| 1. |
- Hladyz, Sally, et al.
(författare)
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Stream ecosystem functioning in an agricultural landscape : the importance of terrestrial-aquatic linkages
- 2011
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Ingår i: Ecosystems in a human-modified landscape. - San Diego : Academic Press. - 9780123747945 ; 44, s. 211-276
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Bokkapitel (refereegranskat)abstract
- The loss of native riparian vegetation and its replacement with non-native species or grazing land for agriculture is a worldwide phenomenon, but one that is prevalent in Europe, reflecting the heavily-modified nature of the continent's landscape. The consequences of these riparian alterations for freshwater ecosystems remain largely unknown, largely because bioassessment has traditionally focused on the impacts of organic pollution on community structure. We addressed the need for a broader perspective, which encompasses changes at the catchment scale, by comparing ecosystem processes in woodland reference sites with those with altered riparian zones. We assessed a range of riparian modifications, including clearance for pasture and replacement of woodland with a range of low diversity plantations, in 100 streams to obtain a continental-scale perspective of the major types of alterations across Europe. Subsequently, we focused on pasture streams, as an especially prevalent widespread riparian alteration, by characterising their structural (e.g. invertebrate and fish communities) and functional (e.g. litter decomposition, algal production, herbivory) attributes in a country (Ireland) dominated by this type of landscape modification, via field and laboratory experiments. We found that microbes became increasingly important as agents of decomposition relative to macrofauna (invertebrates) in impacted sites in general and in pasture streams in particular. Resource quality of grass litter (e.g., carbon : nutrient ratios, lignin and cellulose content) was a key driver of decomposition rates in pasture streams. These systems also relied more heavily on autochthonous algal production than was the case in woodland streams, which were more detrital based. These findings suggest that these pasture streams might be fundamentally different from their native, ancestral woodland state, with a shift towards greater reliance on autochthonous-based processes. This could have a destabilizing effect on the dynamics of the food web relative to the slower, detrital-based pathways that dominate in woodland streams.
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| 2. |
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| 4. |
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| 5. |
- Bender, Brendan C, et al.
(författare)
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Population pharmacokinetic pharmacodynamic modelling in oncology : a tool for predicting clinical response
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 79:1, s. 56-71
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Forskningsöversikt (refereegranskat)abstract
- In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic-pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.
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| 6. |
- Hladyz, Sally, et al.
(författare)
-
Stream ecosystem functioning in an agricultural landscape : the importance of terrestrial-aquatic linkages
- 2011
-
Ingår i: Ecosystems in a human-modified landscape. - San Diego : Academic Press. - 9780123747945 ; 44, s. 211-276
-
Bokkapitel (populärvet., debatt m.m.)abstract
- The loss of native riparian vegetation and its replacement with non-native species or grazing land for agriculture is a worldwide phenomenon, but one that is prevalent in Europe, reflecting the heavily-modified nature of the continent's landscape. The consequences of these riparian alterations for freshwater ecosystems remain largely unknown, largely because bioassessment has traditionally focused on the impacts of organic pollution on community structure. We addressed the need for a broader perspective, which encompasses changes at the catchment scale, by comparing ecosystem processes in woodland reference sites with those with altered riparian zones. We assessed a range of riparian modifications, including clearance for pasture and replacement of woodland with a range of low diversity plantations, in 100 streams to obtain a continental-scale perspective of the major types of alterations across Europe. Subsequently, we focused on pasture streams, as an especially prevalent widespread riparian alteration, by characterising their structural (e.g. invertebrate and fish communities) and functional (e.g. litter decomposition, algal production, herbivory) attributes in a country (Ireland) dominated by this type of landscape modification, via field and laboratory experiments. We found that microbes became increasingly important as agents of decomposition relative to macrofauna (invertebrates) in impacted sites in general and in pasture streams in particular. Resource quality of grass litter (e.g., carbon : nutrient ratios, lignin and cellulose content) was a key driver of decomposition rates in pasture streams. These systems also relied more heavily on autochthonous algal production than was the case in woodland streams, which were more detrital based. These findings suggest that these pasture streams might be fundamentally different from their native, ancestral woodland state, with a shift towards greater reliance on autochthonous-based processes. This could have a destabilizing effect on the dynamics of the food web relative to the slower, detrital-based pathways that dominate in woodland streams.
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| 7. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Panoilia, Eirini, et al.
(författare)
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A pharmacokinetic binding model for bevacizumab and VEGF(165) in colorectal cancer patients
- 2015
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 75:4, s. 791-803
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Tidskriftsartikel (refereegranskat)abstract
- To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF(165) and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF(165) serum concentrations in patients with colorectal cancer stage IV. Bevacizumab and VEGF(165) data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3. A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF(165). The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF(165) levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF(165) was 0.401 day(-1). Body weight was allometrically included in all PK parameters. The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF(165) in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed.
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| 9. |
- Schindler, Emilie, et al.
(författare)
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A pharmacometric analysis of patient-reported outcomes in breast cancer patients through item response theory
- 2018
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 35:6
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Tidskriftsartikel (refereegranskat)abstract
- PurposeAn item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib.MethodsIn the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being. Each breast cancer subscale item was reassigned to one of the other subscales. Longitudinal changes in FACT-B responses and covariate effects were investigated.ResultsThe IRT model could describe both item-level and subscale-level FACT-B data. Non-Asian patients showed better baseline social/family and functional well-being than Asian patients. Moreover, patients with Eastern Cooperative Oncology Group performance status of 0 had better baseline physical and functional well-being. Well-being was described as initially increasing or decreasing before reaching a steady-state, which varied substantially between patients and subscales. T-DM1 exposure was not related to any of the latent variables. Physical well-being worsening was identified in capecitabine-plus-lapatinib-treated patients, whereas T-DM1-treated patients typically stayed stable.ConclusionThe developed framework provides a thorough description of FACT-B longitudinal data. It acknowledges the multi-dimensional nature of the questionnaire and allows covariate and exposure effects to be evaluated on responses.
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| 10. |
- Schindler, Emilie, et al.
(författare)
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A Pharmacometric Framework for Axitinib Exposure, Efficacy, and Safety in Metastatic Renal Cell Carcinoma Patients
- 2017
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 6:6, s. 373-382
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Tidskriftsartikel (refereegranskat)abstract
- The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors.
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