/- 1.0M(circle plus) and radius of 3.03 +/- 0.15R(circle plus), implying a bulk density of 2.73 +/- 0.47. TOI-220b orbits a relative bright (V=10.4) and old (10.1 +/- 1.4Gyr) K dwarf star with a period of similar to 10.69d. Thus, TOI-220b is a new warm sub-Neptune with very precise mass and radius determinations. A Bayesian analysis of the TOI-220b internal structure indicates that due to the strong irradiation it receives, the low density of this planet could be explained with a steam atmosphere in radiative-convective equilibrium and a supercritical water layer on top of a differentiated interior made of a silicate mantle and a small iron core.
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