| 1. |
- Haigh, Daisy B., et al.
(författare)
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The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:20
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.
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| 2. |
- Metzler, Veronika M., et al.
(författare)
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The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer
- 2023
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.
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| 3. |
- Stenler, S., et al.
(författare)
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Micro-minicircle gene therapy : Implications of size on fermentation, complexation, shearing resistance, and expression
- 2014
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Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 3, s. e140-
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Tidskriftsartikel (refereegranskat)abstract
- The minicircle (MC), composed of eukaryotic sequences only, is an interesting approach to increase the safety and efficiency of plasmid-based vectors for gene therapy. In this paper, we investigate micro-MC (miMC) vectors encoding small regulatory RNA. We use a construct encoding a splice-correcting U7 small nuclear RNA, which results in a vector of 650 base pairs (bp), as compared to a conventional 3600 bp plasmid carrying the same expression cassette. Furthermore, we construct miMCs of varying sizes carrying different number of these cassettes. This allows us to evaluate how size influences production, supercoiling, stability and efficiency of the vector. We characterize coiling morphology by atomic force microscopy and measure the resistance to shearing forces caused by an injector device, the Biojector. We compare the behavior of miMCs and plasmids in vitro using lipofection and electroporation, as well as in vivo in mice. We here show that when the size of the miMC is reduced, the formation of dimers and trimers increases. There seems to be a lower size limit for efficient expression. We demonstrate that miMCs are more robust than plasmids when exposed to shearing forces, and that they show extended expression in vivo.
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| 4. |
- Álvarez Asencio, Rubén, et al.
(författare)
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Nanotribology : Tribotronics, ionic liquids and control of surface interactions
- 2013
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Ingår i: 5th World Tribology Congress, WTC 2013. ; , s. 3106-3108
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Konferensbidrag (refereegranskat)abstract
- The interfacial ordering of Ionic liquids leads to interesting nanotribological properties as revealed by colloid probe studies. The first of these is the clear correlation between the number of ion pairs trapped in the tribological contact and the friction coefficient displayed. The second is the fact that the surface electrical potential can be used to control the composition of the boundary layer and thus tune the friction. Thirdly, the interfacial ordering appears to significantly affect the fluid dynamics over large distances.
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| 5. |
- Boschkova, K., et al.
(författare)
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Study of thin surfactant films under shear using the tribological surface force apparatus
- 2001
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Ingår i: Tribology International. - 0301-679X .- 1879-2464. ; 34:12, s. 815-822
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Tidskriftsartikel (refereegranskat)abstract
- Static and dynamic behaviour of thin surfactant films in aqueous solution of hexadecyltrimethylammonium salicylate (C16TASal) were investigated using the tribological surface force apparatus. Normal force measurements show that 0.15 mM C16TASal builds up an innermost film of approximately 8-11 Angstrom thickness at each mica surface, indicating that the surfactant adsorbs in a flat conformation. Furthermore, the height of the force barrier at approximately 60 Angstrom is low (ca 2 mN/m) indicating that the second adsorbed layer is easily pushed out. Addition of salicylate salt to 0.15 mM C16TASal give rise to a more close packed structure, with a total thickness of 62-65 Angstrom. indicative of a micellar or bilayer arrangement at the surfaces. Furthermore, the frequency dependence of the shear modulus was investigated both at close separation at the innermost force barrier and at larger separations (up to 300-400 Angstrom). The visco-elastic measurements show that the elasticity modulus, G ', dominates over the loss modulus, G , for all studied cases, indicative of a more solid-like than liquid-like film. Finally, it is shown that shear at high contact pressures induces new aggregate structures at the surface.
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| 6. |
- Claesson, PM, et al.
(författare)
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Amine functionalized surfactants - pH effects on adsorption and interaction
- 1992
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Ingår i: Progress in Colloid and Polymer Science. - 0340-255X .- 1437-8027. ; 88, s. 64-73
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Tidskriftsartikel (refereegranskat)abstract
- The interactions between layers of two hydrolyzable surfactants, dodecylamine (DA) and tetraoxyethylene dodecylamine (TEDA), adsorbed on negatively charged muscovite mica have been investigated. It was found that the variation of the interaction and adsorption as a function of pH was similar, but not identical, for the two kinds of surfactants. At a concentration of 10-4 M at low pH (below 8) both types of surfactants adsorb electrostatically to form a monolayer. The resulting surfaces have a hydrophobic character, particularly in the case of dodecylamine. A series of events takes place as the pH is increased. For DA the first event is that uncharged molecules adsorb within the monolayer. This does not occur to any significant degree for TEDA due to steric hindrance within the adsorbed layer. In the next step a bilayer builds up on the surface. The binding of the outer layer is stronger for DA than for TEDA. The DA bilayer becomes uncharged at pH 10.3, and liquid dodecylamine droplets, which phase separate from the bulk solution at this pH-value, precipitate on the surface. At pH-values above 11-12 the affinity between both types of surfactants and the surface decreases significantly, resulting in a less ordered first layer. In addition a strong surface charge develops that prevents multilayer build-up.
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| 7. |
- Cooper, P. K., et al.
(författare)
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Tribotronic control of friction in oil-based lubricants with ionic liquid additives
- 2016
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 18:34, s. 23657-23662
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Tidskriftsartikel (refereegranskat)abstract
- Atomic force microscopy (AFM) reveals that tribotronic control of friction using an external potential applied to a gold surface is possible for ionic liquid (IL) concentrations as low as 5 mol% in hexadecane. The IL used is trihexyl(tetradecyl) phosphonium bis(2,4,4-trimethylpentyl)phosphinate, in which both the cation and anion have surfactant-like structures, and is miscible with hexadecane in all proportions. For IL concentrations less than 5 mol% friction does not vary with applied potential, but for 5 mol% and above changing the potential changes the composition of the IL boundary layer from cation-enriched (negative potentials) to anion-enriched (positive potentials). As the lubricities of the cation-rich and anion-rich boundary layers differ, this enables active control of friction in oil-based lubricants.
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| 8. |
- Elbourne, Aaron, et al.
(författare)
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Adsorbed and near-surface structure of ionic liquids determines nanoscale friction
- 2013
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 49:60, s. 6797-6799
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Tidskriftsartikel (refereegranskat)abstract
- Surface-adsorbed and near-surface ion layer structure controls nanotribology in the silica-propylammonium nitrate (PAN)-mica system. Atomic Force Microscopy (AFM) imaging and normal force curves reveal that the normal load dictates the number of interfacial ion layers and the lateral layer structure. Shear force measurements show the lubricity of the interface changes with the number, and lateral structure, of the confined ion layer(s).
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| 9. |
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| 10. |
- Harris, Anna E., et al.
(författare)
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Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.
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