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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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| 2. |
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| 3. |
- Lagisz, Malgorzata, et al.
(författare)
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Optimism, pessimism and judgement bias in animals: A systematic review and meta-analysis
- 2020
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Ingår i: Neuroscience and Biobehavioral Reviews. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0149-7634 .- 1873-7528. ; 118
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Forskningsöversikt (refereegranskat)abstract
- Just as happy people see the proverbial glass as half-full, optimistic or pessimistic responses to ambiguity might also reflect affective states in animals. Judgement bias tests, designed to measure these responses, are an increasingly popular way of assessing animal affect and there is now a substantial, but heterogeneous, literature on their use across different species, affect manipulations, and study designs. By conducting a systematic review and meta-analysis of 459 effect sizes from 71 studies of non-pharmacological affect manipulations on 22 non-human species, we show that animals in relatively better conditions, assumed to generate more positive affect, show more optimistic judgements of ambiguity than those in relatively worse conditions. Overall effects are small when considering responses to all cues, but become more pronounced when non-ambiguous training cues are excluded from analyses or when focusing only on the most divergent responses between treatment groups. Task type (go/no-go; go/go active choice), training cue reinforcement (reward-punishment; reward-null; reward-reward) and sex of animals emerge as potential moderators of effect sizes in judgement bias tests.
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| 4. |
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| 5. |
- Neville, Vikki, et al.
(författare)
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Pharmacological manipulations of judgement bias: A systematic review and meta-analysis
- 2020
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Ingår i: Neuroscience and Biobehavioral Reviews. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0149-7634 .- 1873-7528. ; 108, s. 269-286
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Forskningsöversikt (refereegranskat)abstract
- Validated measures of animal affect are crucial to research spanning numerous disciplines. Judgement bias, which assesses decision-making under ambiguity, is a promising measure of animal affect. One way of validating this measure is to administer drugs with affect-altering properties in humans to non-human animals and determine whether the predicted judgement biases are observed. We conducted a systematic review and meta-analysis using data from 20 published research articles that use this approach, from which 557 effect sizes were extracted. Pharmacological manipulations overall altered judgement bias at the probe cues as predicted. However, there were several moderating factors including the neurobiological target of the drug, whether the drug induced a relatively positive or negative affective state in humans, dosage, and the presented cue. This may partially reflect interference from adverse effects of the drug which should be considered when interpreting results. Thus, the overall pattern of change in animal judgement bias appears to reflect the affect-altering properties of drugs in humans, and hence may be a valuable measure of animal affective valence.
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