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- 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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- Fuente, A., et al.
(författare)
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Gas phase Elemental abundances in Molecular cloudS (GEMS) I. The prototypical dark cloud TMC 1
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 624
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Tidskriftsartikel (refereegranskat)abstract
- GEMS is an IRAM 30 m Large Program whose aim is determining the elemental depletions and the ionization fraction in a set of prototypical star-forming regions. This paper presents the first results from the prototypical dark cloud Taurus molecular cloud (TMC) 1. Extensive millimeter observations have been carried out with the IRAM 30 m telescope (3 and 2mm) and the 40 m Yebes telescope (1.3 cm and 7 mm) to determine the fractional abundances of CO, HCO+, HCN, CS, SO, HCS+, and N2H+ in three cuts which intersect the dense filament at the well-known positions TMC 1-CP, TMC 1-NH3, and TMC 1-C, covering a visual extinction range from A(v) similar to 3 to similar to 20 mag. Two phases with differentiated chemistry can be distinguished: (i) the translucent envelope with molecular hydrogen densities of 1-5 x 10(3) cm(-3); and (ii) the dense phase, located at A(v) > 10 mag, with molecular hydrogen densities >10(4) cm(-3). Observations and modeling show that the gas phase abundances of C and O progressively decrease along the C+/C/CO transition zone (A(v) similar to 3 mag) where C/H similar to 8 x 10(-5) and C/O similar to 0.8-1, until the beginning of the dense phase at A(v) similar to 10 mag. This is consistent with the grain temperatures being below the CO evaporation temperature in this region. In the case of sulfur, a strong depletion should occur before the translucent phase where we estimate an S/H similar to (0.4-2.2) x 10(-6), an abundance similar to 7-40 times lower than the solar value. A second strong depletion must be present during the formation of the thick icy mantles to achieve the values of S/H measured in the dense cold cores (S/H similar to 8 x 10(-8)). Based on our chemical modeling, we constrain the value of zeta(H2) to similar to(0.5-1.8) x 10(-16) s(-1) in the translucent cloud.
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- Bustamante, Mariona, et al.
(författare)
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A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:18, s. 4127-4142
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Tidskriftsartikel (refereegranskat)abstract
- More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N=5758) followed by replication (N=3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
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- Ma, Yunzhi, et al.
(författare)
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A generic TG-186 shielded applicator for commissioning model-based dose calculation algorithms for high-dose-rate Ir-192 brachytherapy
- 2017
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Ingår i: Medical physics (Lancaster). - : WILEY. - 0094-2405 .- 2473-4209. ; 44:11, s. 5961-5976
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Tidskriftsartikel (refereegranskat)abstract
- PurposeA joint working group was created by the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) with the charge, among others, to develop a set of well-defined test case plans and perform calculations and comparisons with model-based dose calculation algorithms (MBDCAs). Its main goal is to facilitate a smooth transition from the AAPM Task Group No. 43 (TG-43) dose calculation formalism, widely being used in clinical practice for brachytherapy, to the one proposed by Task Group No. 186 (TG-186) for MBDCAs. To do so, in this work a hypothetical, generic high-dose rate (HDR) Ir-192 shielded applicator has been designed and benchmarked. MethodsA generic HDR Ir-192 shielded applicator was designed based on three commercially available gynecological applicators as well as a virtual cubic water phantom that can be imported into any DICOM-RT compatible treatment planning system (TPS). The absorbed dose distribution around the applicator with the TG-186 Ir-192 source located at one dwell position at its center was computed using two commercial TPSs incorporating MBDCAs (Oncentra((R)) Brachy with Advanced Collapsed-cone Engine, ACE, and BrachyVision ACUROS) and state-of-the-art Monte Carlo (MC) codes, including ALGEBRA, BrachyDose, egs_brachy, Geant4, MCNP6, and Penelope2008. TPS-based volumetric dose distributions for the previously reported source centered in water and source displaced test cases, and the new source centered in applicator test case, were analyzed here using the MCNP6 dose distribution as a reference. Volumetric dose comparisons of TPS results against results for the other MC codes were also performed. Distributions of local and global dose difference ratios are reported. ResultsThe local dose differences among MC codes are comparable to the statistical uncertainties of the reference datasets for the source centered in water and source displaced test cases and for the clinically relevant part of the unshielded volume in the source centered in applicator case. Larger local differences appear in the shielded volume or at large distances. Considering clinically relevant regions, global dose differences are smaller than the local ones. The most disadvantageous case for the MBDCAs is the one including the shielded applicator. In this case, ACUROS agrees with MC within [-4.2%, +4.2%] for the majority of voxels (95%) while presenting dose differences within [-0.12%, +0.12%] of the dose at a clinically relevant reference point. For ACE, 95% of the total volume presents differences with respect to MC in the range [-1.7%, +0.4%] of the dose at the reference point. ConclusionsThe combination of the generic source and generic shielded applicator, together with the previously developed test cases and reference datasets (available in the Brachytherapy Source Registry), lay a solid foundation in supporting uniform commissioning procedures and direct comparisons among treatment planning systems for HDR Ir-192 brachytherapy.
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