| 1. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 2. |
- Joerger, Markus, et al.
(author)
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Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : a study by the EORTC-PAMM-NDDG
- 2007
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In: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 46:12, s. 1051-1068
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Journal article (peer-reviewed)abstract
- Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. Patients and methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. Results: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 mu mol . h/L [95% CI 889, 1001] vs 602 mu mol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. Conclusions: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group
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| 3. |
- Joerger, Markus, et al.
(author)
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Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients : a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.
- 2007
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:21, s. 6410-6418
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Journal article (peer-reviewed)abstract
- Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
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| 4. |
- Perego, Paola, et al.
(author)
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Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group
- 2018
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In: Cancer Chemotherapy and Pharmacology. - : SPRINGER. - 0344-5704 .- 1432-0843. ; 81:3, s. 427-441
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Research review (peer-reviewed)abstract
- An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumor agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumor agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumor activity using a range of preclinical cellular models of cancer.
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| 5. |
- Ried, Janina S., et al.
(author)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 6. |
- Trame, Mirjam N, et al.
(author)
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Population pharmacokinetics of busulfan in children : increased evidence for body surface area and allometric body weight dosing of busulfan in children.
- 2011
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 17:21, s. 6867-6877
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Journal article (peer-reviewed)abstract
- PURPOSE: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM. EXPERIMENTAL DESIGN: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V. RESULTS: CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation. CONCLUSION: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment.
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| 7. |
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| 8. |
- Wuerthwein, Gudrun, et al.
(author)
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Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar® in Children with Acute Lymphoblastic Leukemia
- 2017
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In: European journal of drug metabolism and pharmacokinetics. - : Springer Science and Business Media LLC. - 0378-7966 .- 2107-0180. ; 42:6, s. 955-963
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Journal article (peer-reviewed)abstract
- The pharmacokinetics of the polyethylene glycol (PEG)-conjugated asparaginase Oncaspar® are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency. In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar® (2500 U/m(2) intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non-linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated. Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (E-max- and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model. The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at www.clinicaltrials.gov, NCT0111744).
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