| 1. |
- 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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| 2. |
- Dieden, A., et al.
(författare)
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Biomarkers associated with prevalent hypertension and higher blood pressure in a population-based cohort : a proteomic approach
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 43:Suppl 2, s. 2189-2189
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundGlobally, hypertension represents an enormous health issue as it is a major, yet modifiable risk factor for developing cardiovascular disease. Recently, chitinase-3-like protein 1 (CHI3L1) was shown to be positively associated with the incidence of hypertension among prehypertensive subjects, and variants of CHI3L1 gene were associated with both CHI3L1-levels and hypertension.PurposeTo explore associations between prevalent hypertension and blood pressure, and 92 proteins with involvement in inflammation and cardiovascular disease.MethodsPlasma samples from 1713 individuals from a Swedish population-based cohort (mean age 67.3±6.0 years; 28.9% women) were analysed with a proximity extension assay panel, consisting of 92 proteins. Prior to all analyses, subjects with prevalent cardiovascular disease, defined as having a history of prevalent coronary or stroke event, were excluded (n=189). Univariate logistic regression models were carried out exploring associations between each of the 92 proteins and prevalent hypertension, defined as systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg, or use of antihypertensive treatment (n=1168, 76.4%). Bonferroni-corrected significant associations between proteins and hypertension were further analysed using stepwise selection of covariates, namely age, body mass index, diabetes status, and cystatin C, in logistic regression models. Proteins with significant adjusted associations with prevalent hypertension were further analysed for associations with systolic and diastolic blood pressure individually in stepwise linear regression models. Complete data on all variables were available in 1527 subjects.ResultsSixteen proteins were significantly associated with prevalent hypertension in univariate analyses. After adjustment, three proteins remained significantly associated with prevalent hypertension (i.e., CHI3L1, low-density lipoprotein receptor (LDL receptor) and tissue plasminogen activator (tPA); Table 1). In analyses of associations with systolic blood pressure, CHI3L1 and LDL receptor showed significant associations. In analyses of associations with diastolic blood pressure, CHI3L1, LDL receptor and tPA showed significant associations (Table 1).ConclusionsHigher CHI3L1, tPA and LDL receptor levels were positively associated with prevalent hypertension after multivariable adjustment, among 1527 elderly subjects without established cardiovascular disease. Furthermore, higher CHI3L and LDL receptor levels were positively associated with mean systolic, as well as mean diastolic blood pressure in multivariable analyses.Funding AcknowledgementType of funding sources: Foundation. Main funding source(s): The Swedish Medical Research Council and The Swedish Heart and Lung Foundation
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| 3. |
- Hansen, C. J., et al.
(författare)
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Silver and palladium help unveil the nature of a second r-process
- 2012
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 545
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Tidskriftsartikel (refereegranskat)abstract
- Context. The rapid neutron-capture process, which created about half of the heaviest elements in the solar system, is believed to have been unique. Many recent studies have shown that this uniqueness is not true for the formation of lighter elements, in particular those in the atomic number range 38 < Z < 48. Among these, palladium (Pd) and especially silver (Ag) are expected to be key indicators of a possible second r-process, but until recently they have been studied only in a few stars. We therefore target Pd and Ag in a large sample of stars and compare these abundances to those of Sr, Y, Zr, Ba, and Eu produced by the slow (s-) and rapid (r-) neutron-capture processes. Hereby we investigate the nature of the formation process of Ag and Pd. Aims. We study the abundances of seven elements (Sr, Y, Zr, Pd, Ag, Ba, and Eu) to gain insight into the formation process of the elements and explore in depth the nature of the second r-process. Methods. By adopting a homogeneous one-dimensional local thermodynamic equilibrium (1D LTE) analysis of 71 stars, we derive stellar abundances using the spectral synthesis code MOOG, and the MARCS model atmospheres. We calculate abundance ratio trends and compare the derived abundances to site-dependent yield predictions (low-mass O-Ne-Mg core-collapse supernovae and parametrised high-entropy winds), to extract characteristics of the second r-process. Results. The seven elements are tracers of different (neutron-capture) processes, which in turn allows us to constrain the formation process(es) of Pd and Ag. The abundance ratios of the heavy elements are found to be correlated and anti-correlated. These trends lead to clear indications that a second/weak r-process, is responsible for the formation of Pd and Ag. On the basis of the comparison to the model predictions, we find that the conditions under which this process takes place differ from those for the main r-process in needing lower neutron number densities, lower neutron-to-seed ratios, and lower entropies, and/or higher electron abundances. Conclusions. Our analysis confirms that Pd and Ag form via a rapid neutron-capture process that differs from the main r-process, the main and weak s- processes, and charged particle freeze-outs. We find that this process is efficiently working down to the lowest metallicity sampled by our analysis ([Fe/H] = -3.3). Our results may indicate that a combination of these explosive sites is needed to explain the variety in the observationally derived abundance patterns.
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| 4. |
- Leosdottir, Margret, et al.
(författare)
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Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts : a cross-sectional study
- 2010
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Ingår i: American Heart Journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 159:3, s. 4-420
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts.METHODS: We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 +/- 6 years) and the Malmö Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 +/- 6 years), evaluating associations with multivariable regression analysis.RESULTS: In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (70-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c.CONCLUSIONS: Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects.
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| 5. |
- Pedersen, Tanja X., et al.
(författare)
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The pro-inflammatory effect of uraemia overrules the anti-atherogenic potential of immunization with oxidized LDL in apoE-/- mice
- 2010
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 25:8, s. 2486-2491
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Tidskriftsartikel (refereegranskat)abstract
- Background. Uraemia increases oxidative stress, plasma titres of antibodies recognizing oxidized low-density lipoprotein (oxLDL) and development of atherosclerosis. Immunization with oxLDL prevents classical, non-uraemic atherosclerosis. We have investigated whether immunization with oxLDL might also prevent uraemia-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mice. Methods. ApoE-/- mice were immunized with either native LDL (n = 25), Cu2+-oxidized LDL (n = 25), PBS (n = 25), the apolipoprotein B-derived peptide P45 (apoB-peptide P45) conjugated to bovine serum albumin (BSA) (n = 25) or BSA (n = 25) prior to induction of uraemia by 5/6 nephrectomy (NX). Results. Immunization with oxLDL increased plasma titres of immunoglobulin G (IgG) recognizing Cu2+-oxLDL and malondialdehyde-modified LDL (MDA-LDL). However, 5/6 NX induced a marked increase in plasma concentrations of anti-oxLDL antibodies as well as pro-atherogenic cytokines [interleukin (IL)-2 (IL-2), IL-4, IL-6 and IL-12)] in native mouse LDL (nLDL)-, oxLDL- and PBS-immunized mice. Even though nLDL- and oxLDL-immunized mice displayed higher anti-MDA-LDL IgG titres than the PBS group, aortic atherosclerosis lesion size was not affected by immunization. Immunization with the apoB-peptide P45, which consistently reduces classical atherosclerosis in non-uraemic mice, also did not reduce lesion size in uraemic apoE-/- mice. Conclusion. The results suggest that the pro-inflammatory and pro-atherogenic effect of uraemia overrules the anti-atherogenic potential of oxLDL immunization in apoE-/- mice.
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| 6. |
- Sayols-Baixeras, Sergi, et al.
(författare)
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Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort
- 2023
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 148:6, s. 459-472
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography–based measures of coronary atherosclerosis and to explore relevant clinical correlates.METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva.RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10–5). Associations were largely similar across coronary computed tomography angiography–based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score.CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.
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| 7. |
- Velichko, A. B., et al.
(författare)
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Formation of Zr I and II lines under non-LTE conditions of stellar atmospheres
- 2010
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Ingår i: Astronomy letters. - : Pleiades Publishing Ltd. - 1063-7737 .- 1562-6873. ; 36:9, s. 664-679
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Tidskriftsartikel (refereegranskat)abstract
- The formation of Zr I and Zr II lines in stellar atmospheres under non-LTE conditions has been considered for the first time. A model zirconium atom has been composed using 148 Zr I levels, 772 Zr II levels, and the ground Zr III state. Non-LTE calculations have been performed for model atmospheres with T eff = 5500 and 6000 K, log g = 2.0 and 4.0, [M/H] = −3, −2, −1, 0. In the entire investigated range of parameters, the Zr I levels are shown to be underpopulated relative to their LTE populations in the line formation region. In contrast, the excited Zr II levels are overpopulated, while the ground state and lower excited levels of Zr II retain their LTE populations. Since the non-LTE effects cause the Zr I and Zr II spectral lines being investigated to weaken, the non-LTE corrections to the abundance derived from Zr I and Zr II lines are positive. For Zr II lines, they increase with decreasing metallicity and surface gravity up to 0.34 dex for the model with T eff = 5500, log g = 2.0, and [M/H] = −2. The non-LTE effects depend weakly on temperature. The non-LTE corrections for Zr I lines reach 0.33 dex for solar-metallicity models. Zr I and Zr II lines in the solar spectrum have been analyzed. The non-LTE zirconium abundances derived from lines in the two ionization stages are shown to agree between themselves within the error limits, while the LTE abundance difference is 0.28 dex. The zirconium abundance in the solar atmosphere (averaged over Zr I and Zr II lines) is log ɛZr,⊙ = 2.63 ± 0.07.
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