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| 2. |
- Metzler, Veronika M., et al.
(author)
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Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development
- 2017
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In: Placenta. - : W B SAUNDERS CO LTD. - 0143-4004 .- 1532-3102. ; 56, s. 79-85
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Journal article (peer-reviewed)abstract
- The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models.
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| 3. |
- Metzler, Veronika M., et al.
(author)
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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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In: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 11
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Journal article (peer-reviewed)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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| 4. |
- Arvidsson, Martin, et al.
(author)
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Multidimensional psychophysics : Surface feel of printing paper as a function of physical properties
- 2009
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In: Fechner Day 2009. - Galway, Irland : International Society for Psychophysics. ; , s. 215-220
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Conference paper (other academic/artistic)abstract
- The aim of this experiment was to explore the perception of tactile surface-feel of 21 printing papers. A multidimensional scaling (MDS) experiment was conducted with 20 women. They scaled similarity among all possible pairs of the papers. Similarity measurements were mapped by INDSCAL and modeled with PREFMAP. Test-retest and concordance coefficients were high. It is not yet established what physical properties best determine tactile feel. It seems likely though that finger friction and surface roughness are strong contenders. Finger friction for the papers was measured as a ratio of friction force to normal force;(while stroking a human finger on the surface. Average surface roughness was measured with a profilometer. Physical properties were rotated into the 3D INDSCAL solution. This solution identified and mapped the tactile surface feel of the papers in an interpretable way with regard to i.e. friction, surface roughness and weight.
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| 5. |
- Atiomo, William, et al.
(author)
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Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome
- 2017
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In: Clinical Endocrinology. - : John Wiley & Sons. - 0300-0664 .- 1365-2265. ; 87:5, s. 557-565
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Journal article (peer-reviewed)abstract
- Objective: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). Aim: To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. Design and Methods: Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. Results: We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). Conclusions: The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.
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| 6. |
- Harris, Anna E., et al.
(author)
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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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In: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
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Research review (peer-reviewed)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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| 7. |
- Plunkett, M. A., et al.
(author)
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Adsorption of a cationic polyelectrolyte followed by surfactant-induced swelling, studied with a quartz crystal microbalance
- 2002
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In: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 18:4, s. 1274-1280
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Journal article (peer-reviewed)abstract
- The adsorption and subsequent surfactant-induced swelling of a 10% charged cationic polyelectrolyte (AM-MAPTAC-10), on a gold surface, was monitored by means of a quartz crystal microbalance with dissipation (QCM-D). This instrument gives information on the total adsorbed amount including any adsorbed solvent and on the manner of adsorption. In this case the total adsorbed amount from a 20 ppm AM-MAPTAC-10 solution registered by the QCM-D device was approximately 0.6 mug cm(-2). X-ray photoelectron spectroscopy results showed that the polyelectrolyte adsorbed mass was 0.16 mug cm(-2); thus the water trapped within the polyelectrolyte layer constitutes about 70% of the mass measured by the quartz crystal microbalance. The adsorption process was found to be rather complex, though the time evolution of the adsorbed mass indicated that the majority of the process was diffusion controlled, Toward the end of the adsorption process, the rate of adsorption drops off and the dissipation rate increases, indicating that as the surface becomes crowded the layer extends further in the direction normal to the surface. The effect of addition of sodium dodecyl sulfate (SIDS) to a preadsorped AM-MAPTAC-10 layer was also investigated. It was found that some swelling of the preadsorbed layer occurred once the bulk surfactant concentration reached 20% of the critical micelle concentration (cmc). Between 60% of the cmc and twice the cmc, the adsorbed layer swelled significantly and desorption started to occur. Rinsing the surface with the surfactant-free electrolyte solution results in a rapid decrease in dissipation and adsorbed mass indicating the removal of the surfactant but not the polyelectrolyte.
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| 8. |
- Plunkett, M. A., et al.
(author)
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Comparison of the adsorption of different charge density polyelectrolytes : A quartz crystal microbalance and X-ray photoelectron spectroscopy study
- 2003
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In: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 19:11, s. 4673-4681
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Journal article (peer-reviewed)abstract
- The adsorption of a series of six cationic polyelectrolytes onto a gold surface was monitored via a quartz crystal microbalance with dissipation (QCM-D). The series of polyelectrolytes were chemically similar but differing in the ratio of two randomly ordered constituent monomers, one of which was charged, the other neutral. Thus the series of polyelectrolytes differed systematically in their charge densities, ranging from a high charge density (100% of monomers charged) to a low charge density (1% charged). It was determined that high charge density polyelectrolytes adsorbed in a relatively flat and rigid layer, while the low charge density polyelectrolyte, as expected, adsorbed in a much more extended structure that coupled strongly to the bulk solvent. By comparison to X-ray photoelectron spectroscopy results, we have also calculated the relative solvent mass hydrodynamically coupled to the adsorbed polymer, which ranges from almost 80% solvent for the 1% charged case down to close to zero for the 100% charged case. Since the QCM-D results are measured relative to uncoated gold in aqueous solution, the latter results should be interpreted as showing that the amount of water hydrodynamically coupled to gold and that coupled to gold coated with the 100% charged polyelectrolyte is very similar. It is believed that this systematic study on the effect of polyelectrolyte structure on the measured dissipation change in the QCM-D may serve as a first guide when inferring structural and viscoelastic information based solely on the QCM-D technique for other similar systems. In addition, a preliminary study on the ability of one polymer to replace another preadsorbed polymer layer was conducted that showed that a steric layer was able to prevent the adsorption of a thermodynamically more favorable polymer. In the reverse case, greater exchange was possible.
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| 9. |
- Rundlöf, M., et al.
(author)
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Application of the JKR method to the measurement of adhesion to Langmuir-Blodgett cellulose surfaces
- 2000
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In: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797 .- 1095-7103. ; 230:2, s. 441-447
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Journal article (peer-reviewed)abstract
- The JKR method has been applied for studying adhesion between poly(dimethylsiloxane) (PDMS) caps and Langmuir-Blodgett cellulose surfaces including the substrate, hydrophobized mica, and two flat mineral surfaces, bare mica and glass, The self-adhesion of PDMS caps and oxidized PDMS caps are included as a reference to compare with literature data. The results of the measurements have been compared with previous studies using the surface force apparatus and similar systems. A satisfactory agreement is obtained for simple systems showing no, or very limited, hysteresis between loading and unloading curves, In several cases, however, a large hysteresis is found between loading and unloading curves, with a larger adhesion measured from the pull-off force than from the JKR-curve determined on loading. This is, for instance, the case for PDMS against cellulose. The situation is analogous to that found in wetting studies showing a large hysteresis between advancing and receding contact angles.
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| 10. |
- Skedung, Lisa, et al.
(author)
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Tribology, texture and touch
- 2014
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In: 5th World Tribology Congress, WTC 2013. - 9781634393522 ; , s. 2270-2273
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Conference paper (peer-reviewed)
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