| 1. |
- Buus, Terkild Brink, et al.
(författare)
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Single-cell heterogeneity in Sézary syndrome
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:16, s. 2115-2126
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Tidskriftsartikel (refereegranskat)abstract
- Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
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| 2. |
- Hedegaard, Sofie Fogh, et al.
(författare)
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Fluorophore labeling of a cell-penetrating peptide significantly alters the mode and degree of biomembrane interaction
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The demand for highly efficient macromolecular drugs, used in the treatment of many severe diseases, is continuously increasing. However, the hydrophilic character and large molecular size of these drugs significantly limit their ability to permeate across cellular membranes and thus impede the drugs in reaching their target sites in the body. Cell-penetrating peptides (CPP) have gained attention as promising drug excipients, since they can facilitate drug permeation across cell membranes constituting a major biological barrier. Fluorophores are frequently covalently conjugated to CPPs to improve detection, however, the ensuing change in physico-chemical properties of the CPPs may alter their biological properties. With complementary biophysical techniques, we show that the mode of biomembrane interaction may change considerably upon labeling of the CPP penetratin (PEN) with a fluorophore. Fluorophore-PEN conjugates display altered modes of membrane interaction with increased insertion into the core of model cell membranes thereby exerting membrane-thinning effects. This is in contrast to PEN, which localizes along the head groups of the lipid bilayer, without affecting the thickness of the lipid tails. Particularly high membrane disturbance is observed for the two most hydrophobic PEN conjugates; rhodamine B or 1-pyrene butyric acid, as compared to the four other tested fluorophore-PEN conjugates.
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| 3. |
- Hedegaard, Sofie Fogh, et al.
(författare)
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Shuffled lipidation pattern and degree of lipidation determines the membrane interaction behavior of a linear cationic membrane-active peptide.
- 2020
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier. - 0021-9797 .- 1095-7103. ; 578, s. 584-597
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Tidskriftsartikel (refereegranskat)abstract
- HYPOTHESIS: Permeation of macromolecular drugs across biological plasma membranes is a major challenge in drug delivery. Cationic cell-penetrating peptides (CPPs) are attractive functional excipient candidates for the delivery of macromolecules across membrane barriers, due to their membrane translocating ability. The properties of CPPs can be tailored by lipidation, a promising approach to facilitate enhanced membrane insertion, potentially promoting increased translocation of the CPP and cargo.EXPERIMENTS: To explore the impact that site and degree of lipidation have on the membrane interaction of a cationic CPP, we designed and investigated CPP conjugates with one or two fatty acid chains.FINDINGS: Compared to the parent CPP and the single-lipidated conjugates, the double-lipidated conjugate exhibited the most pronounced membrane perturbation effects, as measured by several biophysical techniques. The experimental findings were supported by molecular dynamics (MD) simulations, demonstrating that all CPP conjugates interacted with the membrane by insertion of the lipid chain(s) into the core of the bilayer. Moreover, membrane-thinning effects and induced membrane curvature were displayed upon CPP interaction. Our results demonstrate that the impact exerted by the CPP on the membrane is notably affected by positioning and especially the degree of lipidation, which might influence the properties of CPPs as functional excipients.
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| 4. |
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| 5. |
- Vinther, Hanne Fogh, et al.
(författare)
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Effects of coexistence between the blue mussel and eelgrass on sediment biogeochemistry and plant performance
- 2012
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Ingår i: Marine Ecology Progress Series. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 447, s. 139-149
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Tidskriftsartikel (refereegranskat)abstract
- The habitat-modifying suspension-feeding mussel Mytilus edulis may have facilitating or inhibiting effects on seagrass meadows depending on the environmental conditions. We investigated the effects of M. edulis on sediment biogeochemistry in Zostera marina meadows under eutrophic conditions in Flensborg fjord, Denmark. Sediment and plant samples were collected at 5 stations with Z. marina (Eelgrass), 5 with Z. marina and M. edulis (Mixed), and at 2 unvegetated ones, 1 with mussels (Mussel) and 1 with sand (Sand). The Mixed sediment was en riched in fine particles (2 to 3 times), nutrients and sulphides compared to Eelgrass stations. In creased sediment nutrient availability at the Mixed stations was reflected in increased N and P content in eelgrass. However, the plant biomass did not differ significantly between stations, while shoot features (number of leaves and leaf area) were significantly reduced at Mixed stations, suggesting an inhibiting effect of M. edulis on Z. marina. Negative correlations between eelgrass measures and sediment sulphide at Mixed stations indicate that the presence of mussels increases sulphide invasion in the plants. A survey of 318 stations in Danish fjords suggests a threshold of 1.6 kg M. edulis m(-2) beyond which no coexistence between Z. marina and M. edulis was found.
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