Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although ...drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution.
Integrated forest management (IFM) can help reconcile critical trade-offs between goals in forest management, such as nature conservation and biomass production. The challenge of IFM is dealing with ...these trade-offs at the level of practical forest management, such as striving for compromises between biomass extraction and habitat retention. This paper reviews some of the driving factors that influence the integration of nature conservation into forest management. The review was conducted in three steps – a literature review, an expert workshop and an expert-based cooperative analysis. Of 38 driving factors identified, three were prioritised by more of the participants than any of the others: two are socio-cultural factors, identity (how people identify with forest) as well as outreach and education, and one is economic – competitiveness in forest value chains. These driving factors correspond to what are considered in the literature as enablers for IFM. The results reveal that targeted, group-oriented, adaptive and innovative policy designs are needed to integrate nature conservation into forest management. Further, the results reveal that a “one-size-fits-all” governance approach would be ineffective, implying that policy instruments need to consider contextually specific driving factors. Understanding the main driving factors and their overall directions can help to better manage trade-offs between biodiversity conservation and biomass production in European forests.
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•Integrated Forest Management may help to reconcile critical trade-offs in forest management.•38 driving factors identified as important for integrating nature conservation into forest management.•Several driving factors correspond to what can be considered as enablers of Integrated Forest Management.•Policy need to account for contextually specific driving factors to integrate nature conservation.•Integrative approaches demonstrate the need for targeted, group-oriented and adaptive policy designs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Today, multiple-use (or multifunctional) forestry is one of the main concepts guiding European forestry. While there is wide acceptance of the overall concept, here is a lack of coherence in ...definitions, policies and practices. Such outcomes indicate that multiple-use forestry (MUF) may contain the essential properties of a “boundary object”, i.e. something that is robust enough to conceptually unite different interests, but at the same time is flexible enough to encompass different practices in line with local needs and conditions. This study sets out to explore the conceptualization and implementation of MUF as a boundary object, examining the overall trends at an international level, and scrutinising the national specifics in three case countries: Lithuania, the Netherlands and Sweden. The review of international literature finds no consensus on what MUF is, beyond combining two or more forest functions or uses. The case countries show widely different approaches to conceptualizing and implementing MUF, not least in terms of spatial scales for integrating or segregating various functions. The analysis indicates that we should not expect instrumentation of MUF toward uniform guidelines to shape forestry practices throughout Europe. Rather it will continue to serve the profession as a boundary object that serves as a mediating concept between various interests while being inclusive of a wide set of forestry practices.
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Recombineering and multiplex automated genome engineering (MAGE) offer the possibility to rapidly modify multiple genomic or plasmid sites at high efficiencies. This enables efficient creation of ...genetic variants including both single mutants with specifically targeted modifications as well as combinatorial cell libraries. Manual design of oligonucleotides for these approaches can be tedious, time-consuming, and may not be practical for larger projects targeting many genomic sites. At present, the change from a desired phenotype (e.g. altered expression of a specific protein) to a designed MAGE oligo, which confers the corresponding genetic change, is performed manually. To address these challenges, we have developed the MAGE Oligo Design Tool (MODEST). This web-based tool allows designing of MAGE oligos for (i) tuning translation rates by modifying the ribosomal binding site, (ii) generating translational gene knockouts and (iii) introducing other coding or non-coding mutations, including amino acid substitutions, insertions, deletions and point mutations. The tool automatically designs oligos based on desired genotypic or phenotypic changes defined by the user, which can be used for high efficiency recombineering and MAGE. MODEST is available for free and is open to all users at http://modest.biosustain.dtu.dk.
•We studied the bird communities of Sweden’s protected and production oak forests.•Bird communities in production forests partially overlapped with protected forests.•Vulnerable and near threatened ...bird species occurred in production oak stands.•Production oak stands can complement habitats provided by protected oak forests.•Production oak stands can provide important bird habitats as well as other values.
The oak-dominated woodlands and forests of northern Europe have experienced dramatic declines due to agriculture, urbanization, and conifer-dominated production forestry. These losses have had a substantial negative impact on biodiversity due to the large number of forest species which depend on oak and the environments oak-dominated forests provide. Production oak stands may serve as a means of supplementing or complementing the habitat provided by the limited remaining natural oak remnants in this region. Here we evaluate the extent to which oak plantations in temperate southern Sweden provide habitat and resources for bird communities, by surveying and contrasting the bird species composition and diversity found in mature and young production oak stands (5 and 8 replicates respectively) and protected oak-dominated remnant forests (5 replicates). The mature production stands possessed a bird community partially overlapping in bird species composition, and comparable in species richness (34 species) to that found within protected oak forests (39 species). Furthermore, the production oak forests surveyed hosted threatened or near threatened bird species, including black woodpecker (Dryocopus martius), goldcrest (Regulus regulus), starling (Sturnus vulgaris), and yellowhammer (Emberiza citrinella). Though production oak forests cannot replace the habitat provided by protected oak forests, these stands do appear to provide conditions consistent with the habitat and resource requirements of a diverse cross-section of bird species in this region, including species of substantial conservation concern. Production oak forests thus have the capacity to make a positive contribution to biodiversity conservation, as well as providing a diverse range of goods and services to society.
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Background Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference ...has not been explained. Methods In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval CI = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration–time curve (AUC). Statistical tests were two-sided. Results In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval CI = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM × minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. Conclusion Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
Purpose
Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active ...cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum.
Methods
Ten patients treated with cytoreductive surgery and HIPEC (cisplatin 50 mg/m
2
,doxorubicin 15 mg/m
2
) were recruited. Blood and perfusate samples were drawn during and after HIPEC. Cisplatin analysis was conducted using liquid chromatography (LC) with post-column derivatization with diethyldithiocarbamate and compared with inductively coupled plasma-mass spectrometry (ICP-MS).
Results
The mean half-life (t1/2) of perfusate cisplatin was 18.4 min, with area under the time-concentration curve (AUC) 0–90 min of 2.87 mM·min and estimated 0–60 min of 2.45 mM·min. The absorption t1/2 was 9.0 min for cisplatin and 18.2 min for oxaliplatin. The ratio of total platinum to active cisplatin increased in a linear manner by time of perfusion.
Conclusions
Cisplatin is absorbed quicker than oxaliplatin. Lowering the perfusion time to 60 min does not significantly change the pharmacokinetics of cisplatin, and is therefore to be considered. As the HIPEC perfusion progresses, the ICP-MS technique does not adequately reflect active cisplatin levels in the perfusate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
8.
Pharmacokinetics of oxaliplatin in humans Ehrsson, H; Wallin, I; Yachnin, J
Medical oncology (Northwood, London, England),
2002, Volume:
19, Issue:
4
Journal Article
Peer reviewed
Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients ...given 85 mg/m2 of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration. The maximal blood concentration (C(max)) and terminal half-life (t1/2) were 1.44 +/- 0.20 (SD) microg/mL and 14.1 min (range: 10.2-24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V(ss)) were (means +/- SD) 161 +/- 22 microg min/mL, 32.1 +/- 4.2 L/h/m2, and 0.26 +/- 0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r = 0.746; p = 0.017). Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
To evaluate the perfusate and systemic kinetics of oxaliplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) using a selective analytical technique.
Methods
HIPEC was carried out ...in eight patients by the open abdomen coliseum technique for 30 min at 41.5-43°C with an average of 427 mg/m
2
of oxaliplatin in 5% dextrose solution. Blood and perfusate samples were collected during the perfusion. Additional blood samples were taken up to 2 h after the end of perfusion. The analysis was performed by liquid chromatography and post-column derivatization with N,N-diethyldithiocarbamate using microwave heating.
Results
The mean elimination half-life of oxaliplatin in the perfusate was 29.5 min (range 21.1-41.2 min) and in the peripheral circulation 24.7 min (range 21.7-27.7 min). The ratio of the areas under the time concentration curve in perfusate and blood was 12.8 ± 2.9.
Conclusion
The systemic exposure of oxaliplatin measured after HIPEC using a selective analytical technique is considerably lower than previously reported results obtained by atomic absorption spectroscopy.
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Wilhelmsen L, Johansson S, Rosengren A, Wallin I, Dotevall A, Lappas G (Sahlgrenska University Hospital at Östra, Göteborg University; and Astra Hässle AB, Mölndal; Sweden). Risk factors for ...cardiovascular disease during the period 1985–1995 in Göteborg, Sweden. The GOT‐MONICA Project. J Intern Med 1997; 242: 199–211.
Aims
To report levels of cardiovascular risk factors in 1985, 1990 and 1995 in three population samples in Göteborg, Sweden, and to compare with previous population risk factor levels.
Population
The study was performed within the framework of the WHO MONICA Project which compares risk factor levels as well as the incidence of coronary heart disease and stroke in 38 populations.
Methods
Three random samples of men and women aged 25–34, 35–44, 45–54 and 55–64 comprising 152–218 subjects in each age group who responded to the invitation for screening procedures which included questionnaires, physical and laboratory investigations in 1985, 1990 and 1995.
Results
More men than women had smoked, except for those aged 35–44 where there was no difference between men and women. The proportion of men who had smoked decreased strongly between the first and third investigations (P < 0.0001), particularly amongst the younger age‐groups, with a similar tendency amongst women. In the 25–44‐years age group there was a tendency towards more women than men to be smokers in 1995. Snuff was used by 27% and 19% of men aged 25–34 and 35–44 years, respectively, in 1995. Up to 5% of women used snuff; higher in the younger age groups. More young men than women reported regular physical activity during leisure time with a tendency towards an increase from 1985 to 1995. The proportion of men reporting psychological stress varied little over the study period, but women aged 25–34 reported increased stress from 1985 to 1995. Body weight increased whereas height remained stable and consequently body mass index increased in men and women (P= 0.0001). Similarly, waist:hip ratio (measured in 1990 and 1995 only) also increased (P= 0.0001). Mean systolic and diastolic blood pressure increased with age and there was also a small increase between 1985 and 1995. Systolic blood pressure increased by a mean of 1.24 mmHg per 5‐year period independent of sex and age (P= 0.0001). Antihypertensive treatment increased with age, but was stable between 1985 and 1995. Serum total and LDL cholesterol concentrations increased with age, and there was a nonsignificant tendency also to higher HDL cholesterol concentrations at older ages. Serum total cholesterol concentration declined between 1985 and 1995, and HDL cholesterol declined significantly between 1985 and 1995 in all age groups for men and women only when all age groups were analysed together. Similar to total cholesterol, levels of LDL cholesterol declined between 1985 and 1995 for all ages. Serum triglyceride levels increased for men and women between 1985 and 1995.
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