| 1. |
- Menden, MP, et al.
(author)
-
Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
-
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.
|
|
| 2. |
|
|
| 3. |
- Perez-Nadales, Elena, et al.
(author)
-
Predictors of mortality in solid organ transplant recipients with bloodstream infections due to carbapenemase-producing Enterobacterales : The impact of cytomegalovirus disease and lymphopenia
- 2020
-
In: American Journal of Transplantation. - : WILEY. - 1600-6135 .- 1600-6143. ; 20:6, s. 1629-1641
-
Journal article (peer-reviewed)abstract
- Treatment of carbapenemase-producing Enterobacterales bloodstream infections in solid organ transplant recipients is challenging. The objective of this study was to develop a specific score to predict mortality in solid organ transplant recipients with carbapenemase-producing Enterobacterales bloodstream infections. A multinational, retrospective (2004-2016) cohort study (INCREMENT-SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30-day all-cause mortality. The INCREMENT-SOT-CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT-CPE mortality score >= 8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT-CPE score >= 8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI] 0.76-0.88) and classified patients into 3 strata: 0-7 (low mortality), 8-11 (high mortality), and 12-17 (very-high mortality). We performed a stratified analysis of the effect of monotherapy vs combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very-high (adjusted hazard ratio [HR] 2.82, 95% CI 1.13-7.06, P = .03) and high (HR 9.93, 95% CI 2.08-47.40, P = .004) mortality risk strata. A score-based algorithm is provided for therapy guidance.
|
|
| 4. |
|
|
| 5. |
- Ahrens, W, et al.
(author)
-
The IDEFICS cohort: design, characteristics and participations in the baseline survey.
- 2011
-
In: International Journal of Obesity. - 1476-5497. ; 35:suppl 1, s. 3-15
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The European IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study was set up to determine the aetiology of overweight, obesity and related disorders in children, and to develop and evaluate a tailored primary prevention programme. OBJECTIVE: This paper focuses on the aetiological element of the multicentre study, the measures and examinations, sociodemographic characteristics of the study sample and proportions of participation. DESIGN: Prospective cohort study with an embedded intervention study that started with a baseline survey in eight countries in 2007-2008. SUBJECTS AND MEASUREMENTS: Baseline participants of the prospective cohort study were 16,224 children aged 2-9 years. Parents reported sociodemographic, behavioural, medical, nutritional and other lifestyle data for their children and families. Examinations of children included anthropometry, blood pressure, fitness, accelerometry, DNA from saliva and physiological markers in blood and urine. The built environment, sensory taste perception and other mechanisms of children's food choices and consumer behaviour were studied in subgroups. RESULTS: Between 1507 and 2567, children with a mean age of 6.0 years and an even sex distribution were recruited from each country. Of them, 82% lived in two-parent families. The distribution of standardised income levels differed by study sample, with low-income groups being strongly represented in Cyprus, Italy and Germany. At least one 24-h dietary recall was obtained for two-thirds of the children. Blood pressure and anthropometry were assessed in more than 90%. A 3-day accelerometry was performed in 46%, motor fitness was assessed in 41%, cardiorespiratory fitness in 35% and ∼11% participated in taste perception tests. The proportion of children donating venous blood, urine and saliva was 57, 86 and 88%, respectively. CONCLUSION: The IDEFICS cohort provides valuable data to investigate the interplay of social, environmental, genetic, physiological and behavioural factors in the development of major diet- and lifestyle-related disorders affecting children at present.
|
|
| 6. |
- Winters, Z E, et al.
(author)
-
International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.
- 2018
-
In: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 105, s. 209-222
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction.METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross-sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires.RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0·5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P < 0·001). Scale reliability was supported by high Cronbach's α coefficients (over 0·7) and test-retest (intraclass correlation more than 0·8). One item (finding a well fitting bra) was excluded based on high floor/ceiling effects, poor test-retest and weak correlations in factor analysis (below 0·3), thus generating the QLQ-BRECON23 questionnaire.CONCLUSION: The QLQ-BRECON23 is an internationally validated tool to be used alongside the EORTC QLQ-C30 (cancer) and QLQ-BR23 (breast cancer) questionnaires for evaluating quality of life and satisfaction after breast reconstruction.
|
|
