| 1. |
- Gusev, A, et al.
(författare)
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 10979-
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Tidskriftsartikel (refereegranskat)abstract
- Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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| 2. |
- Hedberg, Yolanda S., et al.
(författare)
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Electrochemical surface oxide characteristics of metal nanoparticles (Mn, Cu and Al) and the relation to toxicity
- 2016
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Ingår i: Electrochimica Acta. - : Elsevier BV. - 0013-4686 .- 1873-3859. ; 212, s. 360-371
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Tidskriftsartikel (refereegranskat)abstract
- Most metal nanoparticles (NPs), except noble metal NPs, rapidly form a thin surface oxide in ambient conditions. The protective properties of these oxides improve or worsen depending on the environment, e.g., the human lung. Several properties, including the chemical/electrochemical stability and defect density, determine the capacity of these surface oxides to hinder the bulk metal from further oxidation (corrosion). The aim of this study was to investigate whether electrochemical surface oxide characterization of non-functionalized base metal NPs of different characteristics (Al, Mn and Cu) can assist in understanding their bioaccessibility (metal release) in cell media (DMEM+) and their cytotoxic properties following exposure in lung epithelial (A549) cells. The composition and valence states of surface oxides of metal NPs and their electrochemical activity were investigated using an electrochemical technique based on a graphite paste electrode to perform cyclic voltammetry in buffer solutions and open circuit potential measurements in DMEM+. The electrochemical surface oxide characterization was complemented and verified by Raman spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The open circuit potential trends in DMEM+ correlated well with metal release results in the same solution, and provided information on the kinetics of oxide dissolution in the case of Cu NPs. Extensive particle agglomeration in cell medium (DMEM+) was observed by means of photon-cross correlation spectroscopy for all metal NPs, with sedimentation taking place very quickly. As a consequence, measurements of the real dose of added non-functionalized metal NPs to cell cultures for cytotoxicity testing from a sonicated stock solution were shown necessary. The cytotoxic response was found to be strongly correlated to changes in physico-chemical and electrochemical properties of the surface oxides of the metal NPs, the most potent being Cu NPs, followed by Mn NPs. No cytotoxicity was observed for Al NPs. The electrochemical surface oxide characterization corresponded well with other tools commonly used for nanotoxicological characterization and provided additional information.
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| 3. |
- Hedberg, Yolanda, Docent, 1985-, et al.
(författare)
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Welding fume nanoparticles from solid and flux-cored wires : Solubility, toxicity, and role of fluorides
- 2021
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Ingår i: Journal of Hazardous Materials. - : Elsevier BV. - 0304-3894 .- 1873-3336. ; 413
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Tidskriftsartikel (refereegranskat)abstract
- Welding fume particles are hazardous. Their toxicity likely depends on their composition and reactivity. This study aimed at exploring the role of sodium or other fluorides (NaF), which are intentionally added to flux-cored wire electrodes for stainless steel welding, on the solubility (in phosphate buffered saline) and toxicity of the generated welding fume particles. A multi-analytical particle characterization approach along with in-vitro cell assays was undertaken. The release of Cr(VI) and Mn from the particles was tested as a function of fluoride solution concentration. The welding fume particles containing NaF released significantly higher amounts of Cr (VI) compared with solid wire reference fumes, which was associated with increased cytotoxicity and genotoxicity in-vitro. No crystalline Na or potassium (K) containing chromates were observed. Cr(VI) was incorporated in an amorphous mixed oxide. Solution-added fluorides did not increase the solubility of Cr(VI), but contributed to a reduced Mn release from both solid and flux-cored wire fume particles and the reduction of Cr (VI) release from solid wire fume particles. Chemical speciation modeling suggested that metal fluoride complexes were not formed. The presence of NaF in the welding electrodes did not have any direct, but possibly an indirect, role in the Cr(VI) solubility of welding fumes.
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| 4. |
- Henderson, Rayetta G., et al.
(författare)
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Inter-laboratory validation of bioaccessibility testing for metals
- 2014
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 70:1, s. 170-181
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Tidskriftsartikel (refereegranskat)abstract
- Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intra- and inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (S-r) and reproducibility (S-R) were used to evaluate the intra- and inter-laboratory variability, respectively. Examination of the s(R):s(r) ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between- than within-laboratories. RSD analysis of s(r) showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.
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| 5. |
- McCarrick, S., et al.
(författare)
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Toxtracker reporter cell lines as a tool for mechanism-based (Geno)toxicity screening of nanoparticles—metals, oxides and quantum dots
- 2020
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Ingår i: Nanomaterials. - : MDPI AG. - 2079-4991. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The increased use of nanoparticles (NPs) requires efficient testing of their potential toxic effects. A promising approach is to use reporter cell lines to quickly assess the activation of cellular stress response pathways. This study aimed to use the ToxTracker reporter cell lines to investigate (geno)toxicity of various metal-or metal oxide NPs and draw general conclusions on NP-induced effects, in combination with our previous findings. The NPs tested in this study (n = 18) also included quantum dots (QDs) in different sizes. The results showed a large variation in cytotoxicity of the NPs tested. Furthermore, whereas many induced oxidative stress only few activated reporters related to DNA damage. NPs of manganese (Mn and Mn3O4) induced the most remarkable ToxTracker response with activation of reporters for oxidative stress, DNA damage, protein unfolding and p53-related stress. The QDs (CdTe) were highly toxic showing clearly size-dependent effects and calculations suggest surface area as the most relevant dose metric. Of all NPs investigated in this and previous studies the following induce the DNA damage reporter; CuO, Co, CoO, CdTe QDs, Mn, Mn3O4, V2O5, and welding NPs. We suggest that these NPs are of particular concern when considering genotoxicity induced by metal-and metal oxide NPs.
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| 6. |
- Wan, Y., et al.
(författare)
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Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
- 2004
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Ingår i: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:24, s. 5995-6008
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Tidskriftsartikel (refereegranskat)abstract
- The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.
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