| 1. |
- 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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| 3. |
- Kontro, M, et al.
(author)
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HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia
- 2017
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In: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:2, s. 301-309
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Journal article (peer-reviewed)abstract
- Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.Leukemia advance online publication, 2 September 2016; doi:10.1038/leu.2016.222.
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| 7. |
- Sieberts, SK, et al.
(author)
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Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis
- 2016
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12460-
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.
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| 9. |
- Andersson, M., et al.
(author)
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Using optical tweezers for measuring the interaction forces between human bone cells and implant surfaces: System design and force calibration
- 2007
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In: Rev Sci Instrum. - : AIP Publishing. ; 78:7
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Journal article (peer-reviewed)abstract
- Optical tweezers were used to study the interaction and attachment of human bone cells to various types of medical implant materials. Ideally, the implant should facilitate cell attachment and promote migration of the progenitor cells in order to decrease the healing time. It is therefore of interest, in a controlled manner, to be able to monitor the cell adhesion process. Results from such studies would help foresee the clinical outcome of integrating medical implants. The interactions between two primary cell culture models, human gingival fibroblasts and bone forming human osteoblast cells, and three different implant materials, glass, titanium, and hydroxyapatite, were studied. A novel type of optical tweezers, which has a newly designed quadrant detector and a powerful 3 W laser was constructed and force calibrated using two different methods: one method in which the stiffness of the optical trap was obtained by monitoring the phase lag between the trap and the moved object when imposing a forced oscillation on the trapped object and another method in which the maximum trapping force was derived from the critical velocity at which the object escapes the trap. Polystyrene beads as well as cells were utilized for the calibrations. This is the first time that cells have been used directly for these types of force calibrations and, hence, direct measurements of forces exerted on cells can be performed, thus avoiding the difficulties often encountered when translating the results obtained from cell measurements to the calibrations obtained with reference materials. This more straightforward approach represents an advantage in comparison to established methods.
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| 10. |
- Carlén, A, et al.
(author)
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Surface characteristics and in vitro biofilm formation on glass ionomer and composite resin
- 2001
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In: Biomaterials. - 0142-9612 .- 1878-5905. ; 22, s. 481-487
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Journal article (peer-reviewed)abstract
- In the initial stages of dental plaque formation, early colonizing bacteria bind to receptor structures in the pellicle, a proteinaceous film formed instantly after cleaning of the tooth surface. Dental restorative materials with surface characteristics different from the tooth might affect pellicle formation and the ability of bacteria to colonize the oral cavity. in this study (i) roughness and chemical composition of glass ionomer and composite resin surfaces before and after polishing, and (ii) the adsorption of salivary proteins and bacterial adherence to the pellicle-coated surfaces were examined. Compared with unpolished composite resin, unpolished glass ionomer had higher surface roughness, contained more inorganic, positively charged components, collected more proteins, and promoted better bacterial adherence. Polishing had the most pronounced effect on the composite resin, giving an enlarged and a rougher surface with a more inorganic character. Polishing the composite resin also led to increased biofilm formation
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