| 1. |
- Elgendy, Mohamed, et al.
(författare)
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Dual modulation of MCL-1 and mTOR determines the response to sunitinib
- 2017
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 127:1, s. 153-168
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Tidskriftsartikel (refereegranskat)abstract
- Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
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| 2. |
- Gutjahr, Marcus, et al.
(författare)
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Sub‐Permil Interlaboratory Consistency for Solution‐Based Boron Isotope Analyses on Marine Carbonates
- 2021
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Ingår i: Geostandards and Geoanalytical Research. - : John Wiley & Sons. - 1639-4488 .- 1751-908X. ; 45:1, s. 59-75
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Tidskriftsartikel (refereegranskat)abstract
- Boron isotopes in marine carbonates are increasingly used to reconstruct seawater pH and atmospheric pCO2 through Earth’s history. While isotope ratio measurements from individual laboratories are often of high quality, it is important that records generated in different laboratories can equally be compared. Within this Boron Isotope Intercomparison Project (BIIP), we characterised the boron isotopic composition (commonly expressed in δ11B) of two marine carbonates: Geological Survey of Japan carbonate reference materials JCp‐1 (coral Porites) and JCt‐1 (giant clam Tridacna gigas). Our study has three foci: (i) to assess the extent to which oxidative pre‐treatment, aimed at removing organic material from carbonate, can influence the resulting δ11B; (ii) to determine to what degree the chosen analytical approach may affect the resultant δ11B, and (iii) to provide well‐constrained consensus δ11B values for JCp‐1 and JCt‐1. The resultant robust mean and associated robust standard deviation (s*) for un‐oxidised JCp‐1 is 24.36 ± 0.45‰ (2s*), compared with 24.25 ± 0.22‰ (2s*) for the same oxidised material. For un‐oxidised JCt‐1, respective compositions are 16.39 ± 0.60‰ (2s*; un‐oxidised) and 16.24 ± 0.38‰ (2s*; oxidised). The consistency between laboratories is generally better if carbonate powders were oxidatively cleaned prior to purification and measurement.
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| 3. |
- Pallavicini, Nicola, et al.
(författare)
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A high-throughput method for the determination of Os concentrations and isotope ratio measurements in small-size biological samples
- 2013
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Ingår i: Journal of Analytical Atomic Spectrometry. - : Royal Society of Chemistry (RSC). - 0267-9477 .- 1364-5544. ; 28:10, s. 1591-1599
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Tidskriftsartikel (refereegranskat)abstract
- An analytical method allowing multi-element characterization by external calibration, osmium (Os) concentration determination by isotope dilution (ID) and 187Os/188Os isotope abundance ratio measurement from a single sample preparation was developed. The method consists of microwave-assisted, closed-vessel acid digestion of small (0.01-0.4 g dry weight) biological samples spiked with Os solution enriched in a 190Os isotope followed by concentration and Os isotope ratio measurements using double-focusing, sector field inductively coupled plasma mass-spectrometry (ICP-SFMS) operated with methane addition to the plasma and solution nebulization (SN) sample introduction. For samples with Os content below 500 pg, complementary analysis using gas-phase introduction (GPI) on the remaining sample digests was performed. The use of disposable plastic lab ware for sample digestion and analysis by SN ICP-SFMS circumvents Os carry-over effects and improves the sample throughput and cost-efficiency of the method. For a 0.1 g dried sample, Os method limits of detection (MLODs) of 2 pg g -1 and 0.2 pg g-1 were obtained using SN or GPI, respectively. Long-term reproducibility of 187Os/188Os isotope abundance ratio measurements using the GPI approach was better than 1.5% RSD for our in-house control sample (moose kidney) with an Os concentration of approximately 5 pg g-1. Os data for several commercially available reference materials of biological or plant origin (not certified for Os) are presented. The method was used in the large scale bio-monitoring of free-living bank voles from an area affected by anthropogenic Os emissions.
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| 4. |
- Pallavicini, Nicola, et al.
(författare)
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Cadmium isotope ratio measurements in environmental matrices by MC-ICP-MS
- 2014
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Ingår i: Journal of Analytical Atomic Spectrometry. - : Royal Society of Chemistry (RSC). - 0267-9477 .- 1364-5544. ; 29:9, s. 1570-1584
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Tidskriftsartikel (refereegranskat)abstract
- Various stages of an analytical method for high-precision cadmium (Cd) isotope ratio measurements by MC-ICP-MS (sample preparation, matrix separation, instrumental analysis and data evaluation) were critically evaluated and optimized for the processing of carbon-rich environmental samples. Overall reproducibility of the method was assessed by replicate preparation and Cd isotope ratio measurements in various environmental matrices (soil, sediment, Fe-Mn nodules, sludge, kidney, liver, leaves) and was found to be better than 0.1‰ (2σ for δ114Cd/110Cd) for the majority of samples. Cd isotope ratio data for several commercially-available reference materials are presented and compared with previously published results where available. The method was used in a pilot study focusing on the assessment of factors affecting Cd isotope composition in tree leaves. A summary of results obtained for a large number (n > 80) of birch (Betula pubescenes) leaves collected from different locations in Sweden and through the entire growing season is presented and potential reasons for observed variability in Cd isotope composition are discussed. Seasonal dynamics of element concentrations and isotope compositions in leaves were also compared for Os, Pb, Zn and Cd.
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| 5. |
- Pallavicini, Nicola
(författare)
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Isotope analysis of trace and ultra-trace elements in environmental matrices
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- High precision isotope ratio measurements have found increasing application in various branches of science, from classical isotope geochronology to complex multi-tracer experiments in environmental studies. Progress in analytical technologies in recent years has allowed higher quality data to be obtained through mass spectrometry. Major pitfalls lie in challenges to obtain accurate and reliable isotopic data for trace and ultra-trace element by inductively coupled plasma sector field mass spectrometry (ICP-SFMS) and multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). Sources of errors must therefore be accurately evaluated and avoided at every procedural step. The present study has been focused on analytical method development, optimization and evaluation (including sample preparation, matrix separation, instrumental analysis and data evaluation stages) for isotopic and multi-elemental analyses in environmental samples at trace and ultra-trace levels. The first method tested and optimized has allowed obtaining both osmium concentration and isotopic ratio (187Os/188Os) data together with broad multi-elemental characterization of samples. The procedure was as follows: digestion of small biological samples spiked with Os (enriched in 190Os) followed by concentration and Os isotope measurements by ICP- SFMS, operated with solution nebulization (SN) introduction system and methane addition to the plasma. A specific gas-phase introduction (GPI) system was adopted for samples with low analyte content (<500 pg) for isotopic measurements. Memory effects were avoided with implementation of disposable plastic lab ware. This resulted in a relatively inexpensive and rapid method with high sample throughput capability. SN method limit of detection (MLOD) did not improve compared to previous studies (2 pg g-1), while a MLOD of 0.2 pg g-1 obtained with GPI represents an important improvement, especially taking into account potential further gains due to refined digestion stage. Method reproducibility for 187Os/188Os evaluated using in-house control samples was better than 1.5% RSD. The method, successively applied to a large scale bio-monitoring case, confirmed the presence of an anthropogenic Os in animals from an area affected by emissions from a stainless steel foundry. The second method has been focused on Cd concentration and isotope ratio measurements. Different analytical stages were critically evaluated and optimized for processing carbon-rich environmental samples. Several digestion methods were tested (high pressure ashing, microwave, ultrawave and ashing) followed by ion-exchange chromatography to separate analyte from matrix. Concentrations were measured by ICP-SFMS and subsequently isotopic ratio measurements were performed using Neptune Plus MC-ICP-MS. The latter was tested with two different introduction configurations: a standard SN system and a high sensitivity setup (Aridus II desolvating nebulizer). Overall reproducibility of the method was assessed by replicate preparation and Cd isotope ratio measurements in various environmental matrices (soil, sediments, Fe-Mn nodules, sludge, kidney, liver, leaves, mushroom, lichen) and was found to be better than 0.1‰ (2σ for δ114Cd/110Cd) for the majority of samples. Purification performances were evaluated by analyzing the different elution fractions collected at each separation step by ICP-SFMS. Cadmium recovery in the purified fraction was above 95% for all samples analyzed. Spectrally interfering elements such as Mo and Sn might partially co-elute in the Cd fraction and their effect on isotope ratios was carefully investigated. Though the use of a desolvating nebulizer increases the instrumental sensitivity and reduces oxide formation, at the same time it resulted in degraded in-run precision because of poorer signal stability. Accuracy was difficult to assess due to the absence of certified Cd isotopic values. Therefore, Cd isotope data for several commercially-available reference materials are presented and compared with previously published results where available. The method was then applied to variety of biological samples including birch leaves (Betula pubescenes) collected from various locations and different seasons. Birch leaves showed fractionation towards heavier isotopes with a mean δ114Cd/110Cd of 0.7‰ and found to be influenced by seasonal variations. The reason for such fractionation is assumed to be derived from sample uptake through the root system and translocation in the plant. Cd isotopic patterns were compared with other isotopic systems (Zn, Os, Pb) to provide a more comprehensive view of the observed variations.
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| 6. |
- Pallavicini, Nicola, 1983-
(författare)
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Method development for isotope analysis of trace and ultra-trace elements in environmental matrices
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The increasing load of toxic elements entering the ecosystems, as a consequence of anthropogenic processes, has grown public awareness in the last decades, resulting in a great number of studies focusing on pollution sources, transport, distribution, interactions with living organisms and remediation. Physical/chemical processes that drive the uptake, assimilation, compartmentation and translocation of heavy metals in biota has received a great deal of attention recently, since elemental concentrations and isotopic composition in biological matrices can be used as probes of both natural and anthropogenic sources. Further they can help to evaluate fate of contaminants and to assess bioavailability of such elements in nature. While poorly defined isotopic pools, multiple sources and fractionating processes add complexity to source identification studies, tracing is hindered mainly by poorly known or unidentified fractionating factors.High precision isotope ratio measurements have found increasing application in various branches of science, from classical isotope geochronology to complex multi-tracer experiments in environmental studies. Instrumental development and refining separation schemes have allowed higher quality data to be obtained and played a major role in the recent progress of the field. The use of modern techniques such as inductively coupled plasma sector field mass spectrometry (ICP-SFMS) and multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) for trace and ultra-trace element concentrations and isotope ratio measurements have given new opportunities. However, sources of errors must be accurately evaluated and avoided at every procedural step. Moreover, even with the utilization of sound analytical measurement protocols, source and process tracing in natural systems can be complicated further by spatial and temporal variability.The work described in the present thesis has been focused primarily on analytical method development, optimization and evaluation (including sample preparation, matrix separation, instrumental analysis and data evaluation stages) for isotopic and multi-elemental analyses in environmental samples at trace and ultra-trace levels. Special attention was paid to evaluate strengths and limitations of the methods as applied to complex natural environments, aiming at correct interpretation of isotopic results in environmental forensics. The analytical protocols covered several isotope systems of both stable (Cd, B, Cr, Cu, Fe, Tl and Zn) and radiogenic (Os, Pb and Sr) elements.Paper I was dedicated to the optimization and testing of a rapid and high sample throughput method for Os concentrations and isotope measurements by ICP-SFMS. If microwave (MW) digestion followed by sample introduction to ICP-SFMS by traditional solution nebulization (SN) offered unparalleled throughput important for processing large number of samples, high-pressure ashing (HPA) combined with gas-phase introduction (GPI) proved to be advantageous for samples with low (below 500 pg) analyte content. The method was applied to a large scale bio-monitoring case, confirming accumulation of anthropogenic Os in animals from an area affected by emissions from a stainless steel foundry.The method for Cr concentrations and isotope ratios in different environmental matrices was optimized in Paper II. A coupling between a high pressure/temperature acid digestion and a one pass, single column matrix separation allowed the analysis of chromites, soils, and biological matrices (first Cr isotope study in lichens and mosses) by ICP-SFMS and MC-ICP-MS. With an overall reproducibility of 0.11‰ (2σ), the results suggested a uniform isotope composition in soil depth profiles. On the other hand a strong negative correlation found between δ53Cr and Cr concentrations in lichens and mosses indicates that airborne Cr from local anthropogenic source(s) is depleted in heavy isotopes, therefore highlighting the possibility of utilization of Cr isotopes to trace local airborne pollution source from steel foundries. Paper III describes development of high-precision Cd isotope ratio measurement by MC-ICP-MS in a variety of environmental matrices. Several digestion methods (HPA, MW, ultrawave and ashing) were tested for sample preparation, followed by analyte separation from matrix using ion-exchange chromatography. The reproducibility of the method (2σ for δ114Cd/110Cd) was found to be better than 0.1‰. The method was applied to a large number of birch leaves (n>80) collected at different locations and growth stages. Cd in birch leaves is enriched in heavier isotopes relative to the NIST SRM 3108 Cd standard with a mean δ114Cd/110Cd of 0.7‰. The fractionation is assumed to stem from sample uptake through the root system and element translocation in the plant and it exhibits profound between-tree as well as seasonal variations. The latter were compared with seasonal isotopic variations for other isotopic systems (Zn, Os, Pb) in the same trees to aid a better understanding of underlying processes.In Paper IV the number of isotope systems studied was extended to include B, Cd, Cu, Fe, Pb, Sr, Tl and Zn. The analytical procedure utilized a high pressure acid digestion (UltraCLAVE), which provides complete oxidation of the organic material in biological samples, and a two-column ion-exchange separation which represents further development of the separation scheme described in Paper III. Such sample preparation ensures low blank levels, efficient separation of matrix elements, sufficiently high analyte recoveries and reasonably high sample throughput. The method was applied to a large number of biological samples (n>240) and the data obtained represent the first combined characterization of variability in isotopic composition for eight elements in leaves, needles, lichens and mushrooms collected from a geographically confined area.To further explore the reason of variability observed, soil profiles from the same area were analyzed for both concentrations and isotopic compositions of B, Cd, Cr, Cu, Fe, Pb, Sr, Tl and Zn in Paper V. Results of this study suggest that the observed high variability can be dependent on operationally-defined fractions (assessed by applying a modified SEP to process soil samples) and on the typology of the individual matrix analyzed (assessed through the coupling of soil profile results to those obtained for other matrices: lysimetric waters, mushrooms, litter, needles, leaves and lichens).The method development conducted in this work highlights the importance of considering all possible sources of biases/errors as well as possibility to use overlapping sample preparation schemes for multi-isotope studies. The results obtained for different environmental matrices represent a starting point for discussing the role of natural isotopic variability in isotope applications and forensics, and the importance of in-depth knowledge of the multiple parameters affecting the variability observed.
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| 7. |
- Pallavicini, Nicola, et al.
(författare)
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Ranges of B, Cd, Cr, Cu, Fe, Pb, Sr, Tl, and Zn Concentrations and Isotope Ratios in Environmental Matrices from an Urban Area
- 2018
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Ingår i: Journal of Spectroscopy. - : Hindawi Publishing Corporation. - 2314-4920 .- 2314-4939. ; , s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Isotopic information may provide powerful insight into the elemental cycling processes which occur in natural compartments. Further implementation of isotopic techniques in natural sciences requires a better understanding of the range of elemental and isotopic compositional variability in environmental matrices. This study assesses the local-scale concentration and isotopic composition variability of nine elements: boron (B), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), strontium (Sr), thallium (Tl), and zinc (Zn) in lysimetric waters, mushrooms, litter, needles, leaves, and lichens. Sequential extractions were also performed on soil samples from 6 depth profiles providing more detailed information on the variability of elemental concentrations and isotope ratios between the elemental pools present in soil. For most of the sample types studied the range of isotopic variability between samples spans almost the entire ranges reported in the literature for natural samples. These results represent a starting point for discussing the role of natural variability in isotopic studies (for example, as a limiting factor in the use of isotopic mixing models) and a baseline for future in-depth studies examining the controls on isotope fraction in natural systems
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| 8. |
- Pontér, Simon, et al.
(författare)
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Chromium isotope ratio measurements in environmental matrices by MC-ICP-MS
- 2016
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Ingår i: Journal of Analytical Atomic Spectrometry. - 0267-9477 .- 1364-5544. ; 31:7, s. 1464-1471
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Tidskriftsartikel (refereegranskat)abstract
- An analytical procedure consisting of high pressure/temperature acid digestion using an UltraCLAVE system and a one pass, single column matrix separation using DOWEX AG 1X8 anion exchange resin was applied to the determination of Cr concentrations and δ53Cr in chromites, soils, and biological matrices (epiphytic lichens and mosses) using a combination of ICP-SFMS and MC-ICP-MS. The overall reproducibility of the method was assessed by replicate preparation and Cr isotope ratio measurements performed by different operators in multiple analytical sessions over a few months and was found to be 0.11‰ (2σ). The accuracy was evaluated using commercially available reference materials for which measured data were compared with certified values (for Cr concentrations) and previously published results (for isotope data). The results demonstrate a uniform Cr isotope composition in soil depth profiles sampled in different urban environments. A strong negative correlation between δ53Cr and Cr concentrations in lichens and mosses indicates that airborne Cr from local anthropogenic source(s) is depleted in heavy isotopes.
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| 9. |
- Pontér, Simon, et al.
(författare)
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Chromium isotope ratio measurements in environmental matrices by MC-ICP-MS
- 2016
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Ingår i: Journal of Analytical Atomic Spectrometry. - : Royal Society of Chemistry (RSC). - 0267-9477 .- 1364-5544. ; 31:7, s. 1464-1471
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Tidskriftsartikel (refereegranskat)abstract
- An analytical procedure consisting of high pressure/temperature acid digestion using an UltraCLAVE system and a one pass, single column matrix separation using DOWEX AG 1X8 anion exchange resin was applied to the determination of Cr concentrations and delta Cr-53 in chromites, soils, and biological matrices (epiphytic lichens and mosses) using a combination of ICP-SFMS and MC-ICP-MS. The overall reproducibility of the method was assessed by replicate preparation and Cr isotope ratio measurements performed by different operators in multiple analytical sessions over a few months and was found to be 0.11 parts per thousand (2 sigma). The accuracy was evaluated using commercially available reference materials for which measured data were compared with certified values (for Cr concentrations) and previously published results (for isotope data). The results demonstrate a uniform Cr isotope composition in soil depth profiles sampled in different urban environments. A strong negative correlation between delta Cr-53 and Cr concentrations in lichens and mosses indicates that airborne Cr from local anthropogenic source(s) is depleted in heavy isotopes.
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| 10. |
- Rodushkin, Ilia, et al.
(författare)
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Application of double-focusing sector field ICP-MS for determination of ultratrace constituents in samples characterized by complex composition of the matrix
- 2018
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Ingår i: Science of the Total Environment. - : ELSEVIER SCIENCE BV. - 0048-9697 .- 1879-1026. ; 622-623, s. 203-213
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Tidskriftsartikel (refereegranskat)abstract
- The performance of double focusing, sector fieldmass spectrometry (ICP-SFMS) for determination of analytes, including technology critical elements (TCE), at ultra-trace levels in environmental and clinical matrices was critically evaluated. Different configurations of the ICP-SFMS introduction system as well as various sample preparations, pre-concentration andmatrix separation methods were employed and compared. Factors affecting detection capabilities and accuracy of data produced (instrumental sensitivity, contamination risks, purity of reagents, spectral interferences, matrix effects, analyte recovery and losses) were discussed. Optimized matrixspecific methods were applied to a range of reference and control materials (riverine, brackish and seawaters; whole blood, serumand urine) as well as tap water and snow samples collected in the area of Lulea city, northern Sweden; brackish and seawater from the Laptev Sea; venous blood samples with a special emphasis on determination of Au, Ag, Ir, Os, Pd, Pt, Re, Rh, Ru, Sb and Te. Even though these low abundant elements are relatively under-documented, the results produced were compared with published data, where available.
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| 11. |
- Rodushkin, Ilia, et al.
(författare)
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Assessment of the natural variability of B, Cd, Cu, Fe, Pb, Sr, Tl and Zn concentrations and isotopic compositions in leaves, needles and mushrooms using single sample digestion and two-column matrix separation
- 2016
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Ingår i: Journal of Analytical Atomic Spectrometry. - 0267-9477 .- 1364-5544. ; 31:1, s. 220-233
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Tidskriftsartikel (refereegranskat)abstract
- An analytical procedure allowing multi-elemental analyses and isotope ratio measurements of eight of these (B, Cd, Cu, Fe, Pb, Sr, Tl and Zn) in matrices relevant for bio-monitoring using a single highpressure acid digestion was developed. Method blanks, separation efficiency of matrix elements, repeatability and reproducibility were evaluated using sets of preparation blanks, certified reference materials and duplicate samples prepared and analyzed over a period of several months. The method was used to assess the natural variability of concentrations and isotopic compositions in bio-indicators (tree leaves, needles and mushrooms, over 240 samples) collected mainly from a confined area in North-East Sweden. Ranges found from leaves and needles were compared with data obtained for limited numbers of samples collected in Spain, Italy, France, United Kingdom and Iceland.
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