J Vis Exp. 2012 Jan 6;(59). pii: 3396. doi: 10.3791/3396.

Mouse Model of Surgically-induced Endometriosis by Auto-transplantation of Uterine Tissue.

Pelch KE, Sharpe-Timms KL, Nagel SC.

Source

Obstetrics, Gynecology and Women’s Health and Division of Biological Sciences, University of Missouri.

Abstract

Endometriosis is a chronic, painful disease whose etiology remains unknown. Furthermore, treatment of endometriosis can require laparoscopic removal of lesions, and/or chronic pharmaceutical management of pain and infertility symptoms. The cost associated with endometriosis has been estimated at 22 billion dollars per year in the United States(1). To further our understanding of mechanisms underlying this enigmatic disease, animal models have been employed. Primates spontaneously develop endometriosis and therefore primate models most closely resemble the disease in women. Rodent models, however, are more cost effective and readily available(2). The model that we describe here involves an autologous transfer of uterine tissue to the intestinal mesentery (Figure 1) and was first developed in the rat(3) and later transferred to the mouse(4). The goal of the autologous rodent model of surgically-induced endometriosis is to mimic the disease in women. We and others have previously shown that the altered gene expression pattern observed in endometriotic lesions from mice or rats mirrors that observed in women with the disease(5,6). One advantage of performing the surgery in the mouse is that the abundance of transgenic mouse strains available can aid researchers in determining the role of specific components important in the establishment and growth of endometriosis. An alternative model in which excised human endometrial fragments are introduced to the peritoneum of immunocompromised mice is also widely used but is limited by the lack of a normal immune system which is thought to be important in endometriosis(2,7). Importantly, the mouse model of surgically induced endometriosis is a versatile model that has been used to study how the immune system(8), hormones(9,10) and environmental factors(11,12) affect endometriosis as well as the effects of endometriosis on fertility(13) and pain(14).

Ultrasound Obstet Gynecol. 2012 Jan 17. doi: 10.1002/uog.11102. [Epub ahead of print]

Comparison between transvaginal ultrasound, sonovaginography and magnetic resonance imaging in the diagnosis of posterior deep infiltrating endometriosis.

Saccardi C, Cosmi E, Borghero A, Alberto T, Dessole S, Litta P.

Source

Department of Gynaecological Sciences and Human Reproduction. University of Padova, Padova, Italy; Department of Gynaecological and Obstetrical Sciences and Neonatology, University of Parma, Parma, Italy. carlosaccardi@yahoo.it.

Abstract

Objective: to compare clinical evaluation, transvaginal ultrasound, sonovaginography and magnetic resonance imaging in the diagnosis of posterior deep pelvic endometriosis. Methods: women suspected of having posterior deep pelvic endometriosis on the basis of subjective symptoms and clinical evaluation, underwent clinical evaluation, transvaginal ultrasound, sonovaginography and magnetic resonance imaging. Laparoscopy was performed and specimens were sent to histological examination. Sensitivity, specificity, positive and negative predictive value, as well as positive and negative likelihood ratios was analysed for every diagnostic method. Results: Fifty-four patients out of 102 women suspected of having posterior DPE underwent laparoscopic surgery. Among these, in 46 (85.2%) cases DPE was confirmed at laparoscopic and histological examination. Sonovaginography correctly identified 43 (93.5%) cases, presenting higher accuracy compared to other procedures. Sonovaginography and even magnetic resonance imaging were more accurate in diagnosing and discriminating the different localizations of endometriotic lesions, with sensibility respectively of 94.7% and 73.1% for vaginal fornix, 88.9% and 66.7% for utero-sacral ligaments, and 80.6% and 83.3% for recto-vaginal septum involvement; Specificity of sonovaginography and MRI was respectively of 97.1% and 94.3% for vaginal fornix, 95.6% and 95.6% for utero-sacral ligaments, and 100% and 77.8% for recto-vaginal septum involvement. In the diagnosis of rectal endometriosis, we found mean values of sensibility, 66.7% for both the two techniques and specificity of 93.8% and 95.8%, for sonovaginography and magnetic resonance imaging, respectively. Conclusions: transvaginal ultrasound should be used as first-line diagnostic techniques and both sonovaginography and/or magnetic resonance imaging as second-line methods in the diagnosis of deep pelvic endometriosis.

Hum Reprod. 2012 Jan 16. [Epub ahead of print]

Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis.

Chapron C, Santulli P, de Ziegler D, Noel JC, Anaf V, Streuli I, Foulot H, Souza C, Borghese B.

Source

Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique – Hôpitaux de Paris (AP- HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine (Professor Chapron), Paris, France.

Abstract

BACKGROUNDThe objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA).METHODSThree hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model.RESULTSAfter multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3).CONCLUSIONSIn case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.

Diagn Cytopathol. 2012 Feb;40(2):159-62. doi: 10.1002/dc.21608. Epub 2011 Feb 9.

Endometriosis of sigmoid colon mimicking malignant tumor diagnosed by intraoperative imprint cytology.

Ohsaki H, Nakamura M, Arie K, Hirakawa E, Haba R, Norimatsu Y.

Source

Department of Medical Technology, Ehime Prefectural University of Health Sciences, Ehime, Japan. ohsaki@epu.ac.jp.

Abstract

A case of endometriosis of the sigmoid colon on imprint cytology from an intraoperative biopsy is discussed. Cytologic specimens showed sheets or tubular epithelial clusters and stromal fragments. The epithelial cell nuclei were small and round to ovoid with finely granular chromatin and inconspicuous nucleoli. The background showed a few scattered spindle-type stromal cells without pigment-laden histiocytes. A definitive diagnosis of endometriosis can be based on cytology, provided that the cytologic findings are interpreted in the appropriate clinical context. Diagn.

Tohoku J Exp Med. 2012;226(2):95-9.

Primate model research for endometriosis.

Yamanaka A, Kimura F, Takebayashi A, Kita N, Takahashi K, Murakami T.

Source

Department of Obstetrics and Gynecology, Shiga University of Medical Science.

Abstract

Endometriosis is defined as the existence of endometrial tissue outside the uterine cavity, and it includes a chronic, inflammatory reaction associated with female infertility and pelvic pain. Endometriosis occurs in 7 to 10% of women. Although it has been studied for more than 50 years, the pathogenesis and development of endometriosis are still poorly understood. There is no curative therapy for endometriosis, which often recurs after surgical or medical treatment. There is a consensus that the adverse current of menstrual blood plays a crucial role in the development of endometriosis. This places a major limitation on research using rodent models of endometriosis, although these are still widely employed, because rodents do not menstruate and endometriosis does not occur spontaneously in these animals. In fact, menstruation and spontaneous endometriosis only occur in women and some non-human primates, making models that employ non-human primates the best animal models for research into the pathogenesis, pathophysiology, spontaneous onset, and treatment of endometriosis. This review assesses the effectiveness and potential of the non-human primate models of endometriosis. It also describes the current findings and theories on the pathogenesis of endometriosis that have been obtained by research using non-human primates.

J Steroid Biochem Mol Biol. 2012 Jan 8;130(1-2):16-25. [Epub ahead of print]

Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins.

Beranič N, Brožič P, Brus B, Sosič I, Gobec S, Rižner TL.

Source

Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.

Abstract

The human aldo-keto reductase AKR1C2 converts 5α-dihydrotestosterone to the less active 3α-androstanediol and has a minor 20-ketosteroid reductase activity that metabolises progesterone to 20α-hydroxyprogesterone. AKR1C2 is expressed in different peripheral tissues, but its role in uterine diseases like endometriosis has not been studied in detail. Some progestins used for treatment of endometriosis inhibit AKR1C1 and AKR1C3, with unknown effects on AKR1C2. In this study we investigated expression of AKR1C2 in the model cell lines of peritoneal endometriosis, and examined the ability of recombinant AKR1C2 to metabolise progesterone and progestin dydrogesterone, as well as its potential inhibition by progestins. AKR1C2 is expressed in epithelial and stromal endometriotic cell lines at the mRNA level. The recombinant enzyme catalyses reduction of progesterone to 20α-hydroxyprogesterone with a 10-fold lower catalytic efficiency than the major 20-ketosteroid reductase, AKR1C1. AKR1C2 also metabolises progestin dydrogesterone to its 20α-dihydrodydrogesterone, with 8.6-fold higher catalytic efficiency than 5α-dihydrotestosterone. Among the progestins that are currently used for treatment of endometriosis, dydrogesterone, medroxyprogesterone acetate and 20α-dihydrodydrogesterone act as AKR1C2 inhibitors with low μM K(i) values in vitro. Their potential in vivo effects should be further studied.

Kyobu Geka. 2011 Dec;64(13):1201-3.

Diaphragmatic endometriosis-associated pneumothorax triggered by abortion; report of a case.

[Article in Japanese]

Hayashi T, Tachibana S, Nakao K, Tokitsu K, Nakata K.

Source

Department of Chest Surgery, Hokusetsu General Hospital, Takatsuki, Japan.

Abstract

The patient was a 36-year-old woman. She had previously undergone surgery for hysteromyoma and endometriosis. At 8 week of pregnancy, the fetus’s heart stopped beating, and the woman underwent abortion. On the same day, she began experiencing difficulty in breathing in the evening. After 4 days, she was referred to our hospital with dyspnea. Chest X-ray finding showed a right pneumothorax. Tube toracotomy was performed, and the right lung re-expanded immediately. Two months later, pneumothorax recurred without any association with the menstruation cycle. Thoracoscopic surgery was performed. No lesion was detected in the lung or visceral pleura, but a small hole and some thinned areas were noted in the diaphragm. Partial resection of the diaphragm was performed. Microscopic examination revealed endometriosis and localized lymphocyte infiltration in the resected diaphragm. It was suggested that the recurrence of pneumothorax without menstruation was caused by the thinning of the diaphragm due to endometriosis.

PLoS One. 2012;7(1):e29252. Epub 2012 Jan 5.

Hydroxybenzothiazoles as New Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1).

Spadaro A, Negri M, Marchais-Oberwinkler S, Bey E, Frotscher M.

Source

Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.

Abstract

17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC(50)-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics.

Obstet Gynecol Int. 2012;2012:786132. Epub 2011 Dec 26.

Infertility and adenomyosis.

Campo S, Campo V, Benagiano G.

Source

Institute of Obstetrics and Gynaecology, Catholic University of Sacred Heart, Largo Agostino Gemelli, 00168 Roma, Italy.

Abstract

Classically, the diagnosis of adenomyosis has only been possible on a hysterectomy specimen, usually in women in their late fourth and fifth decades, and, therefore, evaluating any relationship with infertility was simply not possible. As a consequence, to this day, no epidemiologic data exists linking adenomyosis to a state of subfertility. Today, new imaging techniques have enabled a noninvasive diagnosis at a much earlier time and a number of single-case or small series reports have appeared showing that medical, surgical, or combined treatment can restore fertility in women with adenomyosis, an indirect proof of an association. At the functional level, several anomalies found in the so-called junctional zone, or inner myometrium, in adenomyosis patients have been shown to be associated with poor reproductive performance, mainly through perturbed uterine peristalsis. Additional evidence for an association comes from experimental data: in baboons, adenomyosis is associated with lifelong primary infertility, as well as to endometriosis. Finally, indirect proof comes from studies of the eutopic and ectopic endometrium in women with adenomyosis proving the existence of an altered endometrial function and receptivity. In conclusion, sufficient indirect proof exists linking adenomyosis to infertility to warrant systematic clinical studies.

Transpl Int. 2012 Mar;25(3):357-65. doi: 10.1111/j.1432-2277.2011.01427.x. Epub 2012 Jan 13.

Danazol induces prolonged survival of fully allogeneic cardiac grafts and maintains the generation of regulatory CD4(+) cells in mice.

Uchiyama M, Jin X, Zhang Q, Hirai T, Bashuda H, Watanabe T, Amano A, Niimi M.

Source

Department of Cardiovascular Surgery, Juntendo University Hospital, Tokyo, Japan  Department of Surgery, Teikyo University, Tokyo, Japan  Department of Immunology, Juntendo University Hospital, Tokyo, Japan  Department of Cardiovascular and Thoracic Surgery, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China  Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan.

Abstract

Danazol, a derivative of testosterone, is useful for treatment of endometriosis as well as pretreatment for in vitro fertilization and embryo transfer, although its mechanisms of action are unclear. The aim of this study was to investigate the effect of danazol on alloimmune responses in murine heart transplantation. CBA male mice (H2(k) ) underwent transplantation of C57BL/6 male (H2(b) ) hearts and received a single dose of danazol (0.4, 1.2 or 4 mg/kg/day) by intraperitoneal injection on the day of transplantation and for 6 days thereafter. An adoptive transfer study was performed to determine whether regulatory cells were generated. The median survival time (MST) of allografts in danazol-treated (1.2 and 4 mg/kg/day) mice was 28 and 63 days, respectively, compared with 7 days in untreated mice. Moreover, secondary CBA recipients given whole splenocytes or CD4(+) cells from primary danazol-treated (4 mg/kg/day) CBA recipients 30 days after transplantation had prolonged allograft survival (MSTs, 29 and 60 days, respectively). Cell proliferation, interleukin (IL)-2 and interferon-γ were suppressed in danazol-treated mice, whereas IL-4 and IL-10 were up-regulated. Moreover, danazol directly suppressed allo-proliferation in a mixed leukocyte culture. Flow cytometry showed an increased CD4(+) CD25(+) Foxp3(+) cell population in splenocytes from danazol-treated mice. Danazol prolongs cardiac allograft survival and generates regulatory CD4(+) cells.

Hum Reprod. 2012 Jan 11. [Epub ahead of print]

Robotic treatment of colorectal endometriosis: technique, feasibility and short-term results.

Ercoli A, D’asta M, Fagotti A, Fanfani F, Romano F, Baldazzi G, Salerno MG, Scambia G.

Source

Department of Gynecology, Policlinico Abano Terme, Piazza Cristoforo Colombo, 1- 35031 Abano Terme (PD), Italy.

Abstract

BACKGROUNDDeep infiltrating endometriosis (DIE) is a complex disease that impairs the quality of life and the fertility of women. Since a medical approach is often insufficient, a minimally invasive approach is considered the gold standard for complete disease excision. Robotic-assisted surgery is a revolutionary approach, with several advantages compared with traditional laparoscopic surgery.METHODSFrom March 2010 to May 2011, we performed 22 consecutive robotic-assisted complete laparoscopic excisions of DIE endometriosis with colorectal involvement. All clinical data were collected by our team and all patients were interviewed preoperatively and 3 and 6 months post-operatively and yearly thereafter regarding endometriosis-related symptoms. Dysmenorrhoea, dyschezia, dyspareunia and dysuria were evaluated with a 10-point analog rating scale.RESULTSThere were 12 patients, with a median larger endometriotic nodule of 35 mm, who underwent segmental resection, and 10 patients, with a median larger endometriotic nodule of 30 mm, who underwent complete nodule debulking by colorectal wall-shaving technique. No laparotomic conversions were performed, nor was any blood transfusion necessary. No intra-operative complications were observed and, in particular, there were no inadvertent rectal perforations in any of the cases treated by the shaving technique. None of the patients had ileostomy or colostomy. No major post-operative complications were observed, except one small bowel occlusion 14 days post-surgery that was resolved in 3 days with medical treatment. Post-operatively, a statistically significant improvement of patient symptoms was shown for all the investigated parameters.CONCLUSIONSTo our knowledge, this is the first study reporting the feasibility and short-term results and complications of laparoscopic robotic-assisted treatment of DIE with colorectal involvement. We demonstrate that this approach is feasible and safe, without conversion to laparotomy.

J Gen Intern Med. 2012 Jan 11. [Epub ahead of print]

Thoracic Endometriosis Unmasked by Ovarian Hyperstimulation for in vitro Fertilization.

Halvorson SA, Ricker MA, Barker AF, Patton PE, Harrison RA, Hunter AJ.

Source

Assistant Professor of Medicine, OHSU Division of Hospital Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd BTE-119, Portland, Oregon, 97239, USA, halvorss@ohsu.edu.

Abstract

Thoracic endometriosis syndrome is a well-described, rare manifestation of endometriosis. We present a case of a 35-year old woman undergoing controlled ovarian stimulation prior to in vitro fertilization (IVF) who developed bilateral hemorrhagic pleural effusions. She was initially diagnosed with ovarian hyperstimulation syndrome, a complication of infertility therapy; however, she was later found to have occult thoracic endometriosis. We describe ovarian hyperstimulation syndrome and review the manifestations of thoracic endometriosis syndrome. Although endometriosis is a hormone-dependent disease, the rate of IVF complications related to endometriosis is low.

Reprod Biol Endocrinol. 2012 Jan 10;10(1):1. [Epub ahead of print]

Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis-associated infertility.

Szczepanska M, Wirstlein P, Skrzypczak J, Jagodzinski PP.

Abstract

ABSTRACT:

BACKGROUND:

A decrease in HOXA11 expression in eutopic mid-secretory endometrium has been found in women with endometriosis-associated infertility.

METHODS:

Using Real-time quantitative PCR (RQ-PCR) and western blotting analysis we studied the HOXA11 transcript and protein levels in mid-luteal eutopic endometrium from eighteen infertile women with minimal endometriosis, sixteen healthy fertile women and sixteen infertile women with fallopian tubal occlusion from the Polish population. We also evaluated transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in these groups of women.

RESULTS:

There were significantly lower levels of HOXA11 transcripts (p=0.003, p=0.041) and protein (p=0.004, p=0.001) in women with endometriosis as compared to fertile women and infertile women with tubal occlusion. Moreover, we found significantly higher methylation levels of the CpG region in the first exon of HOXA11 in infertile women with endometriosis compared with fertile women (p<0.001) and infertile women with tubal occlusion (p<0.001). We also observed significantly increased levels of DNMT3A transcript in women with endometriosis than fertile women (p=0.044) and infertile women with tubal occlusion (p=0.047). However, we did not observe significant differences in DNMT1 and DNMT3B transcript levels between these investigated groups of women.

CONCLUSIONS:

We confirmed that reduced HOXA11 expression may contribute to endometriosis-associated infertility. Moreover, we found that DNA hypermethylation can be one of the possible molecular mechanisms causing a decrease in HOXA11 expression in the eutopic mid-secretory endometrium in infertile women with endometriosis.

Epigenomics. 2011 Dec;3(6):690-1.

Endometriosis as an epigenetic disease.

Peltomäki P, Bützow R.

Source

Departments of Obstetrics, Gynecology & Pathology, Helsinki University Central Hospital, Helsinki, Finland. paivi.peltomaki@helsinki.fi

Comment on

Hum Reprod. 2012 Jan 9. [Epub ahead of print]

Pertubation with lignocaine as a new treatment of dysmenorrhea due to endometriosis: a randomized controlled trial.

Wickström K, Bruse C, Sjösten A, Spira J, Edelstam G.

Source

Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Abstract

BACKGROUNDEndometriosis is a chronic inflammatory disease of unknown aetiology that can cause severe dysmenorrhea. Lignocaine has anti-inflammatory properties and exerts effects on nerve endings and intra-peritoneal macrophages. The objective of this study was to evaluate the effect of pertubation with Ringer-Lignocaine on dysmenorrhea in women with endometriosis.METHODSA double-blind randomized controlled trial (RCT) was carried out at three sites in Stockholm, Sweden. Eligible patients had endometriosis as diagnosed by laparoscopy, dysmenorrhoic pain >VAS 50 mm (visual analogue scale) and patent Fallopian tubes. The study patients were randomized sequentially to preovulatory pertubations with placebo (n= 18) or study treatment (n= 24) during three consecutive menstrual cycles. The pertubation procedure comprised passing study solution through the uterine cavity and the Fallopian tubes via an intra-cervical balloon catheter. The effect on pain was evaluated with VAS scales before and after the treatments and up to nine menstrual cycles after the last pertubation. Success was defined as a reduction of ≥50% on the VAS scale after the third pertubation. The success rate between the treatment and the placebo group was compared with Fisher’s exact test.RESULTSIn the intention-to-treat analysis, the success rate was 41.7% (10 of 24) in the treatment group compared with 16.7% (3 of 18) in the placebo group (P= 0.10, 95% CI -7.3 to 36.2%). In the per protocol analysis, the success rate in the treatment group was 45% (9 of 20) compared with 7.1% (1 of 14) in the placebo group (P= 0.024, 95% CI -2.6 to 44.8%). Of the nine patients in the lignocaine group who fulfilled the criteria for success after three pertubations, 4 (44%) had an effect persisting after nine months. The treatments were well tolerated.CONCLUSIONSThis small RCT indicates that pertubation with lignocaine is a non-hormonal treatment option for patients with dysmenorrhea and endometriosis.ClinicalTrials.gov identifier: NCT01329796.

Microvasc Res. 2012 Jan 2. [Epub ahead of print]

Expression of vascular endothelial growth factor (VEGF) and its soluble receptor-1 in endometriosis.

Cho S, Choi YS, Jeon YE, Im KJ, Choi YM, Yim SY, Kim H, Seo SK, Lee BS.

Source

Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, Republic of Korea; Institute of Women’s Life Medical Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.

Abstract

The aim of this study is to evaluate the expression of vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) in peritoneal fluid (PF), peritoneal endometriotic lesions and eutopic endometrial tissues of patients with endometriosis. Peritoneal fluid, peritoneal endometriotic lesions and eutopic endometrial samples from patients with endometriosis, and peritoneal fluid, peritoneal tissue and endometrial samples from patients without endometriosis were obtained during an operative laparoscopy. The mean PF concentrations of VEGF and sFlt-1 were significantly higher in patients with endometriosis than in the controls. In the peritoneal tissue, the expressions of VEGF and sFlt-1 were significantly higher, where the expression of sFlt-1in endometrium was significantly lower in patients with endometriosis. These findings indicate that not only abnormal expressions of angiogenic factors, but also aberrant expressions of antiangiogenic factors in the peritoneal and endometrial environment seem to be involved in the pathogenesis of endometriosis.

Am J Reprod Immunol. 2012 Jan 9. doi: 10.1111/j.1600-0897.2011.01102.x. [Epub ahead of print]

Serum sTREM-1 (Soluble Triggering Receptor Expressed on Myeloid Cells-1) Associates Negatively with Embryo Quality in Infertility Patients.

Haller-Kikkatalo K, Sarapik A, Faure GC, Béné MC, Massin F, Salumets A, Uibo R.

Source

Immunology Group, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia; Competence Centre on Reproductive Medicine and Biology, Tartu, Estonia; Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia; Women’s Clinic, Tartu University Hospital, Tartu, Estonia.

Abstract

PROBLEM:

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker of infection and inflammation.

METHOD OF STUDY:

We studied serum and follicular fluid sTREM-1 in infertile patients (N = 110) utilizing enzyme-linked immunosorbent assay.

RESULTS:

Serum and follicular sTREM-1 were in good correlation (Pearson’s correlation 0.56, P < 0.0001) with higher values in follicular fluid (140.4 ± 34.4 and 115.6 ± 35.1 pg/mL, t-test, P < 0.0001). Endometriosis associated with lower follicular and serum sTREM-1 compared with male factor infertility patients (age-adjusted r = -25.7 pg/mL, P = 0.018; r = -22.1 pg/mL, P = 0.030). No associations between follicular or serum sTREM-1 and clinical parameters were found, except higher serum sTREM-1 associated with lower embryo quality in all patients (adjusted r = -0.3%, P = 0.033), with a cutoff value between 111.5 and 113.3 pg/mL (OR = 0.38, P = 0.048; OR = 0.34, P = 0.028) predicting that more than 39% of embryos would be with good quality.

CONCLUSION:

Serum sTREM-1 could represent a prognostic marker for female fecundity, probably indicating impaired inflammatory reaction of immune system.

Am J Reprod Immunol. 2012 Jan 9. doi: 10.1111/j.1600-0897.2011.01101.x. [Epub ahead of print]

Lipoxin A4 Inhibits the Development of Endometriosis in Mice: The Role of Anti-Inflammation and Anti-Angiogenesis.

Xu Z, Zhao F, Lin F, Chen J, Huang Y.

Source

Department of Obstetrics and Gynecology, 1st Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China.

Abstract

PROBLEM:

To evaluate the effects of the anti-inflammatory and anti-angiogenic roles of LXA4 on endometriosis in mice.

METHOD OF STUDY:

Endometriosis was induced in 40 mice and separated into two groups. LXA4 group was administered by LXA4 for 3 weeks. The endometriotic lesions were counted, measured, and identified by pathology. The presence of a panel of pro-inflammatory factors was assessed by real-time RT-PCR, and enzyme-linked immunoassay, the mRNA, protein levels of matrix metalloproteinase (MMPs), and vascular endothelial growth factor (VEGF) were determined by real-time RT-PCR and immunohistochemistry; the activity of MMPs was evaluated by gelatin zymography.

RESULTS:

Treatment with LXA4 significantly inhibited endometriotic lesion development (13.58 ± 4.01 mm(2) in LXA4 group and 23.20 ± 7.49 mm(2) , P = 0.0002), downregulated pro-inflammatory factors, suppressed the activity of MMP9, and reduced the VEGF levels associated with endometriosis in mice.

CONCLUSION:

LXA4 may inhibit the progression of endometriosis possibly by anti-inflammation and anti-angiogenesis.

Biochem Pharmacol. 2011 Dec 29. [Epub ahead of print]

Curcumin as anti-endometriotic agent: Implication of MMP-3 and intrinsic apoptotic pathway.

Jana S, Paul S, Swarnakar S.

Source

Drug Development Diagnostics & Biotechnology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.

Abstract

The disease of reproductive women, endometriosis represents implantation of functional endometrial glands outside uterine cavity. This invasive disorder is associated with dysregulation of matrix metalloproteases (MMP)s and extracellular matrix (ECM) remodeling. In this study, we investigated the role of MMP-3 on apoptosis during endometriosis. We also checked whether curcumin has potency to regress endometriosis by modulating MMP-3 and apoptotic pathway. Mouse model of endometriosis was designed by intraperitoneal inoculation of endometrial tissues to syngeneic female BALB/c. At 15th day, stable endometriotic developments were observed with increased MMP-3 expression. TUNEL positive cells were also found with endometriotic progression, which might resulted from destruction of local immune cells. We speculate that increased MMP-3 activity might be involved in the Fas mediated apoptosis. Curcumin treatment regressed endometriosis by inhibiting NFκB translocation and MMP-3 expression. It also accelerated apoptosis in endometriomas predominantly via cytochrome-c mediated mitochondrial pathway. Involvement of mitochondria in apoptosis was further confirmed by atomic force microscopy (AFM). These results were also supported by our therapeutic study, where curcumin induced apoptosis both by p53 dependent and independent manner, while celecoxib followed only p53 independent pathway. Altogether, our study establishes the novel role of curcumin as a potent anti-endometriotic compound.

J Cell Mol Med. 2012 Jan 6. doi: 10.1111/j.1582-4934.2011.01520.x. [Epub ahead of print]

Raf-1 levels determine the migration rate of primary endometrial stromal cells of patients with endometriosis.

Yotova I, Quan P, Gaba A, Leditznig N, Pateisky P, Kurz C, Tschugguel W.

Source

Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

Abstract

Endometriosis is a disease characterized by the localization of endometrial tissue outside of the uterine cavity. The differences observed in migration of human endometrial stromal cells (hESC) obtained from patients with endometriosis versus healthy controls were proposed to correlate with the abnormal activation of Raf-1/ROCKII signalling pathway. To evaluate the mechanism by which Raf-1 regulates cytoskeleton reorganization and motility, we used primary eutopic (Eu-, n=16) and ectopic (Ec-, n=8; isolated from ovarian cysts) hESC of patients with endometriosis and endometriosis-free controls (Co-hESC, n=14). Raf-1 siRNA knockdown in Co- and Eu-hESC resulted in contraction and decreased migration vs. siRNA controls. This phenotype was reversed following the re-expression of Raf-1 in these cells. Lowest Raf-1 levels in Ec-hESC were associated with hyperactivated ROCKII and ezrin/radixin/moesin (E/R/M), impaired migration and a contracted phenotype similar to Raf-1 knockdown in Co- and Eu-hESC. We further show that the mechanism by which Raf-1 mediates migration in hESC includes direct myosin light chain phosphatase (MYPT1) phosphorylation and regulation of the levels of E/R/M, paxillin, MYPT1 and myosin light chain (MLC) phosphorylation indirectly via the hyperactivation of ROCKII kinase. Further, we suggest that in contrast to Co-and Eu-hESC, where the cellular Raf-1 levels regulate the rate of migration, the low cellular Raf-1 content in Ec-hESC might ensure their restricted migration by preserving the contracted cellular phenotype. In conclusion, our findings suggest that cellular levels of Raf-1 adjust the threshold of hESC migration in endometriosis.

West Indian Med J. 2011 Jun;60(3):351-3.

Abdominal scar endometriosis after caesarean section: report of five cases.

Pikoulis E, Karavokiros J, Veltsista K, Diamantis T, Griniatsos J, Basios N, Avgerinos E, Marinos G, Kaliakmanis V.

Source

First Department of Surgery, Laiko University Hospital, Athens, Greece. mpikoul@med.uoa.gr

Abstract

Scar endometriosis is an under-appreciated or misdiagnosed phenomenon in general surgery and may eventually be more common than reflected in the literature. We herein report five cases of scar endometriosis that were treated in our surgical department one to five years after Caesarean section. Scar endometriosis should be considered when the symptoms are present in a cyclic manner mostly after gynaecological operations and worsening during menstruation. Diagnosis is mainly based upon a high index ofsuspicion. The treatment of choice is surgical resection.

Biom J. 2011 May;53(3):464-76. doi: 10.1002/bimj.201000083.

ROC curve inference for best linear combination of two biomarkers subject to limits of detection.

Perkins NJ, Schisterman EF, Vexler A.

Source

Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6100 Executive Blvd, rm 7b03, Rockville, MD 20852, USA. perkinson@mail.nih.gov.

Abstract

The receiver operating characteristic (ROC) curve is a tool commonly used to evaluate biomarker utility in clinical diagnosis of disease. Often, multiple biomarkers are developed to evaluate the discrimination for the same outcome. Levels of multiple biomarkers can be combined via best linear combination (BLC) such that their overall discriminatory ability is greater than any of them individually. Biomarker measurements frequently have undetectable levels below a detection limit sometimes denoted as limit of detection (LOD). Ignoring observations below the LOD or substituting some replacement value as a method of correction has been shown to lead to negatively biased estimates of the area under the ROC curve for some distributions of single biomarkers. In this paper, we develop asymptotically unbiased estimators, via the maximum likelihood technique, of the area under the ROC curve of BLC of two bivariate normally distributed biomarkers affected by LODs. We also propose confidence intervals for this area under curve. Point and confidence interval estimates are scrutinized by simulation study, recording bias and root mean square error and coverage probability, respectively. An example using polychlorinated biphenyl (PCB) levels to classify women with and without endometriosis illustrates the potential benefits of our methods.

Environ Health Prev Med. 2012 Jan 6. [Epub ahead of print]

Failure to detect significant association between estrogen receptor-alpha gene polymorphisms and endometriosis in Japanese women.

Matsuzaka Y, Kikuti YY, Izumi SI, Goya K, Suzuki T, Cai LY, Oka A, Inoko H, Kulski JK, Kimura M.

Source

Division of Basic Molecular Science and Molecular Medicine, School of Medicine, Tokai University, Bohseidai, Isehara, Kanagawa, 259-1193, Japan, yasunari.matsuzaka@helmholtz-muenchen.de.

Abstract

OBJECTIVES:

The aim of the study was to test whether estrogen receptor 1 (ESR1) gene polymorphisms are correlated with the risk of the development of endometriosis in Japanese women, as a preliminary study.

METHODS:

To compare allelic frequencies and genotype distributions, a case-control study of 100 affected women and 143 women with no evidence of disease was performed using 10 microsatellite repeat markers and 66 single-nucleotide polymorphisms (SNPs) in the ESR1 gene region.

RESULTS:

Although our results might be insufficient to detect genetic susceptibility, owing to the small sample size and low genetic power, statistical analysis of the differences in allelic frequency between the cases and controls at each microsatellite locus demonstrated that no microsatellite locus in the ESR1 gene displayed a significant association with the disease when multiple testing was taken into account. Also, there were no statistically significant differences in the SNP allele frequencies and genotypes between the cases and controls when multiple testing was taken into account.

CONCLUSION:

The findings in our pilot study suggest that ESR1 polymorphisms do not contribute to endometriosis susceptibility.

Hum Immunol. 2011 Dec 11. [Epub ahead of print]

The possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Bianco B, André GM, Vilarino FL, Peluso C, Mafra FA, Christofolini DM, Barbosa CP.

Source

Division of Human Reproduction and Genetics, Department of Gynecology and Obstetrics, Faculdade de Medicina do ABC, Santo André/São Paulo, Brazil.

Abstract

Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti-inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis-associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen-receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Hum Pathol. 2012 Jan 3. [Epub ahead of print]

HMGA gene rearrangement is a recurrent somatic alteration in polypoid endometriosis.

Medeiros F, Wang X, Araujo AR, Erickson-Johnson MR, Lima JF, Meuter A, Winterhoff B, Oliveira AM.

Source

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

The pathogenesis of endometriosis is unclear, and several genetic, endocrine, immune, and environmental agents have been evaluated with no putative causative factors identified. Here, we show somatic genetic alterations involving HMGA1 (6p21) and HMGA2 (12q15) in 3 cases of polypoid endometriosis. The lesions involved the small bowel mesentery and perirectal soft tissue in 1 case and the posterior vaginal fornix and sigmoid colon serosa in 2 other cases, respectively. All had a polypoid configuration with cystically dilated irregular glands and fibrotic stroma, containing thick-walled vessels. Conventional cytogenetic analysis of 1 case showed 46,XX,t(5;12)(q13;q15) in all metaphases. Fluorescence in situ hybridization studies confirmed the balanced rearrangement of HMGA2. HMGA1 rearrangements were present in 2 additional cases. Rearrangements were exclusively found in the stromal component but not in the glandular component. These findings suggest that HMGA rearrangements likely contribute to the pathogenesis of endometriosis. However, additional studies are needed to better define the biologic role of this genetic alteration.

Prescrire Int. 2011 Dec;20(122):292.

Dienogest. Endometriosis: still no progress.

[No authors listed]

Abstract

No more effective for relief of pelvic pain than a GnRH agonist alone (without hormone replacement therapy).

Hum Reprod. 2012 Jan 2. [Epub ahead of print]

Expression pattern of osteopontin and αvβ3 integrin during the implantation window in infertile patients with early stages of endometriosis.

Casals G, Ordi J, Creus M, Fábregues F, Carmona F, Casamitjana R, Balasch J.

Source

Institut Clinic of Gynaecology, Obstetrics and Neonatology, Hospital Clínic – Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c/Casanova 143, 08036 Barcelona, Spain.

Abstract

BACKGROUNDTo study endometrial receptivity in terms of osteopontin (OPN) and αvβ3 integrin expression and co-expression in infertile women with early stages of endometriosis.METHODSWe investigated the immunohistochemical expression and co-expression of OPN and αvβ3 integrin in the endometrium of 20 infertile patients with Stage I or II endometriosis as the only detectable cause of infertility, 20 infertile patients with unexplained infertility and 20 fertile women undergoing tubal sterilization. Two endometrial biopsies were performed during a single menstrual cycle (postovulatory Day +7 to +8 and 4 days later) in each subject.RESULTSNo statistically significant differences regarding OPN and αvβ3 integrin expression were found between infertile patients with endometriosis and the two control groups. There was no significant correlation between OPN and αvβ3 integrin staining intensity in the mid-luteal phase biopsies in any of the groups studied.CONCLUSIONSEndometrial OPN and αvβ3 integrin expression or co-expression is not impaired during the window of implantation in patients with Stage I-II endometriosis. Further studies are needed to determine whether these results imply normal endometrial receptivity in such patients or add to the increasing uncertainty about the clinical value of assessing the endometrium with these markers of implantation.

Hum Reprod. 2012 Jan 2. [Epub ahead of print]

Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis.

Matsuzaki S, Darcha C.

Source

CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, 1, Place Lucie Aubrac, 63003 Clermont-Ferrand, France.

Abstract

BACKGROUNDEndometrium is derived from intermediate mesoderm via mesenchymal to epithelial transition (MET) during development of the urogenital system. By retaining some imprint of their mesenchymal origin, endometrial epithelial cells may be particularly prone to return to this state, via epithelial to mesenchymal transition (EMT). We hypothesized that pelvic endometriosis originates from retrograde menstruation of endometrial tissue and that EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis.METHODSWe investigated commonly used molecular markers for EMT, including cytokeratin, E-cadherin, N-cadherin, vimentin, S100A4 and dephosphorylated beta-catenin by immunohistochemistry in different forms of pelvic endometriosis: deep infiltrating endometriosis, ovarian endometriosis and superficial peritoneal endometriosis (red and black lesions), as well as samples of menstrual endometrium, other benign ovarian cysts (mucinous and serous cyst adenoma), and abdominal scar endometriosis for comparison.RESULTSEpithelial cells of red peritoneal lesions and ovarian endometriosis showed less epithelial marker (cytokeratin, P < 0.0001) expression and more mesenchymal marker (vimentin and/or S100A4, P < 0.0001) expression than those of menstrual endometrium. In contrast, epithelial cells of black peritoneal lesions and deep infiltrating endometriosis showed more epithelial marker (E-cadherin) expression than those of menstrual endometrium (P < 0.03), red peritoneal lesions (P < 0.0001) and ovarian endometriosis (P< 0.0001), but maintained expression of some mesenchymal markers (vimentin, S100A4). In addition, dephosphorylated beta-catenin protein expression was significantly higher in epithelial cells of deep infiltrating endometriosis (P < 0.0001) than in epithelial cells of red and black peritoneal lesions and ovarian endometriosis.CONCLUSIONSEMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis.

J Neurol. 2012 Jan 4. [Epub ahead of print]

Sciatic endometriosis presenting as periodic (catamenial) sciatic radiculopathy.

Ghezzi L, Arighi A, Pietroboni AM, Jacini F, Fumagalli GG, Esposito A, Bresolin N, Galimberti D, Scarpini E.

Source

Department of Neurological Sciences, “Dino Ferrari” Center, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, lauraghezzi@me.com.

Int J Gynecol Cancer. 2012 Feb;22(2):238-44.

The utility of human epididymal protein 4, cancer antigen 125, and risk for malignancy algorithm in ovarian cancer and endometriosis.

Kadija S, Stefanovic A, Jeremic K, Radojevic MM, Nikolic L, Markovic I, Atanackovic J.

Source

*Faculty of Medicine, University of Belgrade; †Clinic for Gynecology and Obstetrics of the Clinical Center of Serbia; and ‡Instituteof Biochemistry, Faculty of Medicine, University of Belgrade, Serbia.

Abstract

BACKGROUND:

In women with pelvic mass, cancer antigen 125 (CA125) had not achieved satisfactory sensitivity and specificity in the detection of ovarian cancer, particularly in patients with underlying endometriosis. The aim of this study was to determine the diagnostic potential of human epididymal protein 4 (HE4), the combination of HE4+CA125, and the Risk of Ovarian Malignancy Algorithm (ROMA) for patients with pelvic mass, particularly in differentiating endometriosis from carcinoma.

METHODS:

A prospective cross-sectional study was conducted at the Clinic for Gynecology and Obstetrics, Clinical Center of Serbia. Serum samples were obtained preoperatively from 108 women undergoing surgery for pelvic mass; 29 of them had ovarian carcinoma, and 79 had a nonmalignant ovarian disease (39 with benign tumor, 20 with endometriosis, 20 healthy controls). Sera were analyzed for the levels of HE4 and CA125 and were then compared with the final pathologic results. The diagnostic performance of HE4 and CA125 was estimated using receiver operating characteristic curve and area under the receiver operating characteristic curve.

RESULTS:

The level of HE4 and CA125 was significantly higher among the patients with malignant tumors, compared with patients with nonmalignant disease. At the predefined specificity of 95%, HE4 and CA125 showed sensitivity of 65.5% and 58.6%, respectively, whereas the combination of HE4+CA125 reached 68.9% at the same specificity. Importantly, the level of HE4 did not differ significantly between the patients with endometriosis and with other nonmalignant diseases (which was not the case with CA125). Risk of Ovarian Malignancy Algorithm classified 96% of benign premenopausal cases as at low risk for ovarian cancer.

CONCLUSIONS:

HE4 showed satisfactory capability of distinguishing endometriosis from ovarian cancer, which CA125 lacked. The Risk of Ovarian Malignancy Algorithm score proved to be useful in excluding malignant diagnosis in premenopausal women.

In Vivo. 2012 Jan-Feb;26(1):119-27.

KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis.

Makri A, Msaouel P, Petraki C, Milingos D, Protopapas A, Liapi A, Antsaklis A, Magkou C, Koutsilieris M.

Source

Department of Physiology, Medical School, National & Kapodistrian University of Athens, 75 Micras Asias, Goudi, Athens, 115 27, Greece.

Abstract

BACKGROUND:

The KISS1/KISS1R system has been implicated in the physiology of reproduction and many studies have documented the stimulatory effect of kisspeptin on Gonadotropin-releasing Hormone (GnRH) and gonadotropin secretion. In addition, the KISS1/KISS1R system has been implicated in several pathophysiological processes, including cancer.

MATERIALS AND METHODS:

We examined the pattern of KISS1 and KISS1R expression in eutopic and ectopic endometrium tissues which were obtained from 24 women suffering from endometriosis and 16 control women who underwent laparoscopic excision for other benign gynecological diseases.

RESULTS:

Significant KISS1R expression was detected in 10 out of the 24 samples of eutopic endometrial biopsies of women suffering from endometriosis, while their matched biopsies of ectopic endometrial lesions did not reveal any KISS1R expression. KISS1R expression was not detected in the endometrial biopsies of control women. In addition, KISS1 expression was not detected in practically any the endometrial tissues of either control women or women with endometriosis.

CONCLUSION:

The expression of KISS1R in 10/24 samples of human endometrial biopsies of women suffering from endometriosis and the loss of its expression in the samples of matched ectopic endometrial tissues, suggests that the KISS1/KISS1R system may play a role in the pathophysiology of endometriosis only for a particular group of patients. Since KISS1 is not expressed by the endometrium and endometriotic tissue, it is conceivable that the activation of KISS1R in this particular group is mediated by KISS1 expression by non-endometrial tissues (endocrine action).

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