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Sökning: WFRF:(Poutanen J.)

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1.
  • Acharya, B. S., et al. (författare)
  • Introducing the CTA concept
  • 2013
  • Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 43, s. 3-18
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. (C) 2013 Elsevier B.V. All rights reserved.
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2.
  • Aartsen, M. G., et al. (författare)
  • Very high-energy gamma-ray follow-up program using neutrino triggers from IceCube
  • 2016
  • Ingår i: Journal of Instrumentation. - 1748-0221. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe and report the status of a neutrino-triggered program in IceCube that generates real-time alerts for gamma-ray follow-up observations by atmospheric-Cherenkov telescopes (MAGIC and VERITAS). While IceCube is capable of monitoring the whole sky continuously, high-energy gamma-ray telescopes have restricted fields of view and in general are unlikely to be observing a potential neutrino-flaring source at the time such neutrinos are recorded. The use of neutrino-triggered alerts thus aims at increasing the availability of simultaneous multi-messenger data during potential neutrino flaring activity, which can increase the discovery potential and constrain the phenomenological interpretation of the high-energy emission of selected source classes (e. g. blazars). The requirements of a fast and stable online analysis of potential neutrino signals and its operation are presented, along with first results of the program operating between 14 March 2012 and 31 December 2015.
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3.
  • Feroci, M., et al. (författare)
  • The large observatory for x-ray timing
  • 2014
  • Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 9780819496126
  • Konferensbidrag (refereegranskat)abstract
    • The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final downselection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supranuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m2 effective area, 2-30 keV, 240 eV spectral resolution, 1° collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study.
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4.
  • Feroci, M., et al. (författare)
  • LOFT - The large observatory for x-ray timing
  • 2012
  • Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE - International Society for Optical Engineering. - 9780819491442 ; , s. 84432D-
  • Konferensbidrag (refereegranskat)abstract
    • The LOFT mission concept is one of four candidates selected by ESA for the M3 launch opportunity as Medium Size missions of the Cosmic Vision programme. The launch window is currently planned for between 2022 and 2024. LOFT is designed to exploit the diagnostics of rapid X-ray flux and spectral variability that directly probe the motion of matter down to distances very close to black holes and neutron stars, as well as the physical state of ultradense matter. These primary science goals will be addressed by a payload composed of a Large Area Detector (LAD) and a Wide Field Monitor (WFM). The LAD is a collimated (<1 degree field of view) experiment operating in the energy range 2-50 keV, with a 10 m2 peak effective area and an energy resolution of 260 eV at 6 keV. The WFM will operate in the same energy range as the LAD, enabling simultaneous monitoring of a few-steradian wide field of view, with an angular resolution of <5 arcmin. The LAD and WFM experiments will allow us to investigate variability from submillisecond QPO's to yearlong transient outbursts. In this paper we report the current status of the project.
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5.
  • Ahnen, M. L., et al. (författare)
  • Limits to dark matter annihilation cross-section from a combined analysis of MAGIC and Fermi-LAT observations of dwarf satellite galaxies
  • 2016
  • Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the first joint analysis of gamma-ray data from the MAGIC Cherenkov telescopes and the Fermi Large Area Telescope (LAT) to search for gamma-ray signals from dark matter annihilation in dwarf satellite galaxies. We combine 158 hours of Segue 1 observations with MAGIC with 6-year observations of 15 dwarf satellite galaxies by the Fermi-LAT. We obtain limits on the annihilation cross-section for dark matter particle masses between 10 GeV and 100 TeV - the widest mass range ever explored by a single gamma-ray analysis. These limits improve on previously published Fermi-LAT and MAGIC results by up to a factor of two at certain masses. Our new inclusive analysis approach is completely generic and can be used to perform a global, sensitivity-optimized dark matter search by combining data from present and future gamma-ray and neutrino detectors.
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6.
  • De Angelis, A., et al. (författare)
  • Science with e-ASTROGAM A space mission for MeV-GeV gamma-ray astrophysics
  • 2018
  • Ingår i: Journal of High Energy Astrophysics. - : Elsevier. - 2214-4048 .- 2214-4056. ; 19, s. 1-106
  • Tidskriftsartikel (refereegranskat)abstract
    • e-ASTROGAM ('enhanced ASTROGAM') is a breakthrough Observatory space mission, with a detector composed by a Silicon tracker, a calorimeter, and an anticoincidence system, dedicated to the study of the non-thermal Universe in the photon energy range from 0.3 MeV to 3 GeV - the lower energy limit can be pushed to energies as low as 150 keV for the tracker, and to 30 keV for calorimetric detection. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with polarimetric capability. Thanks to its performance in the MeV-GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LIGO-Virgo-GEO600-KAGRA, SKA, ALMA, E-ELT, TMT, LSST, JWST, Athena, CTA, IceCube, KM3NeT, and LISA.
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7.
  • Brasseur, Z., et al. (författare)
  • Measurement report: Introduction to the HyICE-2018 campaign for measurements of ice-nucleating particles and instrument inter-comparison in the Hyytiala boreal forest
  • 2022
  • Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 22:8, s. 5117-5145
  • Tidskriftsartikel (refereegranskat)abstract
    • The formation of ice particles in Earth's atmosphere strongly influences the dynamics and optical properties of clouds and their impacts on the climate system. Ice formation in clouds is often triggered heterogeneously by ice-nucleating particles (INPs) that represent a very low number of particles in the atmosphere. To date, many sources of INPs, such as mineral and soil dust, have been investigated and identified in the low and mid latitudes. Although less is known about the sources of ice nucleation at high latitudes, efforts have been made to identify the sources of INPs in the Arctic and boreal environments. In this study, we investigate the INP emission potential from high-latitude boreal forests in the mixed-phase cloud regime. We introduce the HyICE-2018 measurement campaign conducted in the boreal forest of Hyytiala, Finland, between February and June 2018. The campaign utilized the infrastructure of the Station for Measuring Ecosystem-Atmosphere Relations (SMEAR) II, with additional INP instruments, including the Portable Ice Nucleation Chamber I and II (PINC and PINCii), the SPectrometer for Ice Nuclei (SPIN), the Portable Ice Nucleation Experiment (PINE), the Ice Nucleation SpEctrometer of the Karlsruhe Institute of Technology (INSEKT) and the Microlitre Nucleation by Immersed Particle Instrument (mu L-NIPI), used to quantify the INP concentrations and sources in the boreal environment. In this contribution, we describe the measurement infrastructure and operating procedures during HyICE-2018, and we report results from specific time periods where INP instruments were run in parallel for inter-comparison purposes. Our results show that the suite of instruments deployed during HyICE-2018 reports consistent results and therefore lays the foundation for forthcoming results to be considered holistically. In addition, we compare measured INP concentrations to INP parameterizations, and we observe good agreement with the Tobo et al. (2013) parameterization developed from measurements conducted in a ponderosa pine forest ecosystem in Colorado, USA.
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8.
  • Marinucci, A., et al. (författare)
  • Polarization constraints on the X-ray corona in Seyfert Galaxies : MCG-05-23-16
  • 2022
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 516:4, s. 5907-5913
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on the first observation of a radio-quiet active galactic nucleus (AGN) in polarized X-rays: the Seyfert 1.9 galaxy MCG-05-23-16. This source was pointed at with the Imaging X-ray Polarimetry Explorer (IXPE) starting on 2022 May 14 for a net observing time of 486 ks, simultaneously with XMM-Newton (58 ks) and NuSTAR (83 ks). A polarization degree Π smaller than 4.7 per cent (at the 99 per cent confidence level) is derived in the 2–8 keV energy range, where emission is dominated by the primary component ascribed to the hot corona. The broad-band spectrum, inferred from a simultaneous fit to the IXPE, NuSTAR, and XMM-Newton data, is well reproduced by a power law with photon index Γ = 1.85 ± 0.01 and a high-energy cutoff EC = 120 ± 15 keV. A comparison with Monte Carlo simulations shows that a lamp-post and a conical geometry of the corona are consistent with the observed upper limit, a slab geometry is allowed only if the inclination angle of the system is less than 50°.
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9.
  • Kaput, J, et al. (författare)
  • The case for strategic international alliances to harness nutritional genomics for public and personal health
  • 2005
  • Ingår i: The British journal of nutrition. - : Cambridge University Press (CUP). - 0007-1145 .- 1475-2662. ; 94:5, s. 623-632
  • Tidskriftsartikel (refereegranskat)abstract
    • Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene–nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient–genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.
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10.
  • Patyra, K., et al. (författare)
  • Congenital Hypothyroidism and Hyperthyroidism Alters Adrenal Gene Expression, Development, and Function
  • 2022
  • Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 32:4, s. 459-471
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The human adrenal cortex undergoes several rapid remodeling steps during its lifetime. In rodents, similar remodeling occurs postnatally in the "X-zone" layer through unknown mechanisms. Furthermore, little is known regarding the impact of thyroid hormone (TH) on adrenal glands in humans.Methods: To investigate the impact of TH on adrenal pathophysiology, we created two genetic murine models mimicking human nonautoimmune hypothyroidism and hyperthyroidism. Moreover, we analyzed serum thyrotropin (TSH) and steroid hormone concentrations in patients diagnosed with congenital hypothyroidism and premature adrenarche (PA).Results: We found that TH receptor beta-mediated hypertrophy of the X-zone significantly elevated the adrenal weights of hyperthyroid women. In the hypothyroid model, the X-zone was poorly developed in both sexes. Moreover, large reciprocal changes in the expression levels of genes that regulate adrenal cortical function were observed with both models. Unexpectedly, up- and downregulation of several genes involved in catecholamine synthesis were detected in the adrenal glands of the hypothyroid and hyperthyroid models, respectively. Furthermore, TSH and adrenal steroid concentrations correlated positively in pediatric patients with congenital hypothyroidism and PA.Conclusions: Our results revealed that congenital hypothyroidism and hyperthyroidism functionally affect adrenal gland development and related steroidogenic activity, as well as the adrenal medulla.
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11.
  • Pollinger, F., et al. (författare)
  • The European GeoMetre project : developing enhanced large-scale dimensional metrology for geodesy
  • 2023
  • Ingår i: Applied Geomatics. - : Springer Science and Business Media Deutschland GmbH. - 1866-9298 .- 1866-928X. ; 15:2, s. 371-381
  • Tidskriftsartikel (refereegranskat)abstract
    • We provide a survey on the joint European research project “GeoMetre”, which explores novel technologies and their inclusion to existing surveying strategies to improve the traceability of geodetic reference frames to the SI definition of the metre. This work includes the development of novel distance meters with a range of up to 5 km, the realisation of optical multilateration systems for large structure monitoring at an operation distance of 50 m and beyond, and a novel strategy for GNSS-based distance determination. Different methods for refractivity compensation, based on classical sensors, on dispersion, on spectroscopic thermometry, and on the speed of sound to reduce the meteorological uncertainties in precise distance measurements, are developed further and characterised. These systems are validated at and applied to the novel European standard baseline EURO5000 at the Pieniny Kippen Belt, Poland, which was completely refurbished and intensely studied in this project. We use our novel instruments for a reduced uncertainty of the scale in the surveillance networks solutions for local tie measurements at space-geodetic co-location stations. We also investigate novel approaches like close-range photogrammetry to reference point determination of space-geodetic telescopes. Finally, we also investigate the inclusion of the local gravity field to consider the deviations of the vertical in the data analysis and to reduce the uncertainty of coordinate transformations in this complex problem. 
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12.
  • Roa, J., et al. (författare)
  • Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
  • 2022
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1/kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function. Kiss1 neurons are essential for puberty and fertility. Here, the authors show that canonical microRNA biosynthesis in Kiss1 neurons plays an essential role in the control of puberty and fertility, especially in females, likely via repression of repressors on the Kiss1 gene.
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13.
  • Uusitupa, M., et al. (författare)
  • Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome : a randomized study (SYSDIET)
  • 2013
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 274:1, s. 52-66
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. Methods We conducted a randomized dietary study lasting for 18-24weeks in individuals with features of metabolic syndrome (mean age 55years, BMI 31.6kgm-2, 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. Results Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmolL-1 95% CI -0.35; -0.01, P=0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P=0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P=0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37ngL-1, P= 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P=0.049) and magnesium (mg, -0.23, -0.41; -0.05, P=0.012) were associated with IL-1 Ra. Conclusions Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.
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14.
  • El Kharraz, S., et al. (författare)
  • The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation
  • 2021
  • Ingår i: Embo Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 22:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Whereas dimerization of the DNA-binding domain of the androgen receptor (AR) plays an evident role in recognizing bipartite response elements, the contribution of the dimerization of the ligand-binding domain (LBD) to the correct functioning of the AR remains unclear. Here, we describe a mouse model with disrupted dimerization of the AR LBD (AR(Lmon/Y)). The disruptive effect of the mutation is demonstrated by the feminized phenotype, absence of male accessory sex glands, and strongly affected spermatogenesis, despite high circulating levels of testosterone. Testosterone replacement studies in orchidectomized mice demonstrate that androgen-regulated transcriptomes in AR(Lmon/Y) mice are completely lost. The mutated AR still translocates to the nucleus and binds chromatin, but does not bind to specific AR binding sites. In vitro studies reveal that the mutation in the LBD dimer interface also affects other AR functions such as DNA binding, ligand binding, and co-regulator binding. In conclusion, LBD dimerization is crucial for the development of AR-dependent tissues through its role in transcriptional regulation in vivo. Our findings identify AR LBD dimerization as a possible target for AR inhibition.
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15.
  • Franssen, D, et al. (författare)
  • AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction.
  • 2021
  • Ingår i: Metabolism: clinical and experimental. - 1532-8600. ; 115
  • Tidskriftsartikel (refereegranskat)abstract
    • Reproduction is tightly coupled to body energy and metabolic status. GnRH neurons, master elements and final output pathway for the brain control of reproduction, directly or indirectly receive and integrate multiple metabolic cues to regulate reproductive function. Yet, the molecular underpinnings of such phenomenon remain largely unfolded. AMP-activated protein kinase (AMPK), the fundamental cellular sensor that becomes activated in conditions of energy deficit, has been recently shown to participate in the control of Kiss1 neurons, essential gatekeepers of the reproductive axis, by driving an inhibitory valence in situations of energy scarcity at puberty. However, the contribution of AMPK signaling specifically in GnRH neurons to the metabolic control of reproduction remains unknown.Double immunohistochemistry (IHC) was applied to evaluate expression of active (phosphorylated) AMPK in GnRH neurons and a novel mouse line, named GAMKO, with conditional ablation of the AMPK α1 subunit in GnRH neurons, was generated. GAMKO mice of both sexes were subjected to reproductive characterization, with attention to puberty and gonadotropic responses to kisspeptin and metabolic stress.A vast majority (>95%) of GnRH neurons co-expressed pAMPK. Female (but not male) GAMKO mice displayed earlier puberty onset and exaggerated LH (as surrogate marker of GnRH) responses to kisspeptin-10 at the prepubertal age. In adulthood, GAMKO females retained increased LH responsiveness to kisspeptin and showed partial resilience to the inhibitory effects of conditions of negative energy balance on the gonadotropic axis. The modulatory role of AMPK in GnRH neurons required preserved ovarian function, since the differences in LH pulsatility detected between GAMKO and control mice subjected to fasting were abolished in ovariectomized animals.Altogether, our data document a sex-biased, physiological role of AMPK signaling in GnRH neurons, as molecular conduit of the inhibitory actions of conditions of energy deficit on the female reproductive axis.
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16.
  • Kalinen, Sofia, et al. (författare)
  • Differences in Gut Microbiota Profiles and Microbiota Steroid Hormone Biosynthesis in Men with and Without Prostate Cancer.
  • 2024
  • Ingår i: European urology open science. - 2666-1683. ; 62, s. 140-150
  • Tidskriftsartikel (refereegranskat)abstract
    • Although prostate cancer (PCa) is the most common cancer in men in Western countries, there is significant variability in geographical incidence. This might result from genetic factors, discrepancies in screening policies, or differences in lifestyle. Gut microbiota has recently been associated with cancer progression, but its role in PCa is unclear.Characterization of the gut microbiota and its functions associated with PCa.In a prospective multicenter clinical trial (NCT02241122), the gut microbiota profiles of 181 men with a clinical suspicion of PCa were assessed utilizing 16S rRNA sequencing.Sequences were assigned to operational taxonomic units, differential abundance analysis, and α- and β-diversities, and predictive functional analyses were performed. Plasma steroid hormone levels corresponding to the predicted microbiota steroid hormone biosynthesis profiles were investigated.Of 364 patients, 181 were analyzed, 60% of whom were diagnosed with PCa. Microbiota composition and diversity were significantly different in PCa, partially affected by Prevotella 9, the most abundant genus of the cohort, and significantly higher in PCa patients. Predictive functional analyses revealed higher 5-α-reductase, copper absorption, and retinol metabolism in the PCa-associated microbiome. Plasma testosterone was associated negatively with the predicted microbial 5-α-reductase level.Gut microbiota of the PCa patients differed significantly compared with benign individuals. Microbial 5-α-reductase, copper absorption, and retinol metabolism are potential mechanisms of action. These findings support the observed association of lifestyle, geography, and PCa incidence.In this report, we found that several microbes and potential functions of the gut microbiota are altered in prostate cancer compared with benign cases. These findings suggest that gut microbiota could be the link between environmental factors and prostate cancer.
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17.
  • Knuuttila, M., et al. (författare)
  • Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer
  • 2018
  • Ingår i: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 25:9, s. 807-819
  • Tidskriftsartikel (refereegranskat)abstract
    • Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (P < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG- negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and - negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.
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18.
  • Kuuttila, J., et al. (författare)
  • Flux decay during thermonuclear X-ray bursts analysed with the dynamic power-law index method
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 604
  • Tidskriftsartikel (refereegranskat)abstract
    • The cooling of type-I X-ray bursts can be used to probe the nuclear burning conditions in neutron star envelopes. The flux decay of the bursts has been traditionally modelled with an exponential, even if theoretical considerations predict power-law-like decays. We have analysed a total of 540 type-I X-ray bursts from five low-mass X-ray binaries observed with the Rossi X-ray Timing Explorer. We grouped the bursts according to the source spectral state during which they were observed (hard or soft), flagging those bursts that showed signs of photospheric radius expansion (PRE). The decay phase of all the bursts were then fitted with a dynamic power-law index method. This method provides a new way of probing the chemical composition of the accreted material. Our results show that in the hydrogen-rich sources the power-law decay index is variable during the burst tails and that simple cooling models qualitatively describe the cooling of presumably helium-rich sources 4U 1728-34 and 3A 1820-303. The cooling in the hydrogen-rich sources 4U 1608-52, 4U 1636-536, and GS 1826-24, instead, is clearly different and depends on the spectral states and whether PRE occurred or not. Especially the hard state bursts behave differently than the models predict, exhibiting a peculiar rise in the cooling index at low burst fluxes, which suggests that the cooling in the tail is much faster than expected. Our results indicate that the drivers of the bursting behaviour are not only the accretion rate and chemical composition of the accreted material, but also the cooling that is somehow linked to the spectral states. The latter suggests that the properties of the burning layers deep in the neutron star envelope might be impacted differently depending on the spectral state.
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19.
  • Lietzow, J., et al. (författare)
  • Comparative Analysis of the Effects of Long-Term 3,5-diiodothyronine Treatment on the Murine Hepatic Proteome and Transcriptome Under Conditions of Normal Diet and High-Fat Diet
  • 2021
  • Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 31:7, s. 1135-1146
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Materials and Methods: Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 mu g/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. Results: We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. Conclusion: While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.
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20.
  • Nättilä, J., et al. (författare)
  • Equation of state constraints for the cold dense matter inside neutron stars using the cooling tail method
  • 2016
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 591
  • Tidskriftsartikel (refereegranskat)abstract
    • The cooling phase of thermonuclear (type-I) X-ray bursts can be used to constrain neutron star (NS) compactness by comparing the observed cooling tracks of bursts to accurate theoretical atmosphere model calculations. By applying the so-called cooling tail method, where the information from the whole cooling track is used, we constrain the mass, radius, and distance for three different NSs in low-mass X-ray binaries 4U 1702-429, 4U 1724-307, and SAX J1810.8-260. Care is taken to use only the hard state bursts where it is thought that the NS surface alone is emitting. We then use a Markov chain Monte Carlo algorithm within a Bayesian framework to obtain a parameterized equation of state (EoS) of cold dense matter from our initial mass and radius constraints. This allows us to set limits on various nuclear parameters and to constrain an empirical pressure-density relationship for the dense matter. Our predicted EoS results in NS a radius between 10.5-12.8 km (95% confidence limits) for a mass of 1.4 M, depending slightly on the assumed composition. Because of systematic errors and uncertainty in the composition, these results should be interpreted as lower limits for the radius.
  •  
21.
  • Velasco, I., et al. (författare)
  • Gonadal hormone-dependent vs. -independent effects of kisspeptin signaling in the control of body weight and metabolic homeostasis
  • 2019
  • Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 98:September, s. 84-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Kisspeptins, encoded by Kiss1, have emerged as essential regulators of puberty and reproduction by primarily acting on GnRH neurons, via their canonical receptor, Gpr54. Mounting, as yet fragmentary, evidence strongly suggests that kisspeptin signaling may also participate in the control of key aspects of body energy and metabolic homeostasis. However, characterization of such metabolic dimension of kisspeptins remains uncomplete, without an unambiguous discrimination between the primary metabolic actions of kisspeptins vs. those derived from their ability to stimulate the secretion of gonadal hormones, which have distinct metabolic actions on their own. In this work, we aimed to tease apart primary vs. secondary effects of kisspeptins in the control of key aspects of metabolic homeostasis using genetic models of impaired kisspeptin signaling and/or gonadal hormone status. Methods: Body weight (BW) gain and composition, food intake and key metabolic parameters, including glucose tolerance, were comparatively analyzed, in lean and obesogenic conditions, in mice lacking kisspeptin signaling due to global inactivation of Gpr54 (displaying profound hypogonadism; Gpr54−/−) vs. Gpr54 null mice with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54−/−Tg), where kisspeptin signaling elsewhere than in GnRH neurons is ablated but gonadal function is preserved. Results: In male mice, global elimination of kisspeptin signaling resulted in decreased BW, feeding suppression and increased adiposity, without overt changes in glucose tolerance, whereas Gpr54−/− female mice displayed enhanced BW gain at adulthood, increased adiposity and perturbed glucose tolerance, despite reduced food intake. Gpr54−/−Tg rescued mice showed altered postnatal BW gain in males and mildly perturbed glucose tolerance in females, with intermediate phenotypes between control and global KO animals. Yet, body composition and leptin levels were similar to controls in gonadal-rescued mice. Exposure to obesogenic insults, such as high fat diet (HFD), resulted in exaggerated BW gain and adiposity in global Gpr54−/− mice of both sexes, and worsening of glucose tolerance, especially in females. Yet, while rescued Gpr54−/−Tg males displayed intermediate BW gain and feeding profiles and impaired glucose tolerance, rescued Gpr54−/−Tg females behaved as controls, except for a modest deterioration of glucose tolerance after ovariectomy. Conclusion: Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner. Summary of translational relevance: Kisspeptins, master regulators of reproduction, may also participate in the control of key aspects of body energy and metabolic homeostasis; yet, the nature of such metabolic actions remains debatable, due in part to the fact that kisspeptins modulate gonadal hormones, which have metabolic actions on their own. By comparing the metabolic profiles of two mouse models with genetic inactivation of kisspeptin signaling but different gonadal status (hypogonadal vs. preserved gonadal function), we provide herein a systematic dissection of gonadal-dependent vs. -independent metabolic actions of kisspeptins. Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner. These data pave the way for future analyses addressing the eventual contribution of altered kisspeptin signaling in the development of metabolic alterations especially in conditions linked to reproductive dysfunction. © 2019 Elsevier Inc.
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22.
  • Wu, Jianyao, et al. (författare)
  • Androgen receptor SUMOylation regulates bone mass in male mice
  • 2019
  • Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 479:January, s. 117-122
  • Tidskriftsartikel (refereegranskat)abstract
    • The crucial effects of androgens on the male skeleton are at least partly mediated via the androgen receptor (AR). In addition to hormone binding, the AR activity is regulated by post-translational modifications, including SUMOylation. SUMOylation is a reversible modification in which Small Ubiquitin-related MOdifier proteins (SUMOs) are attached to the AR and thereby regulate the activity of the AR and change its interactions with other proteins. To elucidate the importance of SUMOylation of AR for male bone metabolism, we used a mouse model devoid of the two AR SUMOylation sites (AR(SUM-);K381R and K500R are substituted). Six-month-old male AR(SUM-) mice displayed significantly reduced trabecular bone volume fraction in the distal metaphyseal region of femur compared with wild type (WT) mice (BV/TV, -19.1 +/- 4.9%, P < 0.05). The number of osteoblasts per bone perimeter was substantially reduced (-60.5 +/- 7.2%, P < 0.001) while no significant effect was observed on the number of osteoclasts in the trabecular bone of male AR(SUM-) mice. Dynamic histomorphometric analysis of trabecular bone revealed a reduced bone formation rate (-32.6 +/- 7.4%, P < 0.05) as a result of reduced mineralizing surface per bone surface in AR(SUM-) mice compared with WT mice (-24.3 +/- 3.6%, P < 0.001). Furthermore, cortical bone thickness in the diaphyseal region of femur was reduced in male AR(SUM-) mice compared with WT mice (-7.3 +/- 2.0%, P < 0.05). In conclusion, mice devoid of AR SUMOylation have reduced trabecular bone mass as a result of reduced bone formation. We propose that therapies enhancing AR SUMOylation might result in bone-specific anabolic effects with minimal adverse effects in other tissues.
  •  
23.
  • Barroso, A., et al. (författare)
  • Neonatal exposure to androgens dynamically alters gut microbiota architecture
  • 2020
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 247:1, s. 69-85
  • Tidskriftsartikel (refereegranskat)abstract
    • Gonadal steroids strongly contribute to the metabolic programming that shapes the susceptibility to the manifestation of diseases later in life, and the effect is often sexually dimorphic. Microbiome signatures, together with metabolic traits and sex steroid levels, were analyzed at adulthood in neonatally androgenized female rats, and compared with those of control male and female rats. Exposure of female rats to high doses of androgens on early postnatal life resulted in persistent alterations of the sex steroid profile later on life, namely lower progesterone and higher estr adiol and estrone levels, with no effect on endogenous androgens. Neonatally androgenized females were heavier (10% at early adulthood and 26% at adulthood) than controls and had impaired glucose homeostasis observed by higher AUC of glucose in GTT and ITT when subjected to obesogenic manipulations. Androgenized female displayed overt alterations in gut microbiota, indicated especially by higher Bacteroidetes and lower Firmicutes abundance at early adulthood, which disappeared when animals were concurrently overfed at adulthood. Notably, these changes in gut microbiota were related with the intestinal expression of several miRNAs, such as miR-27a-3p, miR-29a-5p, and miR-100-3p. Our results suggest that nutritional and hormonal disruption at early developmental periods not only alters the metabolic programming of the individual later in life but also perturbs the architecture of gut microbiota, which may interact with the host by a cross-talk mediated by intestinal miRNAs; phenomena that may contribute to amplify the metabolic derangement caused by obesity, as seen in neonatally androgenized female rats.
  •  
24.
  • Dragsted, L., et al. (författare)
  • Metabolomic response to Nordic foods
  • 2015
  • Ingår i: Annals of Nutrition and Metabolism. - 0250-6807 .- 1421-9697. ; 67, s. 55-55
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
  •  
25.
  • Gathercole, L. L., et al. (författare)
  • AKR1D1 knockout mice develop a sex-dependent metabolic phenotype
  • 2022
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 253:3, s. 97-113
  • Tidskriftsartikel (refereegranskat)abstract
    • Steroid 5 beta-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids and glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Akr1d1(-/-) mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile add homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin tolerance were evaluated. Molecular changes were assessed by RNA-Seq and Western blotting. Male Akr1d1(-/-) mice were challenged with a high fat diet (60% kcal from fat) for 20 weeks. Akr1d1(-/-) mice had a sex-specific metabolic phenotype. At 30 weeks of age, male, but not female, Akr1d1(-/-) mice were more insulin tolerant and had reduced lipid accumulation in the liver and adipose tissue yet had hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was associated with sexually dimorphic changes in bile acid metabolism and composition but without overt effects on circulating glucocorticoid levels or glucocorticoid-regulated gene expression in the liver. Male Akr1d1(-/-) mice were not protected against diet-induced obesity and insulin resistance. In conclusion, this study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.
  •  
26.
  • Kajava, J. J. E., et al. (författare)
  • Detection of burning ashes from thermonuclear X-ray bursts
  • 2017
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966 .- 1745-3925 .- 1745-3933. ; 464:1, s. L6-L10
  • Tidskriftsartikel (refereegranskat)abstract
    • When neutron stars (NS) accrete gas from low-mass binary companions, explosive nuclear burning reactions in the NS envelope fuse hydrogen and helium into heavier elements. The resulting thermonuclear (type-I) X-ray bursts produce energy spectra that are fit well with black bodies, but a significant number of burst observations show deviations from Planck spectra. Here we present our analysis of RXTE/ PCA observations of X-ray bursts from the NS low-mass X-ray binary HETE J1900.1-2455. We have discovered that the non-Planckian spectra are caused by photoionization edges. The anticorrelation between the strength of the edges and the colour temperature suggests that the edges are produced by the nuclear burning ashes that have been transported upwards by convection and become exposed at the photosphere. The atmosphere model fits show that occasionally the photosphere can consist entirely of metals, and that the peculiar changes in blackbody temperature and radius can be attributed to the emergence and disappearance of metals in the photosphere. As the metals are detected already in the Eddington-limited phase, it is possible that a radiatively driven wind ejects some of the burning ashes into the interstellar space.
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27.
  • Kajava, J. J. E., et al. (författare)
  • Variable spreading layer in 4U 1608-52 during thermonuclear X-ray bursts in the soft state
  • 2017
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 472:1, s. 78-89
  • Tidskriftsartikel (refereegranskat)abstract
    • Thermonuclear (type-I) X-ray bursts, observed from neutron star (NS) low-massX-ray binaries (LMXB), provide constraints on NS masses and radii and consequently the equation of state of NS cores. In such analyses, various assumptions are made without knowing if they are justified. We have analysed X-ray burst spectra from the LMXB 4U 1608-52, with the aim of studying how the different persistent emission components react to the bursts. During some bursts in the soft spectral state we find that there are two variable components: one corresponding to the burst blackbody component and another optically thick Comptonized component. We interpret the latter as the spreading layer between the NS surface and the accretion disc, which is not present during the hard-state bursts. We propose that the spectral changes during the soft-state bursts are driven by the spreading layer that could cover almost the entire NS in the brightest phases due to the enhanced radiation pressure support provided by the burst, and that the layer subsequently returns to its original state during the burst decay. When deriving the NS mass and radius using the soft-state bursts two assumptions are therefore not met: the NS is not entirely visible and the burst emission is reprocessed in the spreading layer, causing distortions of the emitted spectrum. For these reasons, the NS mass and radius constraints using the soft-state bursts are different compared to the ones derived using the hard-state bursts.
  •  
28.
  • Kajava, J. J. E., et al. (författare)
  • X-ray burst-induced spectral variability in 4U 1728-34
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 599
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims. INTEGRAL has been monitoring the Galactic center region for more than a decade. Over this time it has detected hundreds of type-I X-ray bursts from the neutron star low-mass X-ray binary 4U 1728-34, also known as the slow burster. Our aim is to study the connection between the persistent X-ray spectra and the X-ray burst spectra in a broad spectral range. Methods. We performed spectral modeling of the persistent emission and the X-ray burst emission of 4U 1728-34 using data from the INTEGRAL JEM-X and IBIS/ISGRI instruments. Results. We constructed a hardness intensity diagram to track spectral state variations. In the soft state, the energy spectra are characterized by two thermal components likely coming from the accretion disc and the boundary/spreading layer, together with a weak hard X-ray tail that we detect in 4U 1728-34 for the first time in the similar to 40 to 80 keV range. In the hard state, the source is detected up to similar to 200 keV and the spectrum can be described by a thermal Comptonization model plus an additional component: either a powerlaw tail or reflection. By stacking 123 X-ray bursts in the hard state, we detect emission up to 80 keV during the X-ray bursts. We find that during the bursts the emission above 40 keV decreases by a factor of approximately three with respect to the persistent emission level. Conclusions. Our results suggest that the enhanced X-ray burst emission changes the spectral properties of the accretion disc in the hard state. The likely cause is an X-ray burst induced cooling of the electrons in the inner hot flow near the neutron star.
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29.
  • Movérare-Skrtic, Sofia, et al. (författare)
  • The bone-sparing effects of estrogen and WNT16 are independent of each other
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:48, s. 14972-14977
  • Tidskriftsartikel (refereegranskat)abstract
    • Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16-/- mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females isWNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl- Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl- Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16-/- mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16-/- and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16- targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.
  •  
30.
  • Nättilä, Jonas, et al. (författare)
  • Neutron star mass and radius measurements from atmospheric model fits to X-ray burst cooling tail spectra
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 608
  • Tidskriftsartikel (refereegranskat)abstract
    • Observations of thermonuclear X-ray bursts from accreting neutron stars (NSs) in low-mass X-ray binary systems can be used to constrain NS masses and radii. Most previous work of this type has set these constraints using Planck function fits as a proxy: the models and the data are both fit with diluted blackbody functions to yield normalizations and temperatures that are then compared with each other. For the first time, we here fit atmosphere models of X-ray bursting NSs directly to the observed spectra. We present a hierarchical Bayesian fitting framework that uses current X-ray bursting NS atmosphere models with realistic opacities and relativistic exact Compton scattering kernels as a model for the surface emission. We test our approach against synthetic data and find that for data that are well described by our model, we can obtain robust radius, mass, distance, and composition measurements. We then apply our technique to Rossi X-ray Timing Explorer observations of five hard-state X-ray bursts from 4U 1702-429. Our joint fit to all five bursts shows that the theoretical atmosphere models describe the data well, but there are still some unmodeled features in the spectrum corresponding to a relative error of 1-5% of the energy flux. After marginalizing over this intrinsic scatter, we find that at 68% credibility, the circumferential radius of the NS in 4U 1702-429 is R = 12.4 +/- 0.4 km, the gravitational mass is M = 1.9 +/- 0.3 M-circle dot, the distance is 5.1 < D/kpc < 6.2, and the hydrogen mass fraction is X < 0.09.
  •  
31.
  • Pollinger, F., et al. (författare)
  • Metrology for long distance surveying : A joint attempt to improve traceability of long distance measurements
  • 2016
  • Ingår i: IAG 150 Years. - Cham : Springer International Publishing. - 9783319246031 ; , s. 651-656
  • Konferensbidrag (refereegranskat)abstract
    • Based on the current state of technology, distance measurements over a few hundred metres in air with relative uncertainties significantly better than 10_6 are still an almost impossible challenge. In the European Joint Research Project (JRP) “Metrology for long distance surveying” measurement uncertainties in GNSS-based and optical distance metrology are going to be thoroughly investigated, novel technologies and primary standards developed and guidelines to improve surveying practice in the field worked out. A better understanding and a decrease of measurement uncertainty is also targeted for the critical local tie measurement at geodetic fundamental stations.
  •  
32.
  • Poutanen, J., et al. (författare)
  • The nature of spectral transitions in accreting black holes - The case of CYG X-1
  • 1997
  • Ingår i: \mnras. ; 292
  • Tidskriftsartikel (refereegranskat)abstract
    • Accreting black holes radiate in one of several spectral states, switching from one to another for reasons that are as yet not understood. Using the best-studied example, Cyg X-1, we identify the geometry and physical conditions characterizing these states. In particular, we show that in the hard state most of the accretion energy is dissipated in a corona-like structure which fills the inner few tens of gravitational radii around the black hole and has Compton optical depth of order unity. In this state, an optically thick accretion disk extends out to greater distance, but penetrates only a short way into the coronal region. In the soft state, the optically thick disk moves inward and receives the majority of the dissipated energy, while the ’corona’ becomes optically thin and extends around much of the inner disk. The mass-accretion rate in both states is about 1 x 10 exp -8 solar mass/yr.
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33.
  • Sánchez-Fernández, C., et al. (författare)
  • Burst-induced coronal cooling in GS 1826-24 The clock wagging its tail
  • 2020
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 634
  • Tidskriftsartikel (refereegranskat)abstract
    • Type I X-ray bursts in GS 1826-24, and in several other systems, may induce cooling of the hot inner accretion flow that surrounds the bursting neutron star. Given that GS 1826-24 remained persistently in the hard state over the period 2003-2008 and presented regular bursting properties, we stacked the spectra of the X-ray bursts detected by INTEGRAL (JEM-X and ISGRI) and XMM-Newton (RGS) during that period to study the effect of the burst photons on the properties of the Comptonizing medium. The extended energy range provided by these instruments allows the simultaneous observation of the burst and persistent emission spectra. We detect an overall change in the shape of the persistent emission spectrum in response to the burst photon shower. For the first time, we observe simultaneously a drop in the hard X-ray emission, together with a soft X-ray excess with respect to the burst blackbody emission. The hard X-ray drop can be explained by burst-induced coronal cooling, while the bulk of the soft X-ray excess can be described by fitting the burst emission with an atmosphere model, instead of a simple blackbody model. Traditionally, the persistent emission was assumed to be invariant during X-ray bursts, and more recently to change only in normalization but not in spectral shape; the observed change in the persistent emission level during X-ray bursts may thus trigger the revision of existing neutron star mass-radius constraints, as the derived values rely on the assumption that the persistent emission does not change during X-ray bursts. The traditional burst fitting technique leads to up to a 10% overestimation of the bolometric burst flux in GS 1826-24, which significantly hampers the comparisons of the KEPLER and MESA model against this textbook burster.
  •  
34.
  • Vehmas, A. P., et al. (författare)
  • Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse
  • 2016
  • Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919. ; 133, s. 66-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM + mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal beta-oxidation in the liver of AROM + mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM + liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM + mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal beta-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism. (C) 2015 Elsevier B.V. All rights reserved.
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35.
  • Zhang, F. P., et al. (författare)
  • Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction
  • 2019
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKl) in which the conserved SUMO acceptor lysines of AR are permanently abolished (Ar-K381R, (K500R)) ArKl males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKl males are infertile. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice.
  •  
36.
  • Adam, M., et al. (författare)
  • Hydroxysteroid (17 beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice
  • 2018
  • Ingår i: Faseb Journal. - 0892-6638. ; 32:6, s. 3434-3447
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydroxysteroid (17(3) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd1 7b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcamitines, suggesting impaired mitochondrial beta-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsdl7b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.
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37.
  •  
38.
  • Antonson, P., et al. (författare)
  • Generation of an all-exon Esr2 deleted mouse line: Effects on fertility
  • 2020
  • Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 529:2, s. 231-237
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor beta (ER beta), encoded by the Esr2 gene, is one of two nuclear receptors that mediate the functions of the steroid hormone estradiol. The binding of estradiol to the receptor results in enhanced transcription of many genes that have estrogen response elements in promoter or enhancer regions. Several genetically modified mouse lines with mutations or deletions of exons in the Esr2 gene have been developed and results from analysis of these are not completely consistent, especially regarding ER beta's role in fertility. To address these controversies, we have used the CRISPR/Cas9 genome editing system to make a deletion of the entire Esr2 gene in the mouse genome and determined the effect of this mutation on fertility. We show that female Esr2 deleted mice, Esr2(Delta E1-10), are subfertile at young age, with fewer litters and smaller litter size, and that they become infertile/have severely reduced fertility at around six months of age, while the male Esr2(Delta E1-10) mice are fertile. Ovaries from Esr2(Delta E1-10) mice are smaller than those from wild-type littermates and the morphology of the ovary displays very few corpora lutea, indicating a defect in ovulation. We also show that the estradiol levels are reduced at diestrus, the phase in the estrous cycle when levels are expected to start to increase before ovulation. Our results verify that ER beta has an important function in female reproduction, likely as a regulator of serum estradiol levels, and that its loss does not affect male reproductive function. (C) 2020 The Authors. Published by Elsevier Inc.
  •  
39.
  • Bjorkgren, I., et al. (författare)
  • Targeted inactivation of the mouse epididymal beta-defensin 41 alters sperm flagellar beat pattern and zona pellucida binding
  • 2016
  • Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 427:C, s. 143-154
  • Tidskriftsartikel (refereegranskat)abstract
    • During epididymal maturation, sperm acquire the ability to swim progressively by interacting with proteins secreted by the epididymal epithelium. Beta-defensin proteins, expressed in the epididymis, continue to regulate sperm motility during capacitation and hyperactivation in the female reproductive tract. We characterized the mouse beta-defensin 41 (DEFB41), by generating a mouse model with iCre recombinase inserted into the first exon of the gene. The homozygous Defb41(iCre/iCre) knock-in mice lacked Defb41 expression and displayed iCre recombinase activity in the principal cells of the proximal epididymis. Heterozygous Defb41(iCre/+) mice can be used to generate epididymis specific conditional knock-out mouse models. Homozygous Defb41(iCre/iCre) sperm displayed a defect in sperm motility with the flagella primarily bending in the pro-hook conformation while capacitated wild-type sperm more often displayed the anti-hook conformation. This led to a reduced straight line motility of Defb41(iCre/liCre) sperm and weaker binding to the oocyte. Thus, DEFB41 is required for proper sperm maturation.
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40.
  • Brader, Lea, et al. (författare)
  • Effects of a healthy Nordic diet on plasma 25-hydroxyvitamin D concentration in subjects with metabolic syndrome: a randomized, placebo-controlled trial (SYSDIET)
  • 2014
  • Ingår i: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6215 .- 1436-6207. ; 53:4, s. 1123-1134
  • Tidskriftsartikel (refereegranskat)abstract
    • At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors. In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (a parts per thousand yen300 g/week, including a parts per thousand yen200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention. At baseline, 45 % had vitamin D inadequacy (< 50 nmol/l), whereas 8 % had deficiency (< 25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes. Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.
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41.
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42.
  • Elo, Teresa D., et al. (författare)
  • Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice
  • 2010
  • Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 12:11, s. 94-915
  • Tidskriftsartikel (refereegranskat)abstract
    • Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.
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43.
  • Grimaldi, Giulia, et al. (författare)
  • Down-regulation of the histone methyltransferase EZH2 contributes to the epigenetic programming of decidualizing human endometrial stromal cells.
  • 2011
  • Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 25:11, s. 1892-903
  • Tidskriftsartikel (refereegranskat)abstract
    • Differentiation of human endometrial stromal cells (HESC) into decidual cells represents a highly coordinated process essential for embryo implantation. We show that decidualizing HESC down-regulate the histone methyltransferase enhancer of Zeste homolog 2 (EZH2), resulting in declining levels of trimethylation of histone 3 on lysine 27 (H3K27me3) at the proximal promoters of key decidual marker genes PRL and IGFBP1. Loss of H3K27me3 was associated with a reciprocal enrichment in acetylation of the same lysine residue, indicating active remodeling from repressive to transcriptionally permissive chromatin. Chromatin immunoprecipitation coupled with DNA microarray analysis demonstrated that decidualization triggers genome-wide changes in H3K27me3 distribution that only partly overlap those observed upon EZH2 knockdown in undifferentiated HESC. Gene ontology revealed that gain of the repressive H3K27me3 mark in response to decidualization and upon EZH2 knockdown in undifferentiated cells was enriched at the promoter regions of genes involved in transcriptional regulation and growth/cell proliferation, respectively. However, loss of the H3K27me3 mark (indicating increased chromatin accessibility) in decidualizing cells and upon EZH2 knockdown occurred at selective loci enriched for genes functionally implicated in responses to stimulus. In agreement, EZH2 knockdown in undifferentiated HESC was sufficient to augment the induction of decidual marker genes in response to cyclic AMP and progesterone signaling. Thus, loss of EZH2-dependent methyltransferase activity in the endometrium is integral to the process of chromatin remodeling that enables the transition from a proliferative to a decidual phenotype in response to differentiation cues.
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44.
  • Gruber, T, et al. (författare)
  • Geodetic SAR for Height System Unification and Sea Level Research - Observation Concept and Results in the Baltic Sea
  • 2021
  • Konferensbidrag (refereegranskat)abstract
    • Traditionally, sea level is observed at tide gauge stations, which usually also serve as height reference stations for national leveling networks and therefore define a height system of a country. Thus, sea level research across countries is closely linked to height system unification and needs to be regarded jointly. One of the main deficiencies to use tide gauge data for geodetic sea level research and height systems unification is that only a few stations are connected to permanent GNSS receivers next to the tide gauge in order to systematically observe vertical land motion. As a new observation technique, absolute positioning by SAR using active transponders on ground can fill this gap by systematically observing time series of geometric heights at tide gauge stations. By additionally knowing the tide gauge geoid heights in a global height reference frame, one can finally obtain absolute sea level heights at each tide gauge. With this information the impact of climate change on the sea level can be quantified in an absolute manner and height systems can be connected across the oceans. First results from applying this technique at selected tide gauges at the Baltic coasts are promising but also exhibit some problems related to the new technique. The paper presents the concept of using the new observation type in an integrated sea level observing system and provides results for a test network in the Baltic sea area by combining geometric and physical heights with tide gauge readings.
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45.
  • Gürdeniz, Gözde, et al. (författare)
  • Analysis of the SYSDIET Healthy Nordic Diet randomized trial based on metabolic profiling reveal beneficial effects on glucose metabolism and blood lipids
  • 2021
  • Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 41:2, s. 441-451
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic markers.METHODS: During 18-24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolic profiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, and inflammatory markers.RESULTS: The profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipids containing palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = -0.06; 95% CI: -0.09, -0.03; P < 0.001). PC2 scores were related with glucose metabolism (2 h Glucose, β = 0.1; 95% CI: 0.05, 0.15; P < 0.001), LDL (β = 0.06; 95% CI: 0.01, 0.1; P = 0.02) and triglycerides (β = 0.11; 95% CI: 0.06, 0.15; P < 0.001). For urine, the scores were related with LDL cholesterol.CONCLUSIONS: Plasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials. The study was registered at clinicaltrials.gov with NCT00992641.
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46.
  • Hakkarainen, J., et al. (författare)
  • Hydroxysteroid (17 beta)-dehydrogenase 1-deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production
  • 2015
  • Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:9, s. 3806-3816
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydroxysteroid (17 beta)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testosterone (T) and E2, respectively. In this study, the importance of HSD17B1 in ovarian estrogen production was determined using Hsd17b1 knockout (HSD17B1KO) mice. In these mice, the ovarian HSD17B enzyme activity was markedly reduced, indicating a central role of HSD17B1 in ovarian physiology. The lack of Hsd17b activity resulted in increased ovarian E1: E2 and A-dione: T ratios, but we also observed reduced progesterone concentration in HSD17B1KO ovaries. Accordingly with the altered steroid production, altered expression of Star, Cyp11a1, Lhcgr, Hsd17b7, and especially Cyp17a1 was observed. The ovaries of HSD17B1KO mice presented with all stages of folliculogenesis, while the corpus luteums tructure was less defined and number reduced. Surprisingly, bundles of large granular cells of unknown origin appeared in the stroma of the KO ovaries. The HSD17B1KO mice presented with severe subfertility and failed to initiate pseudopregnancy. However, the HSD17B1KO females presented with normal estrous cycle defined by vaginal smears and normal puberty appearance. This study indicates that HSD17B1 is a key enzyme in ovarian steroidogenesis and has a novel function in initiation and stabilization of pregnancy.
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47.
  • Hakkarainen, J., et al. (författare)
  • Hydroxysteroid (17 beta) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility
  • 2018
  • Ingår i: Faseb Journal. - 0892-6638. ; 32:6, s. 3229-3241
  • Tidskriftsartikel (refereegranskat)abstract
    • The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17 beta) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17 beta-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.
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48.
  • Huhtaniemi, R., et al. (författare)
  • Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts
  • 2018
  • Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 188:12, s. 2890-2901
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P4 and in a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor–dependent growth of CRPC. © 2018 American Society for Investigative Pathology
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49.
  • Huhtaniemi, R., et al. (författare)
  • High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
  • 2022
  • Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
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50.
  • Huhtinen, Kaisa, et al. (författare)
  • Endometrial and Endometriotic Concentrations of Estrone and Estradiol Are Determined by Local Metabolism Rather than Circulating Levels.
  • 2012
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 97:11, s. 4228-35
  • Tidskriftsartikel (refereegranskat)abstract
    • Context:Aberrant estrogen synthesis and metabolism have been suggested to increase local estradiol (E2) concentration in endometriosis and thus to promote the growth of the lesions. However, tissue estrogen concentrations within the endometrium and different types of endometriosis lesions have not been described.Objective:The aim of the study was to evaluate local E2 and estrone (E1) concentrations in the endometrium and different types of endometriosis lesions, and to correlate them with the expression of estrogen-metabolizing enzymes.Patients:Patients with endometriosis (n = 60) and healthy controls (n = 16) participated in the study.Main Outcome Measures:We measured serum and tissue concentrations of E2 and E1 as well as mRNA expression of the estrogen-metabolizing enzymes.Results:Endometrial or endometriotic intratissue E2 concentrations did not reflect the corresponding serum levels. In the proliferative phase, endometrial E2 concentration was five to eight times higher than in the serum, whereas in the secretory phase the E2 concentration was about half of that in the serum. Accordingly, a markedly higher E2/E1 ratio was observed in the endometrium at the proliferative phase compared with the secretory phase. In the endometriosis lesions, E2 levels were predominating over those of E1 throughout the menstrual cycle. Among the hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes analyzed, HSD17B2 negatively correlated with the E2 concentration in the endometrium, and HSD17B6 was strongly expressed, especially in the deep lesions.Conclusions:Endometrial or endometriotic tissue E2 concentrations are actively regulated by local estrogen metabolism in the tissue. Thus, the inhibition of local E2 synthesis is a valid, novel approach to reduce local E2-dependent growth of endometriotic tissue.
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