| 1. |
- 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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| 2. |
- Pettersson, Lars, et al.
(författare)
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Sex ratio dynamics and fluctuating selection pressures in natural populations of the Trinidadian guppy, Poecilia reticulata
- 2004
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Ingår i: Behavioral Ecology and Sociobiology. - : Springer Science and Business Media LLC. - 1432-0762 .- 0340-5443. ; 55:5, s. 461-468
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Tidskriftsartikel (refereegranskat)abstract
- In many species, population sex ratios have far-reaching consequences for a wide variety of population-level and behavioural processes and can directly influence sexual selection through differential effects on male and female mating behaviour. Although sex ratios are often treated as more or less stable population characteristics, recent theoretical evidence suggests that sex ratios fluctuate under many conditions, and that the amplitude of these fluctuations can be considerable. Few studies have attempted to quantify this variation in systems with prominent, sex ratio-dependent sexual conflict. One of the species with the greatest potential to integrate these factors in the wild is the Trinidadian guppy, Poecilia reticulata. In this study, we quantified natural sex ratio variation both as detailed longitudinal studies of focal guppy populations and as snapshot estimates across a range of freshwater habitats. In line with theoretical predictions, we expected to detect significant sex ratio variation over time. We also investigated the association between juvenile and adult sex ratios to quantify a possible compensatory feedback implied in standard models of sex ratio evolution. Our results confirm that population-level sex ratios in wild guppy populations have a range of dynamic features, with all four focal populations showing significant variation in sex ratio over time. The survey showed that juveniles were generally close to equal (50:50) sex ratios whereas 7 out of 11 adult sex ratios differed significantly from equality. We found no evidence that a surplus of juveniles of the locally rarer sex had been produced. The results indicate that sex ratios and hence the balance between sexual selection and sexual coercion is normally fluctuating in nature, despite juvenile ratios being close to equality.
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