| 1. |
- Artigas, J., et al.
(författare)
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Towards a renewed research agenda in ecotoxicology
- 2012
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 160, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- New concerns about biodiversity, ecosystem services and human health triggered several new regulations increasing the need for sound ecotoxicological risk assessment. The PEER network aims to share its view on the research issues that this challenges. PEER scientists call for an improved biologically relevant exposure assessment. They promote comprehensive effect assessment at several biological levels. Biological traits should be used for Environmental risk assessment (ERA) as promising tools to better understand relationships between structure and functioning of ecosystems. The use of modern high throughput methods could also enhance the amount of data for a better risk assessment. Improved models coping with multiple stressors or biological levels are necessary to answer for a more scientifically based risk assessment. Those methods must be embedded within life cycle analysis or economical models for efficient regulations. Joint research programmes involving humanities with ecological sciences should be developed for a sound risk management. (C) 2011 Elsevier Ltd. All rights reserved.
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| 2. |
- Bergfur, Jenny, et al.
(författare)
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The Tarland Catchment Initiative and Its Effect on Stream Water Quality and Macroinvertebrate Indices
- 2012
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Ingår i: Journal of Environmental Quality. - : American society of Agronomy, Inc. - 0047-2425 .- 1537-2537. ; 41:2, s. 314-321
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Tidskriftsartikel (refereegranskat)abstract
- The Tarland Catchment Initiative is a partnership venture between researchers, land managers, regulators, and the local community. Its aims are to improve water quality, promote biodiversity, and increase awareness of catchment management. In this study, the effects of buffer strip installations and remediation of a large septic tank effluent were appraised by water physico-chemistry (suspended solids, NO3, NH4, soluble reactive P) and stream macroinvertebrate indices used by the Scottish Environmental Protection Agency. It was done during before and after interventions over an 8-yr period using a paired catchment approach. Because macroinvertebrate indices were previously shown to respond negatively to suspended solid concentrations in the study area, the installation of buffer strips along the headwaters was expected to improve macroinvertebrate scores. Although water quality (soluble reactive P, NH4) improved downstream of the septic tank effluent after remediation, there was no detectable change in macroinvertebrate scores. Buffer strip installations in the headwaters had no measurable effects (beyond possible weak trends) on water quality or macroinvertebrate scores. Either the buffer strips have so far been ineffective or ineffectiveness of assessment methods and sampling frequency and time lags in recovery prevent us detecting reliable effects. To explain and appreciate these constraints on measuring stream recovery, continuous capacity building with land managers and other stakeholders is essential; otherwise, the feasibility of undertaking sufficient management interventions is likely to be compromised and projects deemed unsuccessful.
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| 3. |
- Bergmann, T K, et al.
(författare)
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Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer
- 2011
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Ingår i: PHARMACOGENOMICS JOURNAL. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 11:2, s. 113-120
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Tidskriftsartikel (refereegranskat)abstract
- The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P = 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P = 0.04) and ABCC1 g.7356253C andgt; G (P = 0.04).
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| 4. |
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| 5. |
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| 6. |
- Brunnström, Hans, et al.
(författare)
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Differential degeneration of the locus coeruleus in dementia subtypes.
- 2011
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Ingår i: Clinical Neuropathology. - 0722-5091. ; 30:3, s. 104-110
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Neuronal loss in the locus coeruleus (LC) is common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The aims of the present study were to investigate LC degeneration in different dementia disorders including vascular dementia (VaD) and frontotemporal lobar degeneration (FTLD), to compare LC degeneration with severity of pathology in AD and DLB/PDD, to further evaluate the usefulness of a previously presented scoring system and to examine the predictive value of macroscopic assessment of the LC. Methods: A horizontal mid-level section of the pons was examined in 200 neuropathologically examined cases with clinical dementia. A previous macroscopic assessment of the LC was performed in 149 of the cases. Results: Cases with DLB/ PDD and AD presented with the highest microscopic LC degeneration scores, with significant differences compared to combined AD + VaD, in turn with a higher score than VaD, FTLD and other dementia disorders. Interrater agreement (weighted kappa;) for LC degeneration scoring was 0.83 - 0.91. DLB/ PDD, AD and AD + VaD were the diagnoses for 85% of the cases with macroscopic LC depigmentation. Conclusion: LC degeneration, which may be macroscopically noted, often indicates synuclein and/or Alzheimer pathology among demented. When clinical information is scarce or inconsistent, a macroscopic assessment of the LC may facilitate focusing of the subsequent neuropathological investigation. Also, the semiquantitative scoring system is a reliable tool for histological assessment of LC degeneration.
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| 7. |
- de Graan, Anne-Joy M., et al.
(författare)
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A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:18, s. 5210-5217
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training-and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance.
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| 8. |
- de Graan, Anne-Joy M., et al.
(författare)
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CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:12, s. 3316-3324
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel ((log)AUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, C-max, or T->0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.
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| 9. |
- de Graan, Anne-Joy M., et al.
(författare)
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Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:16, s. 4433-4440
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination.Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213).Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05).Conclusions: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.
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| 10. |
- Dinca, Vlad, et al.
(författare)
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Reproductive isolation and patterns of genetic differentiation in a cryptic butterfly species complex
- 2013
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Ingår i: Journal of Evolutionary Biology. - : Wiley. - 1010-061X .- 1420-9101. ; 26:10, s. 2095-2106
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Tidskriftsartikel (refereegranskat)abstract
- Molecular studies of natural populations are often designed to detect and categorize hidden layers of cryptic diversity, and an emerging pattern suggests that cryptic species are more common and more widely distributed than previously thought. However, these studies are often decoupled from ecological and behavioural studies of species divergence. Thus, the mechanisms by which the cryptic diversity is distributed and maintained across large spatial scales are often unknown. In 1988, it was discovered that the common Eurasian Wood White butterfly consisted of two species (Leptidea sinapis and Leptidea reali), and the pair became an emerging model for the study of speciation and chromosomal evolution. In 2011, the existence of a third cryptic species (Leptidea juvernica) was proposed. This unexpected discovery raises questions about the mechanisms preventing gene flow and about the potential existence of additional species hidden in the complex. Here, we compare patterns of genetic divergence across western Eurasia in an extensive data set of mitochondrial and nuclear DNA sequences with behavioural data on inter- and intraspecific reproductive isolation in courtship experiments. We show that three species exist in accordance with both the phylogenetic and biological species concepts and that additional hidden diversity is unlikely to occur in Europe. The Leptidea species are now the best studied cryptic complex of butterflies in Europe and a promising model system for understanding the formation of cryptic species and the roles of local processes, colonization patterns and heterospecific interactions for ecological and evolutionary divergence.
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| 11. |
- Eechoute, Karel, et al.
(författare)
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A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:20, s. 5780-5787
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm 3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.
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| 12. |
- Friberg, E., et al.
(författare)
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Alcohol intake and endometrial cancer risk : a meta-analysis of prospective studies
- 2010
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Ingår i: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 103:1, s. 127-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies on alcohol intake in relation to endometrial cancer risk have produced inconsistent results. METHODS: For a meta-analysis, we identified cohort studies of alcohol and endometrial cancer by a literature search of Pub-Med and Embase up to 1 March 2010 and by searching the reference lists of relevant articles. RESULTS: Seven cohort studies, including 1 511 661 participants and 6086 endometrial cancer cases, were included in the dose-response random-effect meta-regression model. Compared with non-drinkers, women drinking less than 1 drink of alcohol (13 g of ethanol) per day had a lower risk for endometrial cancer; this risk was lower by 4% (95% confidence interval (95% CI): 0.93-1.00) for consumption up to 0.5 drink per day and by 7% (95% CI: 0.85 1.02) for consumption up to 1 drink. However, we found evidence of an increased risk for endometrial cancer for intakes higher than two alcoholic drinks per day: compared with non-drinkers, the risk was higher by 14% (95% CI: 0.95-1.36) for 2-2.5 drinks per day and by 25% (95% CI: 0.98-1.58) for >2.5 drinks per day. CONCLUSION: Our meta-analysis indicates a possible J-shaped relationship between alcohol intake and endometrial cancer risk. British Journal of Cancer (2010) 103, 127-131. doi:10.1038/sj.bjc.6605698 www.bjcancer.com Published online 18 May 2010 (C) 2010 Cancer Research UK
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| 13. |
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| 14. |
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| 15. |
- Friberg, Magne, et al.
(författare)
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Extreme divergence in floral scent among woodland star species (Lithophragma spp.) pollinated by floral parasites
- 2013
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Ingår i: Annals of Botany. - : Oxford University Press (OUP). - 0305-7364 .- 1095-8290. ; 111:4, s. 539-550
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Tidskriftsartikel (refereegranskat)abstract
- A current challenge in coevolutionary biology is to understand how suites of traits vary as coevolving lineages diverge. Floral scent is often a complex, variable trait that attracts a suite of generalized pollinators, but may be highly specific in plants specialized on attracting coevolved pollinating floral parasites. In this study, floral scent variation was investigated in four species of woodland stars (Lithophragma spp.) that share the same major pollinator (the moth Greya politella, a floral parasite). Three specific hypotheses were tested: (1) sharing the same specific major pollinator favours conservation of floral scent among close relatives; (2) selection favours private channels of rare compounds particularly aimed at the specialist pollinator; or (3) selection from rare, less-specialized co-pollinators mitigates the conservation of floral scent and occurrence of private channels. Dynamic headspace sampling and solid-phase microextraction were applied to greenhouse-grown plants from a common garden as well as to field samples from natural populations in a series of experiments aiming to disentangle the genetic and environmental basis of floral scent variation. Striking floral scent divergence was discovered among species. Only one of 69 compounds was shared among all four species. Scent variation was largely genetically based, because it was consistent across field and greenhouse treatments, and was not affected by visits from the pollinating floral parasite. The strong divergence in floral scents among Lithophragma species contrasts with the pattern of conserved floral scent composition found in other plant genera involved in mutualisms with pollinating floral parasites. Unlike some of these other obligate pollination mutualisms, Lithophragma plants in some populations are occasionally visited by generalist pollinators from other insect taxa. This additional complexity may contribute to the diversification in floral scent found among the Lithophragma species pollinated by Greya moths.
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| 16. |
- Friberg, Magne, et al.
(författare)
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Floral Scent Contributes to Interaction Specificity in Coevolving Plants and Their Insect Pollinators
- 2014
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Ingår i: Journal of Chemical Ecology. - : Springer Science and Business Media LLC. - 0098-0331 .- 1573-1561. ; 40:9, s. 955-965
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Tidskriftsartikel (refereegranskat)abstract
- Chemical defenses, repellents, and attractants are important shapers of species interactions. Chemical attractants could contribute to the divergence of coevolving plant-insect interactions, if pollinators are especially responsive to signals from the local plant species. We experimentally investigated patterns of daily floral scent production in three Lithophragma species (Saxifragaceae) that are geographically isolated and tested how scent divergence affects attraction of their major pollinator the floral parasitic moth Greya politella (Prodoxidae). These moths oviposit through the corolla while simultaneously pollinating the flower with pollen adhering to the abdomen. The complex and species-specific floral scent profiles were emitted in higher amounts during the day, when these day-flying moths are active. There was minimal divergence found in petal color, which is another potential floral attractant. Female moths responded most strongly to scent from their local host species in olfactometer bioassays, and were more likely to oviposit in, and thereby pollinate, their local host species in no-choice trials. The results suggest that floral scent is an important attractant in this interaction. Local specialization in the pollinator response to a highly specific plant chemistry, thus, has the potential to contribute importantly to patterns of interaction specificity among coevolving plants and highly specialized pollinators.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Iyer, Srinivasan, 1984-
(författare)
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Effects of surface plasmons in subwavelength metallic structures
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The study of optical phenomena related to the strong electromagnetic response of noble metals (silver (Ag) and gold (Au) being most popular) over the last couple of decades has led to the emergence of a fast growing research area called plasmonics named after 'surface plasmons' which are electron density waves that propagate along the interface of a metal and a dielectric medium. Surface plasmons are formed by the coupling of light to the electrons on the metal surface subject to the fulfillment of certain physical conditions and they are bound to the metal surface. Depending on whether the metallic medium is a continuous film or a structure having dimensions less than or comparable to the wavelength of the exciting light, propagating or localized surface plasmons can be excited. The structure can be either a hole or an arbitrary pattern in a metal film, or a metallic particle. An array of subwavelength structures can behave as an effective homogeneous medium to incident light and this is the basis of a new class of media known as metamaterials. Metallic metamaterials enable one to engineer the electromagnetic response to incident light and provide unconventional optical properties like negative refractive index as one prominent example. Metamaterials exhibiting negative index (also called negative index materials (NIMs)) open the door for super resolution imaging and development of invisibility cloaks. However, the only problem affecting the utilization of plasmonic media to their fullest potential is the intrinsic loss of the metal, and it becomes a major issue especially at visible-near infrared (NIR) frequencies.The frequency of the surface plasmon is the same as that of the exciting light but its wavelength could be as short as that of X-rays. This property allows light of a given optical frequency to be conned into very small volumes via subwave lengthmetallic structures, that can be used to develop ecient sensors, solar cells, antennas and ultrasensitive molecular detectors to name a few applications. Also, interaction of surface plasmons excited in two or more metallic subwavelength structures in close proximity inuences the far-eld optical properties of the overall coupled system. Some eects of plasmonic interaction in certain coupled particles include polarization conversion, optical activity and transmission spectra mimicking electromagnetically-induced transparency (EIT) as observed in gas based atomicsy stems.In this thesis, we mainly focus on the optical properties of square arrays of certain plasmonic structures popularly researched in the last decade. The structures considered are as follows: (1) subwavelength holes of a composite hole-shape providing superior near-eld enhancement such as two intersecting circles (called' double hole') in an optically thick Au/Ag lm, (2) double layer shnets, (3) subwavelength U-shaped particles and (4) rectangular bars. The entire work is based on electromagnetic simulations using time and frequency domain methods.Au/Ag lms with periodic subwavelength holes provide extraordinarily high transmission of light at certain wavelengths much larger than the dimension of the perforations or holes. The spectral positions of the maxima depend on the shape of the hole and the intra-hole medium, thereby making such lms function as a refractive index sensor in the transmission mode. The sensing performance of the double-hole geometry is analyzed in detail and compared to rectangular holes.Fishnet metamaterials are highly preferred when it comes to constructing a NIM at optical frequencies. A shnet design that theoretically oers a negative refractive index with least losses at telecommunication wavelengths (1.4 1.5 microns) is presented.U-shaped subwavelength metallic particles, in particular single-slit split-ring resonators (SSRRs), provide a large negative response to the magnetic eld of light at a specic resonance frequency. The spectral positions of the structural resonances of the U-shaped particle can be found from its array far field transmission spectrum at normal incidence. An effort is made to clarify our understanding of these resonances with the help of localized surface plasmon modes excited in the overall particle. From an application point of view, it is found that a planar square array of SSRRs eectively functions as an optical half-wave waveplate at the main resonance frequency by creating a polarization in transmission that is orthogonal to that of incident light. A similar waveplate eect can be obtained purely by exploiting the near-eld interaction of dierently oriented neighbouring SSRRs. The physical reasons behind polarization conversion in dierent SSRR-array systems are discussed.A rectangular metallic bar having its dipolar resonance in the visible-NIR is called a nanoantenna, owing to its physical length in the order of nanometers. The excitation of localized surface plasmons, metal dispersion and the geometry of the rectangular nanoantenna make an analytical estimation of the physical length of the antenna from the desired dipolar resonance dicult. A practical map of simulated resonance values corresponding to a variation in geometrical parameters of Au bar is presented. A square array of a coupled plasmonic system comprising of three nanoantennas provides a net transmission response that mimicks the EIT effect. The high transmission spectral window possesses a peculiar dispersion profile that enables light with frequencies in that region to be slowed down. Two popular designs of such plasmonic EIT systems are numerically characterized and compared.
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| 21. |
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| 22. |
- N Fransson, Martin, et al.
(författare)
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Influence of Cremophor EL and Genetic Polymorphisms on the Pharmacokinetics of Paclitaxel and Its Metabolites Using a Mechanism-Based Model
- 2011
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Ingår i: DRUG METABOLISM AND DISPOSITION. - : American Soc. for Pharmacology andamp; Experimental Therapeutics. - 0090-9556 .- 1521-009X. ; 39:2, s. 247-255
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Tidskriftsartikel (refereegranskat)abstract
- The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6 alpha-hydroxypaclitaxel and p-3-hydroxypaclitaxel, and its secondary metabolite, 6 alpha-p-3-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6 alpha-hydroxypaclitaxel and p-3-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6 alpha-p-3-dihydroxypaclitaxel. Clearance of 6 alpha-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p andlt; 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6 alpha-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.
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| 23. |
- O'Gorman, Eoin J., et al.
(författare)
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Impacts of Warming on the Structure and Functioning of Aquatic Communities : Individual-to Ecosystem-Level Responses
- 2012
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Ingår i: Advances in Ecological Research, Vol 47. - : Elsevier. - 9780123983152 ; , s. 81-176
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Bokkapitel (refereegranskat)abstract
- Environmental warming is predicted to rise dramatically over the next century, yet few studies have investigated its effects in natural, multi-species systems. We present data collated over an 8-year period from a catchment of geothermally heated streams in Iceland, which acts as a natural experiment on the effects of warming across different organisational levels and spatiotemporal scales. Body sizes and population biomasses of individual species responded strongly to temperature, with some providing evidence to support temperature size rules. Macroinvertebrate and meiofaunal community composition also changed dramatically across the thermal gradient. Interactions within the warm streams in particular were characterised by food chains linking algae to snails to the apex predator, brown trout These chains were missing from the colder systems, where snails were replaced by much smaller herbivores and invertebrate omnivores were the top predators. Trout were also subsidised by terrestrial invertebrate prey, which could have an effect analogous to apparent competition within the aquatic prey assemblage. Top-down effects by snails on diatoms were stronger in the warmer streams, which could account for a shallowing of mass-abundance slopes across the community. This may indicate reduced energy transfer efficiency from resources to consumers in the warmer systems and/or a change in predator-prey mass ratios. All the ecosystem process rates investigated increased with temperature, but with differing thermal sensitivities, with important implications for overall ecosystem functioning (e.g. creating potential imbalances in elemental fluxes). Ecosystem respiration rose rapidly with temperature, leading to increased heterotrophy. There were also indications that food web stability may be lower in the warmer streams.
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| 24. |
- Thompson, John N., et al.
(författare)
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Diversification through multi-trait evolution in a coevolving interaction
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:28, s. 11487-11492
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Tidskriftsartikel (refereegranskat)abstract
- Mutualisms between species are interactions in which reciprocal exploitation results in outcomes that are mutually beneficial. This reciprocal exploitation is evident in the more than a thousand plant species that are pollinated exclusively by insects specialized to lay their eggs in the flowers they pollinate. By pollinating each flower in which she lays eggs, an insect guarantees that her larval offspring have developing seeds on which to feed, whereas the plant gains a specialized pollinator at the cost of some seeds. These mutualisms are often reciprocally obligate, potentially driving not only ongoing coadaptation but also diversification. The lack of known intermediate stages in most of these mutualisms, however, makes it difficult to understand whether these interactions could have begun to diversify even before they became reciprocally obligate. Experimental studies of the incompletely obligate interactions between woodland star (Lithophragma; Saxifragaceae) plants and their pollinating floral parasites in the moth genus Greya (Prodoxidae) show that, as these lineages have diversified, the moths and plants have evolved in ways that maintain effective oviposition and pollination. Experimental assessment of pollination in divergent species and quantitative evaluation of time-lapse photographic sequences of pollination viewed on surgically manipulated flowers show that various combinations of traits are possible for maintaining the mutualism. The results suggest that at least some forms of mutualism can persist and even diversify when the interaction is not reciprocally obligate.
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| 25. |
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