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Sökning: WFRF:(Dabrosin Charlotta)

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  • Dabrosin, Nina, et al. (författare)
  • Postmenopausal Dense Breasts Maintain Premenopausal Levels of GH and Insulin-like Growth Factor Binding Proteins in Vivo
  • 2020
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 105:5
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Context: Dense breast tissue is associated with 4 to 6 times higher risk of breast cancer by poorly understood mechanisms. No preventive therapy for this high-risk group is available. After menopause, breast density decreases due to involution of the mammary gland. In dense breast tissue, this process is haltered by undetermined biological actions. Growth hormone (GH) and insulin-like binding proteins (IGFBPs) play major roles in normal mammary gland development, but their roles in maintaining breast density are unknown. Objective: To reveal in vivo levels of GH, IGFBPs, and other pro-tumorigenic proteins in the extracellular microenvironment in breast cancer, in normal breast tissue with various breast density in postmenopausal women, and premenopausal breasts. We also sought to determine possible correlations between these determinants. Setting and Design: Microdialysis was used to collect extracellular in vivo proteins intratumorally from breast cancers before surgery and from normal human breast tissue from premenopausal women and postmenopausal women with mammographic dense or nondense breasts. Results: Estrogen receptor positive breast cancers exhibited increased extracellular GH (P &amp;lt;.01). Dense breasts of postmenopausal women exhibited similar levels of GH as premenopausal breasts and significantly higher levels than in nondense breasts (P &amp;lt;.001). Similar results were found for IGFBP-1, -2, -3, and -7 (P &amp;lt;.01) and for IGFBP-6 (P &amp;lt;.05). Strong positive correlations were revealed between GH and IGFBPs and pro-tumorigenic matrix metalloproteinases, urokinase-type plasminogen activator, Interleukin 6, Interleukin 8, and vascular endothelial growth factor in normal breast tissue. Conclusions: GH pathways may be targetable for cancer prevention therapeutics in postmenopausal women with dense breast tissue.</p>
  • Abrahamsson, Annelie, et al. (författare)
  • Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo
  • 2016
  • Ingår i: Oncoimmunology. - TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 5:10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.</p>
  • Abrahamsson, Annelie, et al. (författare)
  • Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women
  • 2017
  • Ingår i: OncoTarget. - Impact Journals LCC. - 1949-2553 .- 1949-2553. ; 8:54, s. 92134-92142
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Women with dense breast tissue on mammography are at higher risk of developing breast cancer but the underlying mechanisms are not well understood. De-regulation of microRNAs (miRNAs) has been associated with the onset of breast cancer. miRNAs in the extracellular space participate in the regulation of the local tissue microenvironment. Here, we recruited 39 healthy postmenopausal women attending their mammography-screen that were assessed having extreme dense or entirely fatty breasts (nondense). Microdialysis was performed in breast tissue and a reference catheter was inserted in abdominal subcutaneous fat for local sampling of extracellular compounds. Three miRNAs, associated with tumor suppression, miR-193b, miR-365a, and miR-452 were significantly down-regulated in dense breast tissue compared with nondense breast tissue. In addition, miR-452 exhibited significant negative correlations with several pro-inflammatory cytokines in vivo, which was confirmed in vitro by overexpression of miR-452 in breast cancer cells. No differences were found of miR-21, -29a, -30c, 146a, -148a, -203, or -451 in breast tissue and no miRs were different in plasma. Extracellular miRNAs may be among factors that should be included in studies of novel prevention strategies for breast cancer.</p>
  • Abrahamsson, Annelie, et al. (författare)
  • Equal Pro-inflammatory Profiles of CCLs, CXCLs, and Matrix Metalloproteinases in the Extracellular Microenvironment In Vivo in Human Dense Breast Tissue and Breast Cancer
  • 2018
  • Ingår i: Frontiers in Immunology. - Frontiers Media S.A.. - 1664-3224 .- 1664-3224. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-a, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.</p>
  • Abrahamsson, Annelie, et al. (författare)
  • Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
  • 2012
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - Endocrine Society. - 0021-972X .- 1945-7197. ; 97:11, s. E2044-E2054
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.</p>
  • Abrahamsson, Annelie, 1966-, et al. (författare)
  • Increased nutrient availability in dense breast tissue of postmenopausal women in vivo
  • 2017
  • Ingår i: Scientific Reports. - NATURE PUBLISHING GROUP. - 2045-2322 .- 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.</p>
  • Abrahamsson, Annelie, et al. (författare)
  • Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo
  • 2015
  • Ingår i: OncoTarget. - Albany, NY, United States : Impact Journals LLC. - 1949-2553 .- 1949-2553. ; 6:26, s. 22959-22969
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breast and subcutaneous fat before and after six weeks of tamoxifen therapy, premenopausal women during the menstrual cycle. Samples were initially screened using TaqMan array cards with subsequently absolute quantification. 124 miRNA were expressed in microdialysates. After absolute quantifications extracellular miRNA-21 was found to be significantly increased in breast cancer. In addition, the levels were significantly higher in pre-menopausal breast tissue compared with postmenopausal. In breast tissue of pre-menopausal women miRNA-21 exhibited a cyclic variation during the menstrual cycle and in postmenopausal women six weeks of tamoxifen treatment decreased miRNA-21 suggesting that this miRNA may be important for breast carcinogenesis. None of these changes were found in plasma or microdialysates from subcutaneous fat. Our data revealed tissue specific changes of extracellular circulating miRNAs that would be otherwise unraveled using blood samples.</p>
  • Andersson, Bengt-Åke (författare)
  • Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Huvud- och halscancer (HH-cancer) innefattar tumörer belägna i huvud och halsområdet. Tobaksrökning ökar risken dramatiskt för olika sjukdomar. Knappt hälften av rökande patienter dör i de av rökning orsakade sjukdomarna. Cancer är orsaken till en tredjedel av de rökrelaterade dödsfallen av vilka HH-cancer är en. En andel av patienterna med HH-cancer dör på grund av att tumören varit för stor redan vid diagnos eller att tumören har spridit sig till övriga delar av kroppen. Men för många patienter är det mycket oklart vad som bestämmer behandlingsresultatet. Tumörerna är till synes lika och behandlingen standardiserad.</p><p>Målet med denna doktorsavhandling var att undersöka billiga och lättillgängliga biologiska markörer som kan indikera risk för att drabbas av HH-cancer eller om dessa markörer kan förutspå behandlingsresultat och överlevnad hos de drabbade patienterna. Dessutom undersöktes hur cigarettrökning påverkade nivåerna av markörerna.</p><p>I studie I, undersöktes om molekyler i blodet (biomarkörer), förknippade med immunförsvaret, kunde förutsäga överlevnaden hos HH-cancerpatienter. I jämförelse med friska individer sågs högre nivåer av molekylerna TNF-α och CRP hos patienterna och dessa förhöjningar var relaterade till förkortad överlevnad hos patienterna.</p><p>I studie II, var målet att undersöka om variationer i gener, förknippade med immunförsvaret, celldelning, celldöd eller enzymer som reparerar skadat DNA, kunde påverka risk och prognos för HH-cancer. Resultatet visade framför allt att små ärftliga variationer i gener som reglerar immunförsvaret kunde påverkade risk för HH-cancer, risk för återfall i sjukdomen samt överlevnaden hos patienterna.</p><p>I studie III, jämfördes inflammatoriska och immunförknippade biomarkörer som kunde påverkas av cigarettrökning mellan friska rökare och friska icke-rökare. Rökarna hade en högre inflammatorisk aktivitet med högre nivåer av totalt antal vita blodkroppar och tre av dess olika undergrupper (neutrofiler, monocyter och lymfocyter) samt av biomarköerna CRP, MCP-1 och IFN-γ. De funna lägre nivåerna av den cancerförknippade biomarkören miR-21 och högre nivåer av den förmodat skyddande biomarkören IFN-γ hos rökarna, kan vara ett uttryck för kroppens försvar mot den cancerframkallade cigarettröken. Ärftliga faktorer tycks kunna påverka de högre nivåerna av IFN-γ hos rökarna, eftersom ökningen endast fanns i en grupp individer med viss typ av genetisk uppsättning.</p><p>Eftersom både rökning och HH-cancer ger upphov till inflammation, undersöktes i studie IV hur dessa var för sig påverkade nivåerna av inflammatoriska biomarkörer. Detta för en bättre förståelse hur immunförsvaret reagerar på rökning och HH-cancer. Jämförelser av inflammatoriska markörer från rökande och icke-rökande patienter, och rökande och ickerökande friska individer genomfördes. Rökning hade störst påverkan på de högre nivåerna av totalt antal vita blodkroppar och signalmolekylerna MCP-1 och IFN-γ. HH-cancer hade störst påverkan på högre nivåerna av neutrofiler, monocyter, kvoten mellan neutrofiler och lymfocyter, CRP, MIP-1b och TNF-α.</p><p>Uppkomsten av HH-cancer, behandlingsresultat och överlevnad bland patienterna kan antas inte bara bero på tumörens egenskaper, utan även på värdfaktorer hos patienten. Dessa kan vara ärftliga, eller bero på reglering av gener eller tumörens omgivning av t.ex. immunceller och inflammatoriska molekyler och hur dessa samverkar med miljöfaktorer som tobaksrökning. I denna avhandling presenteras biomarkörer som kan bidra med information om risk och prognos för HH-cancer samt hur tobaksrökning påverkar dessa markörer.</p>
  • Ansell, Anna, 1983- (författare)
  • Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Head and neck squamous cell carcinoma (HNSCC) poses a major health problem in the world with approximately 600 000 new cases yearly. Treatment resistance is a major problem within this patient group and despite advances in treatment strategies the overall survival rate has unfortunately not increased.</p><p>One of the major components of the tumor microenvironment is the cancer associated fibroblasts (CAFs) which can modulate the treatment sensitivity, tumor growth, and the invasive potential of tumor cells.</p><p>The aim of this thesis was to identify predictive markers for treatment response in HNSCC and to study the crosstalk between tumor cells and CAFs that may underlie treatment resistance.</p><p>In paper I, we identified gene expression differences between one cisplatin sensitive cell line and two cisplatin resistant cell lines, by microarray analysis, and found that a high expression of matrix metalloproteinase (MMP) -7 was associated with resistance to cisplatin. In paper II, the epidermal growth factor (EGF) receptor ligands EGF, amphiregulin, and epiregulin were evaluated regarding their potential use as predictive biomarkers for cetuximab treatment response in tongue cancer cell lines and it was shown that EGF may serve as a marker for poor cetuximab response. In paper III and IV, we investigated the influence of CAFs on the proliferation, migration, gene expression, and cetuximab response of tumor cells. It was found that CAFs induced resistance to cetuximab in a MMP-dependent manner. In addition, a microarray analysis, comparing tumor cells co-cultured with CAFs and tumor cells cultured alone, revealed that CAFs induced multiple gene expression changes in tumor cells some of which are related to epithelial to mesenchymal transition. Some of these changes were found to be dependent on cell-cell contact.</p><p>Taken together, we here suggest MMP-7 and EGF to be predictive markers of cisplatin and cetuximab response, respectively. We also show that CAFs protect HNSCC cells from cetuximab treatment; however, the factor responsible for the protective effect is yet to be discovered.</p>
  • Bendrik, Christina, 1964- (författare)
  • Angiogenesis regulation in hormone dependent breast- and ovarian cancer
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Angiogenesis is a key event in tumor progression and a rate-limiting step in the establishment of a clinical cancer disease. The net balance of pro- and anti-angiogenesis mediators in the tissue dictates the angiogenic phenotype of a tumor. Matrix metalloproteinases (MMPs) are major regulators of extracellular matrix turnover and have for long been associated with pro-tumorigenic activities due to their tissue degradation capacities. However, broad-spectra MMP inhibitors as anti-tumor therapy in clinical trials have failed, and it has now become evident that several MMPs may induce biological activities beneficial to the host, such as suppressed angiogenesis. In this thesis the protective role of specific MMPs in breast and ovarian tumor tissues was further demonstrated.</p><p>The process of angiogenesis is essential for physiological functions in the female reproductive tract, where sex steroids regulate new blood vessel formation and regression in each cycle. Despite progress made during the past years, our knowledge in sex steroid regulation of angiogenesis in hormone-dependent tumor tissues remains limited. Tamoxifen is a cornerstone in the treatment of estrogen receptor (ER)-positive breast cancer. The therapeutic value of tamoxifen in the treatment of ER-positive ovarian cancer is to date less investigated. The results presented in this thesis suggest that tamoxifen may induce anti-tumorigenic responses in ER-positive ovarian cancer by means of both anti-proliferative and anti-angiogenic mechanisms. In experimental models of human ovarian cancer in vitro and in vivo, tamoxifen treatment increased extracellular levels of MMP-9 and enhanced generation of the angiogenesis inhibitor endostatin which resulted in significantly decreased angiogenesis and tumor growth. Low levels of MMP-9 and endostatin in ascites collected from ovarian cancer patients suggest a possibility to therapeutically enhance MMP-9 by administration of tamoxifen, and thereby counteract angiogenesis in ovarian tumors by increased generation of anti-angiogenesis fragments, such as endostatin.</p><p>The significance of enhanced MMP activities in tumor tissues was further investigated by experimental models of intratumoral MMP gene transfer to human breast tumor xenografts, which were assessed by using microdialysis. Treatment of tumors with MMP-9 or MMP-3 resulted in dose-dependent inhibition of tumor growth. Low dose of either MMP induced tumor stasis whereas a higher dose induced significant tumor regression. MMP-9 and tamoxifen exerted synergistic therapeutic effects on breast tumor angiogenesis and growth whereas gene transfer of the MMP-inhibitor TIMP-1 counteracted the beneficial effects induced by tamoxifen.</p><p>Further on, we confirm the pro-angiogenic potential of estradiol by demonstrating a significant correlation between local levels of estradiol and the pro-angiogenic cytokine IL-8 in normal human breast tissues and in ER/PgR-positive breast cancers of women. Estradiol-induced IL-8 secretion was additionally confirmed in normal human whole breast biopsies in culture and in experimental human breast cancer in vitro and in vivo.</p><p>In conclusion, the results of this thesis may hopefully increase the overall understanding of several mechanisms involved in angiogenesis regulation and may additionally be useful in the development of novel approaches for targeted therapy in the treatment of hormone-sensitive breast- and ovarian cancer.</p>
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