Mol. Hum. Reprod. Advance Access originally published online on October 10, 2008
Molecular Human Reproduction 2008 14(11):655-663; doi:10.1093/molehr/gan056
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Elevated expression of CYP1A1 and 
-SYNUCLEIN in human ectopic (ovarian) endometriosis compared with eutopic endometrium
1 Lancashire Teaching Hospitals NHS Trust, Fulwood, Preston, UK 2Lancaster Environment Centre, Lancaster University, Lancaster, UK 3Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
4 Correspondence address. E-mail: f.martin{at}lancaster.ac.uk
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Abstract |
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Endometriosis is a debilitating disease in which apoptotic, genetic, immunological, angiogenic and environmental factors have been implicated. Endocrine-disrupting agents (e.g. dioxins) might be involved. Dioxins, via the arylhydrocarbon receptor (AhR), induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Elevated expression of
-SYNUCLEIN (-SYN) has been associated with hormone-related conditions. Tissue sets consisting of eutopic and ectopic (ovarian) endometrium from patients with stage 3 or 4 endometriosis were obtained. Following RNA extraction and reverse transcription, quantitative real-time reverse transcriptase–polymerase chain reaction was performed for anti-apoptotic B-cell leukaemia/lymphoma 2 (BCL-2), CYP1A1, CYP1B1, estrogen receptor (ER)
, ERβ and -SYN. Immunohistochemical analyses for -syn, ER, ERβ and CYP1A1 were also conducted. A 3–9-fold increase in intra-individual expression of CYP1A1 in ectopic (ovarian) endometrium compared with eutopic tissue was observed; immunohistochemical analyses pointed to CYP1A1 being localized to the glandular epithelium. This intra-individual expression profile was not observed for CYP1B1 or BCL-2. However, a 5–53-fold intra-individual increase in -SYN expression was also demonstrated in six of nine tissue sets (a further two showed an increase that was not considered significant) when comparing ectopic to eutopic endometrium; -syn positivity was associated with endothelial cells. An elevation in ERβ was also noted when comparing ectopic to eutopic endometrium; with regard to ER, this was inconsistent. These results suggest an up-regulation of dioxin-inducible CYP1A1 and -SYN occurs in endometriosis. Whether -syn may be a novel diagnostic marker for endometriosis remains to be ascertained.
Key words:
BCL-2/CYP1A1/endometriosis/estrogen receptor/-synuclein
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementsReferences |
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Endometriosis is a debilitating condition characterized by the presence of ectopic endometrium. It occurs primarily in the pelvis of women, although endometriosis has been found in every organ other than the spleen (Jubanyik and Comite, 1997). The rare histological finding of endometriosis in men has been associated with high-dose estrogen treatment for prostate cancer (Schrodt et al., 1980; Beckman et al., 1985). Prevalence is 10–15% among women and incidence is rising (Donnez et al., 2002). The consequences of this condition are variable symptoms of dysmenorrhoea, dyspareunia, dyschezia and dysuria, which may lead to infertility in the presence or absence of tubal damage (Practice Committee of the American Society for Reproductive Medicine, 2006). There is an associated increased risk of clear-cell or endometrioid ovarian carcinoma (Prowse et al., 2006).
Because of its incidence, this condition places a financial burden on both the health service and, because of absenteeism from the workplace, the employers (Eskenazi and Warner, 1997). Current medical treatment modalities that provide relief and regression from this disease include the usage of gonadotrophin-releasing hormone (GnRH) analogues, depo-provera, the oral contraceptive pill, danazol and, more recently, the use of the levogenestrol intrauterine contraceptive device (MirenaTM) (Abou-Setta et al., 2006). However, due to recurrence, major complex surgical intervention via laparoscopic excision or total abdominal hysterectomy and bilateral salpingo-oopherectomy is often required (Donnez et al., 2004).
The aetiology of endometriosis remains obscure. The Sampson (1927) model of retrograde menstruation is the most widely accepted theory; however, the presence of endometriosis in different organ systems points to other mechanisms (Oral and Arici, 1997). The development of the condition is most probably complex, dependent on genetic (Kennedy, 1998), immunological (Witz, 2002), environmental (Rier et al., 1993; Heilier et al., 2005) and angiogenic (Nisolle et al., 1993) factors. Cyclical serum estrogen concentration seems pivotal in the development and propagation of the disease process while pregnancy and/or lactation appear to be protective (Missmer et al., 2004); this forms the rationale of current medical treatment (Abou-Setta et al., 2006).
Environmental toxins such as dioxins may play a role in the pathophysiology of endometriosis. This group of endocrine-disruptors are lipophilic, chlorinated aromatic hydrocarbons that accumulate and persist in the environment and the food chain (Heilier et al., 2005). Chronic exposure (ingestion) to the dioxin 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), was associated with an increase in the prevalence and severity of endometriosis in the rhesus monkey (Rier et al., 1993). However, a direct causal role remains unproven and in the human, evidence remains conflicting (Rier and Foster, 2003; Guo, 2004). Some studies suggest elevated levels of dioxin-like compounds in the serum of women with endometriosis (Heilier et al., 2005; Porpora et al., 2006); others have been less definitive (Pauwels et al., 2001; Fierens et al., 2003). Dioxins may act via their high-affinity binding to the arylhydrocarbon receptor (AhR) (Matthews and Gustafsson, 2006). Upon binding, the AhR translocates to the nucleus where it binds with its dimerization partner, AhR nuclear translocator protein (ARNT) (Matthews and Gustafsson, 2006). This activated AhR/ARNT hetrodimer complex then binds to specific DNA enhancer sequences known as dioxin-response elements to induce dioxin-responsive genes (Whitlock et al., 1997; Schrenk, 1998), such as CYP1A1 (Whitlock et al., 1997) and CYP1B1 (Shimada et al., 1997). The estrogen receptor (ER) is also a ligand-activated transcription factor that may be altered via activated AhR, suggesting that such mechanisms may result in a modulation of estrogenic responses (Matthews et al., 2005).
The ligand-dependent transcriptional activity of ER has been found to be stimulated by -synuclein (-syn) (Jiang et al., 2003); furthermore, human ER requires -syn for efficient transcriptional activity (Bruening et al., 2000). It has also been implicated in hormone-responsive carcinomas of the breast and ovary (Lavedan et al., 1998; Jiang et al., 2003) and has been linked to the process of estrogen-driven tumorigenesis (Ahmad et al., 2007). Utilizing eutopic and ectopic (ovarian) oendometrium from patients with stage 3 or 4 endometriosis, we set out to determine whether intra-individual differences in the expression of estrogen-regulated genes associated with anti-apoptotic effects (i.e. B-cell leukaemia/lymphoma 2, BCL-2), dioxin-inducible metabolism (i.e. CYP1A1 and CYP1B1) or ER might provide insights into the aetiology of endometriosis and whether -SYN might prove to be a diagnostic marker of this condition.
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Materials and Methods |
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Study participants
Consecutive symptomatic patients (n = 9) undergoing total abdominal hysterectomy and bilateral saplingo-oopherectomy for stage 3 or 4 endometriosis (according to the American Fertility Society grading system) were selected (Table I). Eutopic and ectopic (ovarian) endometrial tissue sets were obtained from nine participants and were coded chronologically [N1–N9 for eutopic endometrium, E1–E9 for ectopic (ovarian) endometriosis]. Macroscopically at laparotomy, the patients were all thought to have endometriosis; in all the tissue sets examined, this was confirmed. Symptoms predominantly included dysmenorrhoea, menorrhagia and dyspareunia. All patients were aged between 38 and 51 years, and were menstruating. Of the endometriosis tissue specimens, seven were obtained during the secretory phase of the cycle (N1, N3–N7 and N9) and the remaining two were obtained during the proliferative phase (N2 and N8); these were confirmed by histology of the eutopic endometrium. No patients were currently having any form of hormonal manipulation, although two of the patients (N7 and N8) had received GnRH analogues 3 years previously for a period of 6 months. Informed consent was obtained (LREC no. 05/Q1302/83; Preston, Chorley and South Ribble Ethical Committee).
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Tissue retrieval and storage
After surgical resection, the uterus and ovaries were transported to the pathology laboratory (<15 min) and dissected aseptically. Using forceps and a scalpel, the cervix was amputated from the upper part of the uterus. Incising the anterior wall of the uterus then exposed the endometrial cavity. Tissues (1 cm in length, 0.5 cm in width) were removed from the endometrium and ovarian endometriosis. The obtained tissue sets [eutopic endometrium and ectopic (ovarian) endometriosis per individual] were labelled and the remaining tissue block was formalin-fixed for retrospective histology and immunohistochemistry. Tissue sets destined for gene expression were immediately placed in RNAlater (QIAGEN Ltd, Crawley, West Sussex, UK), refrigerated overnight at 4°C and then transferred for storage to –85°C.
Quantitative real-time reverse transcriptase–polymerase chain reaction
Total RNA extraction was performed using the Qiagen RNeasy® Kit in combination with the Qiagen RNase-free DNase kit (QIAGEN Ltd). RNA (0.4 µg) was reverse transcribed in a final volume of 20 µl containing Taqman® reverse transcription reagents (Applied Biosystems, Warrington, Cheshire, UK): 1x Taqman RT buffer; MgCl2 (5.5 mM); oligo d(T)16 (2.5 µM); dNTP mix (dGTP, dCTP, dATP and dTTP; each at a concentration of 500 µM); RNase inhibitor (0.4 U/µl); reverse transcriptase (MultiScribeTM) (1.25 U/µl) and RNase-free water. Reaction mixtures were then incubated at 25°C (10 min), 48°C (30 min) and 95°C (5 min).
cDNA samples were stored at –20°C prior to use. Primers (Table II) for CYP1A1 (Genbank accession no. BC023019
[GenBank]
), CYP1B1 (Genbank accession no. NM_000104
[GenBank]
), BCL-2 (Genbank accession no. NM_000633
[GenBank]
), -SYN (Genbank accession no. NM_000304
[GenBank]
), ER (Genbank accession no. NM_000125
[GenBank]
.3), ERβ (Genbank accession no. NM_001040275.1) and the endogenous control β-ACTIN (Genbank accession no. AK222925
[GenBank]
) were chosen using Primer Express software 2.0 (Applied Biosystems, Warrington, UK) and designed so that one primer spanned an exon boundary. Specificity was confirmed using the NCBI BLAST search tool. Quantitative real-time PCR was performed using the ABI Prism 7000 Sequence Detection System (Applied Biosystems). Reaction mixtures contained 1x SYBR® Green PCR master mix (Applied Biosystems, Warrington, UK); forward and reverse primers (Invitrogen, Paisley, UK) at a concentration of 300 nM; for CYP1A1, CYP1B1, BCL-2, -SYN, ER, ERβ amplification 20 ng cDNA template or for β-ACTIN amplification 5 ng cDNA template; made to a total volume of 25 µl with sterile H2O. Thermal cycling parameters included activation at 95°C (10 min) followed by 40 cycles each of denaturation at 95°C (15 s) and annealing/extending at 60°C (1 min). Each reaction was performed in triplicate and ‘no-template’ controls were included in each experiment. Dissociation curves were run to eliminate non-specific amplification, including primer-dimers.
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Immunohistochemical staining
Tissues were fixed in formalin prior to wax-embedding. Immunohistochemical staining of tissue sections was performed on a Shandon sequenza immunostainer (Thermo-Fisher Scientific, Loughborough, Leicestershire, UK). Staining took place following de-waxing and re-hydration, and endogenous peroxidase was blocked by immersing the tissue sections in 4% H2O2 in methanol for 15 min. High-temperature antigen retrieval was performed by heating the tissue sections in citrate buffer (pH 6.0) for 2 min, under pressure and at full power (800 W) in a microwave oven. The antisera anti-
-syn (ABCAM; ab6169), anti-ER (ABCAM; ab9269), anti-ERβ (ABCAM; ab27 720) or anti-CYP1A1 (Chemicon Europe; ab1258) were diluted 1:250 (anti--syn), 1:20 (anti-ER), 1:10 (anti-ERβ) or 1:400 (anti-CYP1A1) in 0.2% bovine serum albumin in Tris-buffered saline (TBS) (pH 7.6) (BSAT). The tissue sections were incubated with primary antibody for 30 min at room temperature (except for anti-ERβ, which was incubated overnight at 4°C). Following the manufacturer's instructions for the Vectastain universal Elite ABC kit (Vector Laboratories, Peterborough, UK), the tissue sections were washed with TBS for 5 min, incubated for 30 min with secondary antisera (goat anti-rabbit) in BSAT and washed with TBS for 5 min. The tissue sections were then incubated with tertiary antisera (avidin–biotin complex) in BSAT for 30 min and washed again with TBS for 5 min. 3,3'-Diaminobenzidine (DAB) chromogen in 0.05 M Tris/HCl buffer (pH 7.4) with 0.1% H2O2 was applied to preparations for 5 min after which they were washed for 5 min with tap water. Finally, slides were stained (15 s) with Harris' haematoxylin, rinsed with tap water, blued in warm tap water (15 s) and rinsed again. Preparations were dehydrated with graded alcohol solutions through to xylene and mounted with cover-slips using Styrolite mounting medium (VWR International, Poole, UK). Parallel control slides, in the absence of primary antibody, were prepared to verify the absence of non-specific staining. |
Results |
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Quantitative real-time reverse transcriptase–polymerase chain reaction (RT–PCR) analyses were carried out without prior knowledge of the histopathological findings. The ranges of averaged threshold cycle (CT) values of amplified cDNA for BCL-2 were 25–30, for CYP1A1 28–35, for CYP1B1 25–33, for ER
25–35, for ERβ 28–33 and for -SYN 22–32 in this study, demonstrating that expression was readily quantifiable in all the tissue sets examined. The relative intra- and inter-individual expression levels of BCL-2, CYP1A1, CYP1B1, ER, ERβ and -SYN are shown in Tables III and IV, respectively.
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BCL-2 expression
Intra-individual expression of the anti-apoptotic BCL-2 did not point to a consistent under- or over-expression between eutopic compared with ectopic (ovarian) endometrium (Table III). For instance, when expression between ectopic (ovarian) and eutopic endometrium was compared, a 3-fold differential expression was noted in two patients (E4 > N4 and E7 > N7) and, a 7- and 5-fold difference in others (N5 > E5 and N3 > E3, respectively). Table IV suggests that the approximate inter-individual variation in levels of BCL-2 mRNA transcripts was 10-fold.
CYP1A1 expression and immunohistochemistry
Intra-individual CYP1A1 expression was consistently elevated 3–10-fold in ectopic (ovarian) endometrial tissue compared with eutopic endometrium in seven of the tissue sets examined (Table III). However, in one tissue set, there was a 10-fold reduced expression seen in the ectopic compared with eutopic tissue (N8 > E8) and, only a moderate elevated expression in another (E7 > N7). Among the individuals examined in this study, there was a maximum 25-fold difference in the mRNA transcript levels for this gene, with the highest levels being found in the ectopic tissues (E5, E9; Table IV). This differential expression was associated with elevated immunohistochemical granular staining for CYP1A1 protein in the cytoplasm of glandular epithelium of ectopic (ovarian) endometrial tissue (Fig. 1B and C), although scores for this phenotypic marker did not consistently show this (Table V).
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CYP1B1 expression
In one of the ectopic (ovarian) endometrial tissues (E1), a raised expression of CYP1B1 was observed when compared with eutopic endometrium (N1) in the same individual (Table III). However, in three cases, there was a 4–5-fold reduced expression of CYP1B1 in ectopic (ovarian) endometrial tissue (E2, E3 and E6) compared with corresponding eutopic endometrium (N2, N3 and N6); a similar reduced gene expression level was noted in both negative tissue sets when the corpus luteal cysts initially considered to be ectopic (ovarian) endometrial tissue were compared with eutopic tissue (data not shown). Levels of mRNA transcripts fluctuated
5-fold, except for one tissue (E2) that was noted to be much lower than the rest (Table IV).
-SYN expression and immunohistochemistry
In six of the ectopic (ovarian) endometrial tissues (E1, E2, E4, E7, E8, E9), an elevated level of -SYN expression compared with eutopic endometrium from the same individual was noted; this difference in expression ranged from 5- to 53-fold; a similar pattern, although not considered significant, was observed for E3 and E6 compared with the corresponding eutopic tissues, N3 and N6 (Table III). However, in one eutopic endometrial tissue (N5), an elevated expression was noted in comparison to the corresponding ectopic (ovarian) endometrium (E5) from the same individual. Marked inter-individual differences in -SYN mRNA transcripts were observed; for instance, there was a 125-fold difference between E9 and N7 (Table IV). Immunohistochemical analyses for -syn showed positive staining in eutopic endometrium (Fig. 2D) and myometrium (Fig. 2E), but this was markedly more pronounced in ectopic (ovarian) endometrium (Fig. 2F). However, the staining pattern for this protein was not observed in either the glandular epithelial cells or the stromal matrix but localized in the endothelial cells. Also, of note was the observation that macrophages in ectopic (ovarian) endometrial tissue were often observed to be positively stained for -syn.
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ER expression and immunohistochemistry
Marked inter-individual expression in ER was noted, especially for ER
(Table IV). However, intra-individual expression of ER or ERβ did not point to a consistent under- or over-expression between eutopic compared with ectopic (ovarian) endometrium (Table III). Positive staining in glandular epithelium and stroma was observed for both ER and ERβ (Table V). In somewhat contradictory fashion, there was an elevation in positive staining for ER in some ectopic (ovarian) endometrial tissues (E3, E4, E5) compared with corresponding eutopic tissues, whereas in other tissues (E6, E8, E9), a comparative reduction was observed. However, except for one tissue (E4), an elevation in or maximum positive staining was observed for ERβ in ectopic (ovarian) endometrial tissues compared with corresponding eutopic tissues (Table V). |
Discussion |
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Dysfunction of apoptotic mechanisms might play a role in the pathogenesis of endometriosis. The proto-oncogene product Bcl-2 regulates apoptosis (Hockenbery et al., 1990). It has been demonstrated that ectopic endometrium contains numerous Bcl-2+ leukocytes and stromal cells that are not detected in eutopic endometrium (Jones et al., 1998). Prolonged survival of Bcl-2+ stromal cells in endometriotic lesions may account for the propagation of the disease (Jones et al., 1998). Consistent with previous findings (Braun et al., 2007), our gene expression analyses for BCL-2 did not demonstrate any consistent intra-individual patterns when comparing eutopic with ectopic (ovarian) endometrium (Table III).
One theory regarding the aetiology of endometriosis is that retrograde menstruation occurs in 90–95% of women and this results in a proportion of these (some 8–15%) going on to develop endometriosis. What remains obscure is the mechanism of subsequent implantation of ectopic tissue leading to the propagation of this disease. Dioxins induce CYP1A1 and CYP1B1; over-expression of these cytochrome P450 isoforms may be associated with susceptibility to pathology (Ragavan et al., 2004). These enzymes are involved in estrogen metabolism and their expression is under cell cycle control in hormone-responsive cells (Jiao et al., 2007). They are thought to increase the ‘ability’ of ectopic endometrium from retrograde menstruation to implant. As in a previous study (Bulun et al., 2000), transcripts of the dioxin-inducible CYP1A1 and CYP1B1 were measurable in both eutopic and ectopic endometrial tissue sets, and raised CYP1A1 expression was observed in seven out of the nine ectopic endometrial tissues when compared with eutopic endometrium in the same individual (Table III). However, contrary to the previous finding (Bulun et al., 2000), increased expression of CYP1B1 was observed in ectopic (ovarian) endometrial samples when compared with eutopic endometrium in only one of the tissue sets examined, and the reverse was actually noted in three others. TCDD exposure has been shown to increase both CYP1A1 and CYP1B1 mRNA transcripts in human endometrial explants tissue (Bofinger et al., 2001). Other exogenous agents have also been associated with altered growth kinetics in hormone-responsive cells (Kalantzi et al., 2004; Barber et al., 2006). It has been suggested that dioxins might promote the development of endometriosis by inducing the cytochrome P450 enzyme aromatase (Rier and Foster, 2003) and that this may lead to an increase in micro-environmental aromatization and subsequently estrogen production (Fig. 2).
We also examined a possible role for -SYN expression in human endometriosis. Six out of the nine tissue sets demonstrated a 5–53-fold elevated expression in ectopic (ovarian) endometrium compared with eutopic samples from the same individual (Table III). -SYN seems to be involved in the efficient functioning of ER and has been associated with infiltration of advancing ovarian or breast carcinomas (Ahmad et al., 2007). -SYN is expressed in 20% of preneoplastic lesions of the ovary (Bruening et al., 2000) and over-expressed in ovarian tumours in contrast to low and almost undetectable levels in the surface epithelial cells of normal ovary (Ninkina et al., 1998). Tumours must be able to degrade and remodel the extracellular matrix to assist their migration into the surrounding stroma; this may also be involved in the implantation and propagation of the endometriosis. This is achieved by the production of proteases such as the matrix metalloproteinases (MMPs) and -SYN has been associated with these proteins; -SYN been shown to lead to a moderate increase in MMP2 activity and a strong induction of MMP9 (Surgucheva et al., 2003). Our gene expression findings coupled with the pronounced vascular staining pattern in ectopic (ovarian) endometriotic tissue could suggest that -syn is involved in an angiogenic mechanism pivotal in the pathogenesis of endometriosis. Development of peptide inhibitors that target -syn may provide a therapeutic role for this protein (Singh et al., 2007a).
Pleiotrophic hormone modulators are paradoxically implicated and may therapeutically resolve very different pathological states (Singh et al., 2007b). Elevated 17β-estradiol may be involved in the self-propagation of endometriotic tissue through increased micro-environmental aromatization and downstream of ER, -syn may be integral to the development of ectopic (ovarian) endometriosis (Fig. 1). The ectopic tissue probably requires increased survival capacity, and this might be generated via micro-environmental hormone-mediated mechanisms. Also, estrogen exposure may be genotoxic (Yared et al., 2002; Singh et al., 2008). We believe that this is the first report of an association of -syn with ectopic (ovarian) endometrium. Future research is warranted to determine whether it may provide a novel diagnostic marker of this condition.
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Funding |
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This work is funded by the Rosemere Cancer Foundation and Terry Fox Foundation.
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Acknowledgements |
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We are grateful to all the staff in the Pathology Laboratory at Preston Hospital (Lancashire Teaching Hospitals NHS Trust) for their support and we thank Matthew Briggs for artwork.
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References |
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Submitted on June 16, 2008; resubmitted on August 31, 2008; accepted on September 30, 2008.
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