| 1. |
- Belfrage, Emma, et al.
(författare)
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Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE) : Protocol for a Translational Study
- 2024
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Ingår i: JMIR Research Protocols. - 1929-0748. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin. Mycosis fungoides (MF) is the most common form of CTCL and Sézary syndrome (SS) is more infrequent. Early stages (IA-IIA) have a favorable prognosis, while advanced stages (IIB-IVB) have a worse prognosis. Around 25% of patients with early stages of the disease will progress to advanced stages. Malignant skin-infiltrating T-cells in CTCL are accompanied by infiltrates of nonmalignant T-cells and other immune cells that produce cytokines that modulate the inflammation. Skin infection, often with Staphylococcus aureus, is frequent in advanced stages and can lead to sepsis and death. S. aureus has also been reported to contribute to the progression of the disease. Previous reports indicate a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier in CTCL. Treatment response is highly variable and often unpredictable, and there is a need for new predictive and prognostic biomarkers.OBJECTIVE: This prospective translational study aims to identify prognostic biomarkers in the blood and skin of patients with MF and SS.METHODS: The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study aims to recruit 120 adult patients with MF or SS and a control group of 20 healthy volunteers. The treatments will be given according to clinical routine. The sampling of each patient will be performed every 3 months for 3 years. The blood samples will be analyzed for lactate dehydrogenase, immunoglobulin E, interleukins, thymus and activation-regulated chemokine, and lymphocyte subpopulations. The lymphoma microenvironment will be investigated through digital spatial profiling and single-cell RNA sequencing. Microbiological sampling and analysis of skin barrier function will be performed. The life quality parameters will be evaluated. The results will be evaluated by the stage of the disease.RESULTS: Patient inclusion started in 2021 and is still ongoing in 2023, with 18 patients and 20 healthy controls enrolled. The publication of selected translational findings before the publication of the main results of the trial is accepted.CONCLUSIONS: This study aims to investigate blood and skin with a focus on immune cells and the microbiological environment to identify potential new prognostic biomarkers in MF and SS.TRIAL REGISTRATION: ClinicalTrials.gov NCT04904146; https://www.clinicaltrials.gov/study/NCT04904146.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55723.
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| 2. |
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| 3. |
- Drott, Andreas, et al.
(författare)
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Do Potential Methylation Rates Reflect Accumulated Methyl Mercury in Contaminated Sediments?
- 2008
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 42:1, s. 153-158
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Tidskriftsartikel (refereegranskat)abstract
- Relationships between the short-term mono-methyl mercury (MeHg) production, determined as the specific, potential methylation rate constant Km (day−1) after 48 h of incubation with isotope-enriched 201Hg(II) at 23 °C, and the long-term accumulation of ambient MeHg, were investigated in contaminated sediments. The sediments covered a range of environments from small freshwater lakes to large brackish water estuaries and differed with respect to source and concentration of Hg, salinity, primary productivity, quantity and quality of organic matter, and temperature climate. Significant (p < 0.001), positive relationships were observed between Km (day−1) and the concentration of MeHg normalized to total Hg (%MeHg) for surface sediments (0–10, 0–15, and in one case 0–20 cm) across all environments, and across subsets of organic and minerogenic freshwaters. This suggests that the methylation process (MeHg production) overruled demethylation and net transport processes in the surface sediments. The lack of a relationship between Km and %MeHg in two brackish water sediment depth profiles (0–100 cm) indicates that demethylation and the net effect of input−output are relatively more important at greater depths. Differences in the primary production and subsequent availability of easily degradable organic matter (serving as electron donor for methylating bacteria) was indicated to be the most important factor behind observed differences in %MeHg and Km among sites. In contrast, concentrations of sulfate were not correlated to Km, %MeHg, or absolute concentrations of MeHg. We conclude that total concentrations of Hg are of importance for the long-term accumulation of MeHg, and that %MeHg in surface sediments can be used as a proxy for the rate of methylation, across a range of sites from different environments.
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| 4. |
- Drott, Andreas, et al.
(författare)
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Effects of oxic and anoxic filtration on determined methyl mercury concentrations in sediment pore waters
- 2007
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Ingår i: Marine Chemistry. - : Elsevier BV. - 0304-4203. ; 103, s. 76-83
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Tidskriftsartikel (refereegranskat)abstract
- Accurate determination of methyl mercury (MeHg) concentrations in sediment pore waters is crucial for an improved understanding of mercury (Hg) biogeochemistry, and for improved risk assessment of Hg contaminated sites. In the present study, effects of oxic (air) and anoxic (N2) filtration (after centrifugation) on determined pore water MeHg concentrations were investigated in severely Hg contaminated pulp fibre sediments from two estuaries of the Bothnian Sea, Sweden. MeHg was determined in the filtrate using species-specific isotope dilution gas chromatography inductively coupled plasma mass spectrometry (SSID–GC–ICPMS), after ethylation with sodium tetraethylborate. Determined concentrations of MeHg were greater after anoxic filtration than after oxic filtration for all samples investigated, with MeHg(N2)/MeHg(air) ratios ranging between 3.4 and 343. Adsorption to newly formed Fe(III)/Mn(III/IV)-oxy/hydroxide surfaces is proposed as the main mechanism responsible for MeHg removal during oxic filtration. This is supported by decreases in dissolved Fe and Mn concentrations during oxic filtration, and by decreases in dissolved sulphur concentrations during oxic filtration in the samples with largest effect on MeHg concentrations. The latter is explained by adsorption of SO42− to newly formed Fe(III)/Mn(III/IV)-oxy/hydroxide surfaces. The effect of oxidation during filtration on pore water MeHg concentrations was largest in samples in which FeS(s) was not present, but with calculated pe-values below − 3. Thus, our results indicate that the largest errors with respect to pore water MeHg concentrations when filtering in air can be expected in samples with an intermediate redox potential, possibly buffered by a mixture of oxidation sensitive Fe(II/III) minerals.
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| 5. |
- Drott, Andreas, et al.
(författare)
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Importance of Dissolved Neutral Mercury Sulfides for Methyl Mercury Production in Contaminated Sediments
- 2007
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 41:7, s. 2270-6
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Tidskriftsartikel (refereegranskat)abstract
- Biotic transformation of inorganic mercury, Hg(II), to mono methyl mercury (MeHg) is proposed to be largely controlled by passive uptake of neutral Hg complexes by sulfate reducing bacteria (SRB). In this study, the chemical speciation of Hg(II) in seven locally contaminated sediments covering environments such as (i) brackish water, (ii) low-productivity freshwater, and, (iii) high-productivity freshwater was related to potential Hg methylation rates, determined by incubation at 23 C for 48 h under N2(g), and to total MeHg concentrations in sediments. Pore water speciation was modeled considering Hg complexes with halides, organic thiols [Hg(SR)2(aq), associated to dissolved organic matter], monosulfides, and bisulfides. The sum of neutral mercury sulfides [Hg(SH)20(aq)] and [HgS0(aq)] was significantly, positively (p < 0.001, n = 20) correlated to the specific methylation rate constant (Km, day-1) at depths of 5-100 cm in two brackish water sediments. Total Hg, total mercury sulfides or Hg(SR)2(aq) in pore water gave no significant relationships with Km. In two sub-sets of freshwater sediments, neutral mercury sulfides were positively correlated to total Hg in pore water, and therefore, total Hg also gave significant relationships with Km. The sum of [Hg(SH)20(aq)] and [HgS0(aq)] was significantly, positively correlated to total sediment MeHg (g kg-1) in brackish waters (p < 0.001, n = 23), in southern, high-productivity freshwaters (p < 0.001, n = 20), as well as in northern, low-productivity freshwater (p = 0.048, n = 6). The slopes (b, b') of the relationships Km (day-1) = a + b([Hg(SH)20(aq)] + [HgS0(aq)]) and MeHg (g kg-1) = a' + b'([Hg(SH)20(aq)] + [HgS0(aq)]) showed an inverse relationship with the C/N ratio, supposedly reflecting differences in primary production and energy-rich organic matter availability among sites. We conclude that concentrations of neutral inorganic mercury sulfide species, together with the availability of energy-rich organic matter, largely control Hg methylation rates in contaminated sediments. Furthermore, Hg(SH)20(aq) is suggested to be the dominant species taken up by MeHg producing bacteria in organic-rich sediments without formation of HgS(s).
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| 6. |
- Drott, Andreas, et al.
(författare)
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Potential demethylation rate determinations in relation to concentrations of MeHg, Hg and pore water speciation of MeHg in contaminated sediments
- 2008
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Ingår i: Marine Chemistry. - : Elsevier. - 0304-4203 .- 1872-7581. ; 112:1-2, s. 93-101
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Tidskriftsartikel (refereegranskat)abstract
- Specific, potential demethylation rate constants (kd, day− 1) were determined in fresh and brackish water sediments from seven different sites in Sweden originally contaminated with either Hg0(l) or phenyl-Hg. Variations in kd among and within sites were related to ambient concentrations of Hg (1–1143 nmol g− 1) and MeHg (4.4–575pmol g− 1), and to pore water speciation of MeHg. Chemical speciation modeling revealed that MeHgSH(aq), MeHgS−(aq) and MeHg–thiol complexes [MeHgSR(aq)] associated to dissolved organic matter were the dominant MeHg species in the sediment pore water at all sites. Potential rates of MeHg demethylation were determined as the decomposition of isotopically enriched Me204HgCl during 48 h of incubation in darkness under N2(g) at 23 °C. There was a significant (p < 0.001) positive relationship between ambient MeHg concentrations in sediments and kd across all sites, but no significant relationship between ambient Hg and kd. At the three sites with the highest ambient Hg concentrations in sediments (average ± SD, 185 ± 249 nmol g− 1), kd was not significantly correlated with pore water MeHg speciation. At sites with lower concentrations of ambient Hg in sediments (average ± SD, 11 ± 8.4 nmol g− 1), there was a significant (p = 0.02) positive relationship between calculated concentrations of MeHgSH(aq), MeHgS−(aq), or the sum of these two species, and kd. If it is assumed that an oxidative demethylation process dominated at sites with lower concentrations of ambient Hg in sediments, the results suggest that it may be dependent on a passive uptake of inorganic MeHgSH molecules. It was shown that additions of different amounts of MeHg and Hg tracers, in relation to the ambient concentrations of MeHg and Hg, could result in dramatically different kd values within and between sites. At one brackish water site, both absolute demethylation rates and kds were significantly, inversely related to ambient concentrations of MeHg (and Hg). In contrast, at another brackish water site with generally less kds, samples with low ambient MeHg experienced toxic effects and demethylation was not detected. This implies that added (and possibly ambient) MeHg/Hg, depending on the environmental conditions, may have either stimulating or inhibitory effects on demethylation processes.
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| 7. |
- Drott, Andreas, et al.
(författare)
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Refining Thermodynamic Constants for Mercury(II)-Sulfides in Equilibrium with Metacinnabar at Sub-Micromolar Aqueous Sulfide Concentrations
- 2013
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 47:9, s. 4197-4203
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Tidskriftsartikel (refereegranskat)abstract
- An important issue in mercury (Hg) biogeochemistry is to explore the influence of aqueous Hg(II) forms on bacterial uptake, and subsequent methyl mercury formation, under iron(III) and sulfate reducing conditions. The success of this is dependent on relevant information on the thermodynamic stability of Hg-sulfides. In the present study, we determined the solubility of a commercially available HgS(s) phase, which was shown by X-ray diffraction to be a mixture of 83% metacinnabar and 17% cinnabar. At aqueous sulfide concentrations between 0.060 and 84 µM, well below levels in previous studies, we report a solubility product (log Ksp±SE) of -36.8±0.3 (HgS(s) + H+ = Hg2+ + HS-, I=0, T=25°C, pH 6-10, n=20) for metacinnabar. This value is 0.7 log units higher than previous estimates. Complementing our data with data from Paquette and Helz (1997), we took advantage of a large data set (n=65) covering a wide range of aqueous sulfide (0.06 µM-140 mM), and pH (1-11). Based on this we report refined formation constants (±SE) for the three aqueous Hg(II)-sulfide species proposed by Schwarzenbach and Widmer (1963): Hg2+ + 2HS- = Hg(SH)20; log K = 39.1±0.1, Hg2+ + 2HS- = HgS2H- + H+; log K = 32.5±0.1, Hg2+ + 2HS- = HgS22- + 2H+; log K = 23.2±0.1. Our refined log K values differ from previous estimates by 0.2-0.6 log units. Furthermore, at the low sulfide concentrations in our study we could rule out the value of -10.0 for the reaction HgS(s) + H2O = HgOHSH(aq), as reported by Dyrssén and Wedborg (1991). By establishing a solubility product for the most environmentally relevant HgS(s) phase, metacinnabar, and extending the range of aqueous sulfide concentrations to sub-µM levels, relevant for soils, sediments and waters, this study decreases the uncertainty in stability constants for Hg-sulfides, thereby improving the basis for understanding the bioavailability and mobility of Hg(II) in the environment.
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| 8. |
- Fernández-Gómez, Cristal, et al.
(författare)
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Towards Universal Wavelength-Specific Photodegradation Rate Constants for Methyl Mercury in Humic Waters, Exemplified by a Boreal Lake-Wetland Gradient.
- 2013
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 47:12, s. 6279-6287
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Tidskriftsartikel (refereegranskat)abstract
- We report experimentally determined first-order rate constants of MeHg photolysis in three waters along a Boreal lake-wetland gradient covering a range of pH (3.8-6.6), concentrations of total organic carbon (TOC 17.5-81 mg L(-1)), total Fe (0.8-2.1 mg L(-1)), specific UV254 nm absorption (3.3-4.2 L mg(-1) m(-1)) and TOC/TON ratios (24-67 g g(-1)). Rate constants determined as a function of incident sunlight (measured as cumulative photon flux of photosynthetically active radiation, PAR) decreased in the order dystrophic lake > dystrophic lake/wetland > riparian wetland. After correction for light attenuation by dissolved natural organic matter (DOM), wavelength-specific (PAR: 400-700 nm, UVA: 320-400 nm and UVB: 280-320 nm) first-order photodegradation rate constants (kpd) determined at the three sites were indistinguishable, with average values (±SE) of 0.0023 ± 0.0002, 0.10 ± 0.024 and 7.2 ± 1.3 m(2) E(-1) for kpdPAR, kpdUVA, and kpdUVB, respectively. The relative ratio of kpdPAR, kpdUVA, and kpdUVB was 1:43:3100. Experiments conducted at varying MeHg/TOC ratios confirm previous suggestions that complex formation with organic thiol groups enhances the rate of MeHg photodegradation, as compared to when O and N functional groups are involved in the speciation of MeHg. We suggest that if the photon fluxes of PAR, UVA, and UVB radiation are separately determined and the wavelength-specific light attenuation is corrected for, the first-order rate constants kpdPAR, kpdUVA, and kpdUVB will be universal to waters in which DOM (possibly in concert with Fe) controls the formation of ROS, and the chemical speciation of MeHg is controlled by the complexation with DOM associated thiols.
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| 9. |
- Kronberg, Rose-Marie, et al.
(författare)
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Forest harvest contribution to Boreal freshwater methyl mercury load
- 2016
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 30:6, s. 825-843
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Tidskriftsartikel (refereegranskat)abstract
- Effects of Boreal forest harvest on mercury (Hg) and methyl mercury (MeHg) soil pools and export by stream runoff were quantified by comparing 10 reference watersheds (REFs) covered by >80year old Norway spruce (Picea abies Karst.) forests with 10 similar watersheds subjected to clear-cutting (CCs). While total Hg soil storage did not change, MeHg pools increased seven times (p=0.006) in the organic topsoil 2 years after clear-cutting. In undulating terrain, situated above the postglacial marine limit (ML) of the ancient Baltic Sea, the mass ratio between flux-weighted MeHg and dissolved organic carbon (MeHg/DOC) in stream runoff increased 1.8 times (p<0.004) as a consequence of forest harvest. When recalculated to 100% clear-cutting of the watershed, the annual MeHg stream export increased 3.8 times (p=0.047). Below the ML, where the terrain was flatter, neither the MeHg/DOC ratio nor the annual export of MeHg differed between REFs and CCs, likely because of the larger contribution of MeHg exported from peaty soils and small wetlands. The most robust measure, MeHg/DOC, was used to calculate MeHg loadings to Boreal headwaters. If the forest harvest effect lasts 10years, clear-cutting increases MeHg runoff by 12-20% in Sweden and 2% in the Boreal zone as a whole. In Sweden, having intensely managed forests, 37% and 56% of MeHg are exported from peatlands and forest soils, respectively, and forest clear-cutting is adding another 6.6%. In the Boreal zone as a whole peatlands and forests soils contribute with 53% and 46%, respectively, and clear-cutting is estimated to add another 1.0%. An expected rapid increase in Boreal forest harvest and disturbance urge for inclusion of land use effects in mercury biogeochemical cycling models at different scales.
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| 10. |
- Kronberg, Rose-Marie, et al.
(författare)
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Net degradation of methyl mercury in alder swamps
- 2012
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 46:24, s. 13144-13151
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Tidskriftsartikel (refereegranskat)abstract
- Wetlands are generally considered to be sources of methyl mercury (MeHg) in northern temperate landscapes. However, a recent input-output mass balance study during 2007-2010 revealed a black alder (Alnus glutinosa) swamp in southern Sweden to be a consistent and significant MeHg sink, with a 30-60% loss of MeHg. The soil pool of MeHg varied substantially between years, but it always decreased with distance from the stream inlet to the swamp. The soil MeHg pool was significantly lower in the downstream as compared to the upstream half of the swamp (0.66 and 1.34 ng MeHg g(-1) SOC(-1) annual average(-1), respectively, one-way ANOVA, p = 0.0006). In 2008 a significant decrease of %MeHg in soil was paralleled by a significant increase in potential demethylation rate constant (k(d), p < 0.02 and p < 0.004, respectively). In contrast, the potential methylation rate constant (k(m)) was unrelated to distance (p = 0.3). Our results suggest that MeHg was net degraded in the Alnus swamp, and that it had a rapid and dynamic internal turnover of MeHg. Snapshot stream input-output measurements at eight additional Alnus glutinosa swamps in southern Sweden indicate that Alnus swamps in general are sinks for MeHg. Our findings have implications for forestry practices and landscape planning, and suggest that restored or preserved Alnus swamps may be used to mitigate MeHg produced in northern temperate landscapes.
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| 11. |
- Madestam, Andreas, et al.
(författare)
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Do Political Protests Matter? : Evidence from the Tea Party Movement
- 2013
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Ingår i: Quarterly Journal of Economics. - : Oxford University Press (OUP). - 0033-5533 .- 1531-4650. ; 128:4, s. 1633-1685
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Tidskriftsartikel (refereegranskat)abstract
- Can protests cause political change, or are they merely symptoms of underlying shifts in policy preferences? We address this question by studying the Tea Party movement in the United States, which rose to prominence through coordinated rallies across the country on Tax Day, April 15, 2009. We exploit variation in rainfall on the day of these rallies as an exogenous source of variation in attendance. We show that good weather at this initial, coordinating event had significant consequences for the subsequent local strength of the movement, increased public support for Tea Party positions, and led to more Republican votes in the 2010 midterm elections. Policy making was also affected, as incumbents responded to large protests in their district by voting more conservatively in Congress. Our estimates suggest significant multiplier effects: an additional protester increased the number of Republican votes by a factor well above 1. Together our results show that protests can build political movements that ultimately affect policy making and that they do so by influencing political views rather than solely through the revelation of existing political preferences.
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| 12. |
- Nilsson, Helena Jernmark, et al.
(författare)
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The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:50, s. 87136-87150
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Tidskriftsartikel (refereegranskat)abstract
- The Wilms' tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
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| 13. |
- Papmehl-Dufay, Ludvig, 1976-, et al.
(författare)
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Hos trälar och stormän : Arkeologisk undersökning i Gamla Skogsby september och oktober 2020
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report presents the results from an archaeological excavation in 2020 of an Iron Age house foundation at Gamla Skogsby, Öland, Sweden. The investigated area is rich in prehistoric remains, not least from the mid-Iron Age and the Migration Period which is the period of concern here (c. AD 400–550). The excavation follows that which was initiated at the site in 2019 (Papmehl-Dufay 2020). The house investigated is part of a large farm, just next to an exceptionally large building usually regarded as a cheiftains hall. The finds from the excavation are numerous, including a large animal bone assemblage as well as unusually large amounts of household pottery. As was the case during the excavation in 2019, the bulk of the finds are of ”household” character with an emphasis on preparation of food. The results of the osteological analysis reveal an unusually large proportion of pig bones, which was an important source of meat in connection to Iron Age feasting. Several deposits of animal bones were found suggesting elaborate ritual activities at the site, including the offering of several sheep in connection to the building of the house as well as the offering of a horse in connection to its abandonment. The pottery assemblage includes a large number of vessels of which unusually large portions are preserved, allowing for a detailed analysis of vessel shapes in the Migration Period.The results reinforces the idea of Gamla Skogsby as a major farm in the area in the Migration period, potentially relevant in discussion on the social and cultural context of the Sandby borg massacre that ocurred on eastern land in the same period.
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| 14. |
- Scialdone, Annarita, et al.
(författare)
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Depletion of the transcriptional coactivators CREB-binding protein or EP300 downregulates CD20 in diffuse large B-cell lymphoma cells and impairs the cytotoxic effects of anti-CD20 antibodies
- 2019
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 79, s. 1-46
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Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies targeting CD20 are central in the treatment of B-cell lymphomas. In diffuse large B-cell lymphoma (DLBCL), inactivating mutations of the histone acetyltransferases CREB-binding protein (CBP) and EP300 are common. Moreover, knockdown of CBP in DLBCL has been shown to result in aberrant transcriptional silencing. Expression of CD20 is sensitive to epigenetic manipulation, and histone deacetylase inhibitors have been found to potentiate treatment with anti-CD20 antibodies. Therefore, we studied the role of CBP and EP300 depletion on CD20 expression and effects of the anti-CD20 antibodies rituximab and obinutuzumab in DLBCL cells. Levels of CBP and EP300 were reduced by shRNA in the germinal centre-derived diffuse large B-cell lymphoma cell line SU-DHL4. The levels of CD20 mRNA and protein were determined by quantitative polymerase chain reaction, Western blot, and flow cytometry. Binding of the transcription factors PU.1 and FOXO1 to the CD20 promoter was determined by chromatin immunoprecipitation coupled with quantitative polymerase chain reaction. Response to the monoclonal anti-CD20 antibodies rituximab and obinutuzumab in CBP- or EP300-depleted cells was assessed by complement-dependent cell death, direct cell death, and antibody-dependent cellular cytotoxicity (ADCC). Our results suggest that depletion of CBP and EP300 levels leads to a strong reduction of CD20 expression, accompanied by reduced binding of PU.1 to the CD20 promoter. In CBP-depleted, but not EP300-depleted cells, increased binding of FOXO1 to the CD20 promoter was observed. Interestingly, CBP or EP300 depletion leads to decreased complement-dependent cell death and direct cell death in response to rituximab and obinutuzumab, which was most pronounced in response to rituximab in CBP-depleted cells. Our data suggest that inactivating mutations of CBP, and to a lesser extent EP300, may impair the response to anti-CD20 antibodies. However, these observations should be analyzed in future clinical trials.
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| 15. |
- Scialdone, Annarita, et al.
(författare)
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The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:23, s. 37409-37422
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with anti-CD20 antibodies is only moderately efficient in chronic lymphocytic leukemia (CLL), a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown that CD20 is epigenetically regulated and that histone deacetylase inhibitors (HDACis) can increase CD20 expression in vitro in CLL. To assess whether HDACis can upregulate CD20 also in vivo in CLL, the HDACi valproate was given to three del13q/NOTCH1wt CLL patients and CD20 levels were analysed (the PREVAIL study). Valproate treatment resulted in expected global activating histone modifications suggesting HDAC inhibitory effects. However, although valproate induced expression of CD20 mRNA and protein in the del13q/ NOTCH1wt I83-E95 CLL cell line, no such effects were observed in the patients studied. In contrast to the cell line, in patients valproate treatment resulted in transient recruitment of the transcriptional repressor EZH2 to the CD20 promoter, correlating to an increase of the repressive histone mark H3K27me3. This suggests that valproate-mediated induction of CD20 may be hampered by EZH2 mediated H3K27me3 in vivo in CLL. Moreover, valproate treatment resulted in induction of EZH2 and global H3K27me3 in patient cells, suggesting transcriptionally repressive effects of valproate in CLL. Our results suggest new in vivo mechanisms of HDACis which may have implications on the design of future clinical trials in B-cell malignancies.
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| 16. |
- Skyllberg, Ulf, et al.
(författare)
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Chemical speciation of mercury, sulfur and iron in a dystrophic boreal lake sediment, as controlled by the formation of mackinawite and framboidal pyrite
- 2021
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Ingår i: Geochimica et Cosmochimica Acta. - : Elsevier BV. - 0016-7037 .- 1872-9533 .- 0046-564X. ; 294, s. 106-125
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Tidskriftsartikel (refereegranskat)abstract
- The chemical speciation of mercury (Hg), methyl mercury (MeHg), sulfur and iron was investigated in the sediment and porewater of Lake Angessjon, a boreal, shallow (maximum depth 2.5 m), oligo-/dystrophic lake in northern Sweden. The lake receives terrestrial stream runoff from surrounding coniferous forest soils and peatlands having a low pH (4.6) and high concentrations of dissolved organic matter (DOM, annual average: 45 mg L-1), Fe (60 mu M), sulfate (105 mu M), inorganic Hg (1200 pM) and MeHg (250 pM). Sulfur K-edge XANES and Hg L-m-edge EXAFS spectroscopic measurements were used to characterize and quantify the sulfur speciation in the lake sediment at nine occasions, covering different seasons in the years of 2007 and 2009. In the surface sediment (0-3 cm) sulfate is reduced to zero-valent S and inorganic sulfide, that in turn reacts with Fe to form FeSm (mackinawite) and FeS2 (framboidal pyrite). The latter mineral becomes increasingly dominant by depth in the sediment. Thermodynamic modeling successfully predicted measured porewater concentrations of Hg in the sediment. Metacinnabar (beta-HgS) and Hg(NOM-RS)(2) complexes (the latter formed as a reaction between Hg(II) and thiol groups associated with natural organic matter, NOM-RSH) were the dominant forms of Hg(II) in the solid phase of sediments and Hg(II)-polysulfides (aq) dominated in the porewater. We argue that FeS m is a key component that indirectly controlled the Hg (II) speciation in the sediment by keeping the aqueous phase concentration of inorganic sulfide in the 0.5-2 mu M range throughout the year. Besides providing a pool of readily soluble inorganic sulfide for formation of beta-HgS(s), as demonstrated by previously reported EXAFS experiments, we further suggest FeS m may serve as a precursor for the formation of a more crystalline (less soluble) beta-HgS(s) phase than present in environments devoid of FeSm. Support for this was provided by comparing our results with previously reported thermodynamic modelling results of Hg(II) and MeHg solubility in organic soils devoid of FeSm. In more general terms, we suggest the presence or absence of FeSm, through its influence on the chemical speciation of Hg and MeHg, may be a key factor behind the variability in rates of Hg(II) and MeHg transformation processes, such as methylation, reduction and demethylation, reported for different environmental settings.
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| 17. |
- Skyllberg, Ulf, et al.
(författare)
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Competition between Disordered Iron Sulfide and Natural Organic Matter Associated Thiols for Mercury(II)-An EXAFS Study
- 2010
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 44, s. 1254-1259
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about the chemical speciation of Hg(II) is a prerequisite for a proper understanding of biogeochemical processes in control of the transformation of Hg(II) into toxic and bioaccumulating monomethyl mercury. Of critical importance are structures and the stability of Hg(II)-complexes with inorganic and organic sulfur ligands in aqueous and solid phases of soils and sediments. On the basis of Hg L(III)-edge EXAFS experiments, we report Hg(II) to form a four-coordinated metacinnabar [beta-HgS(s)] phase when reacted with disordered FeS(s) (mackinawite), at pH 9.0 and a Hg(II) to FeS(s) molar ratio of 0.002-0.012. When Hg(II) (1000-20 000 mu g Hg g(-1)) was added to mixtures of <5 days of aged FeS(s) (2-20%) and an organic soil at pH 5.7-6.1, a mixture of Hg(II) coordinated with two organic thiols [Hg(SR)(2)] and Hg(II) coordinated with four inorganic sulfides in a metacinnabar-like phase was formed. Surface complex formation between Hg(II) and FeS(s), or substitution of Hg(II) for Fe(II) in FeS(s), was not observed. Guantities of beta-HgS(s) and Hg(SR)(2) formed (as determined by EXAFS) were in fair agreement with theoretical thermodynamic calculations, as described by the reaction: Hg(SR)(2) + FeS(s) = HAS) + Fe(2+) + 2RS(-). The calculated stability constant for this reaction (log K = -16.1 - -15.4) supports a strong bonding of Hg(II) to organic thiols, corresponding to a log beta(2) for the formation of Hg(SR)(2) on the order of 42 or greater.
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| 18. |
- Skyllberg, Ulf, et al.
(författare)
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Förbättrad riskbedömning av kvicksilverförorenade sediment
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Kunskapen om risker för miljö och människa i och i anslutning till lokalt gravt kvicksilverförorenade sediment och jordar är idag begränsad. Senare års forskning om kvicksilvers biogeokemi i sediment, jordar och vattendrag påverkade av mer diffusa utsläpp pekar entydigt på att bildning, tillgänglighet och spridning av organiska former av kvicksilver, i huvudsak metylkvicksilver (MeHg), är mest kritiskt för ackumulering av kvicksilver i biota. Med detta synsätt som utgångspunkt, har syftet med föreliggande projekt varit att identifiera de faktorer som styr bildning, ackumulering och löslighet av metylkvicksilver i förorenade sediment. Bildning av MeHg ombesörjs i första hand av s.k. sulfatreducerande bakterier. Nettoproduktion av MeHg ges av skillnaden mellan bildning och nedbrytning av MeHg. Dessutom bidrar bort- och tillförsel av MeHg till totalhalten i sedimentet. Baserad på rådande teoribildning, har vår arbetshypotes varit att de kemiska formerna av oorganisk kvicksilver (Hg) i porvattnet, främst halten av neutrala Hgsulfider, styr nettometyleringen medan löst organisk substans och lösta oorganiska sulfider avgör lösligheten av både Hg och MeHg. Sju olika objekt med kvicksilverhaltiga sediment inkluderades i studien. Sediment från Karlshäll, Turingen, Övre Svartsjön och Nötöfjärden har alla påverkats av utsläpp av fenylkvicksilverpreparat tillsammans med massafiber, medan sediment från Köpmanholmen, Skutskär och Marnästjärn i huvudsak är påverkade av utsläpp av Hg0(l) från kloralkaliindustrier och annan industriell verksamhet. Lokalerna täcker in en variation i såväl klimat, salinitet som produktivitet och halt av organiskt material. All provtagning av sediment och porvatten utfördes under reducerad miljö (kvävgas). En delstudie visade att halten av metylkvicksilver i porvatten kan underskattas mer än 100 gånger om extraktion och filtrering av porvatten inte sker i anaerob miljö. Förutom våtkemiska metoder användes röntgenspektroskopi för analys av den fasta fasen. I porvattnet analyserades Hg, MeHg, dominerande anjoner och katjoner, pH, löst sulfid och löst organisk substans. Den kemiska speciationen i porvattnet beräknades med modeller. Dessutom bestämdes metylerings- och demetyleringshastigheten i samtliga sedimentprover under 48 timmar vid 25°C. Resultaten visar att koncentrationen av neutrala Hg-sulfider, tillsammans med tillgången på energirika kolföreningar, bestämmer både metyleringshastighet och den långsiktiga ackumuleringen av metylkvicksilver. Baserat på de sju objekten i studien, visade sötvattenmiljöer med hög primärproduktion och höga halter av neutrala Hg-sulfider både den högsta metyleringshastigheten och den högsta %-andelen MeHg i sedimenten. Resultaten visar att, förutom totalhalter av Hg och MeHg, bör halten av lösta sulfider och en kvantifiering av primärproduktion och energirika kolföreingar ingå som en del i underlaget vid riskbedömning av kvicksilverhaltiga sediment.
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| 19. |
- Skyllberg, Ulf, et al.
(författare)
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Net Methylmercury Production as a Basis for Improved Risk Assessment of Mercury-contaminated Sediments
- 2007
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Ingår i: AMBIO: A Journal of the Human Environment. ; 36:6, s. 437-42
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Tidskriftsartikel (refereegranskat)abstract
- Sediments contaminated by various sources of mercury (Hg) were studied at 8 sites in Sweden covering wide ranges of climate, salinity, and sediment types. At all sites, biota (plankton, sediment living organisms, and fish) showed enhanced concentrations of Hg relative to corresponding organisms at nearby reference sites. The key process determining the risk at these sites is the net transformation of inorganic Hg to the highly toxic and bioavailable methylmercury (MeHg). Accordingly, Hg concentrations in Perca fluviatilis were more strongly correlated to MeHg (p < 0.05) than to inorganic Hg concentrations in the sediments. At all sites, except one, concentrations of inorganic Hg (2–55 μg g−1) in sediments were significantly, positively correlated to the concentration of MeHg (4–90 ng g−1). The MeHg/Hg ratio (which is assumed to reflect the net production of MeHg normalized to the Hg concentration) varied widely among sites. The highest MeHg/Hg ratios were encountered in loose-fiber sediments situated in southern freshwaters, and the lowest ratios were found in brackish-water sediments and firm, minerogenic sediments at the northernmost freshwater site. This pattern may be explained by an increased MeHg production by methylating bacteria with increasing temperature, availability of energy-rich organic matter (which is correlated with primary production), and availability of neutral Hg sulfides in the sediment pore waters. These factors therefore need to be considered when the risk associated with Hg-contaminated sediments is assessed.
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| 20. |
- Ullmark, Tove, et al.
(författare)
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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 102:2, s. 336-345
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Tidskriftsartikel (refereegranskat)abstract
- The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.
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| 21. |
- Wiederhold, Jan G., et al.
(författare)
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Mercury Isotope Signatures in Contaminated Sediments as a Tracer for Local Industrial Pollution Sources
- 2015
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 49:1, s. 177-185
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Tidskriftsartikel (refereegranskat)abstract
- Mass-dependent fractionation (MDF) and mass-independent fractionation (MIF) may cause characteristic isotope signatures of different mercury (Hg) sources and help understand transformation processes at contaminated sites. Here, we present Hg isotope data of sediments collected near industrial pollution sources in Sweden contaminated with elemental liquid Hg (mainly chlor-alkali industry) or phenyl-Hg (paper industry). The sediments exhibited a wide range of total Hg concentrations from 0.86 to 99 mu g g(-1)), consisting dominantly of organically-bound Hg and smaller amounts of sulfide-bound Hg. The three phenyl-Hg sites showed very similar Hg isotope signatures (MDF delta Hg-202: -0.2 parts per thousand to -0.5 parts per thousand; MIF Delta Hg-199: -0.05 parts per thousand to -0.10 parts per thousand). In contrast, the four sites contaminated with elemental Hg displayed much greater variations (delta Hg-202: -2.1 parts per thousand to 0.6 parts per thousand; Delta Hg-199: -0.19 parts per thousand to 0.03 parts per thousand) but with distinct ranges for the different sites. Sequential extractions revealed that sulfide-bound Hg was in some samples up to 1 parts per thousand heavier in delta Hg-202 than organically-bound Hg. The selectivity of the sequential extraction was tested on standard materials prepared with enriched Hg isotopes, which also allowed assessing isotope exchange between different Hg pools. Our results demonstrate that different industrial pollution sources can be distinguished on the basis of Hg isotope signatures, which may additionally record fractionation processes between different Hg pools in the sediments.
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