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- Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways. [JOURNAL ARTICLE]
- Environ Health Perspect 2014 Oct 24.
It is proposed that cadmium (Cd) is an environmental "metalloestrogen" and its action is mediated via the estrogen receptor (ER). Cd mimics the effects of estrogen in the rat uterus, and blood Cd concentrations positively correlate with ER levels in uteri of women with fibroids.This study explored whether Cd could stimulate proliferation of estrogen-responsive human uterine leiomyoma (ht-UtLM) and uterine smooth muscle cells (ht-UtSMCs) through classical interactions with ERα and ERβ, or by nongenomic mechanisms.Estrogen response element (ERE) reporters, phosphorylated receptor tyrosine kinase arrays, western blot analysis, estrogen binding, and cell proliferation assays were used to evaluate the effects of Cd on ht-UtLM cells and ht-UtSMC.Cd stimulated growth of both cell types at lower concentrations and inhibited growth at higher concentrations (≥50 μM). Cd did not significantly bind to ERα or ERβ, or show transactivation in both cell types transiently transfected with ERE reporter genes. However, Cd (0.1 μM and 10 μM) activated p44/42 MAPK (ERK1/2) in both cell types, and a MAPK inhibitor, PD98059, abrogated Cd-induced cell proliferation in both cell types. Cd in ht-UtLM cells, but not in ht-UtSMC activated growth factor receptors, EGFR, HGFR, and VEGF-R1, upstream of MAPK. Additional studies in ht-UtLM cells showed that AG1478, an EGFR inhibitor, abolished Cd-induced phosphorylation of EGFR and MAPK.Our results show how low concentrations of Cd stimulate cell proliferation in estrogen-responsive uterine cells by nongenomic activation of MAPK, but not through classical ER-mediated pathways.
- A case of parasitic myoma 4 years after laparoscopic myomectomy. [Journal Article]
- J Minim Access Surg 2014 Oct; 10(4):202-3.
We present a case of parasitic myoma complaining of abdominal pain, constipation, dyspareunia and dysmenorrhea 4 years after laparoscopic myomectomy. We performed laparoscopic myomectomy for multiple parasitic myomas. Three myomas were very firmly attached to bowel and mesentery. Parasitic myoma after laparoscopic surgery is very rare condition there are almost 35 cases in the literature. It is related with variable symptoms or can be asymptomatic. Laparoscopic surgeons should be aware of this situation, and further investigation should be made in case of suspicion. Surgery for parasitic myomas can be difficult in case of bowel and mesentery involvement and patient should be informed about the extensive surgery.
- Unbiased and Efficient Estimation of the Volume of the Fibroid Uterus Using the Cavalieri Method and Magnetic Resonance Imaging. [JOURNAL ARTICLE]
- Reprod Sci 2014 Oct 20.
The aim of our study was to develop a reliable technique for measuring volume of the fibroid uterus using Magnetic Resonance Imaging. We applied the Cavalieri method and standard calliper technique to measure the volume of the uterus and largest fibroid in 26 patients, and results were compared with "gold-standard" planimetry measurements. We found Cavalieri measurements to be unbiased, while calliper measurements systematically underestimated uterine volume (- 13.2%, P < 10(-5)) and had greater variance. Repeatability was similar for the 2 techniques (standard deviation [SD] = 4.0%-6.9%). Reproducibility of Cavalieri measurements was higher for measurement of uterine (SD = 9.0%) than fibroid volume (SD = 19.1%), whereas the reproducibility of calliper measurements was higher for fibroid (SD = 9.1%) than uterine volume (SD = 15.9%). The additional measurement time for the Cavalieri method was approximately 1 to 2 minutes. In conclusion, the Cavalieri method permits more accurate measurement of uterine and fibroid volumes and is suitable for application in both clinical practice and scientific research.
- Injectable Clostridium Histolyticum Collagenase as a Potential Treatment for Uterine Fibroids. [JOURNAL ARTICLE]
- Reprod Sci 2014 Oct 20.
Purified Clostridium histolyticum collagenase (CHC), an Food and Drug Administration-approved drug that does not affect nerves or blood vessels, was assessed as a potential treatment for fibroids in this proof-of-principle study. Fibroids (1-4 cm, capsules intact) and myometrial specimens from 5 patients were injected posthysterectomy with CHC or vehicle containing methylene blue and incubated for 24 hours. Percentage of collagen-stained area was estimated using Masson-Trichrome-stained slides. Collagen fibers were observed with picrosirius staining. Tissue stiffness was objectively measured by rheometry (complex shear modulus [Pa]). Injected materials spread within and beyond fibroids as visualized by methylene blue. Of the 8 treated fibroids, 7 were softened and some contained liquefied centers. Relative percentage of collagen-stained area (mean ± standard deviation) in treated fibroids (38 ± 12%; n = 7) was less than that in control fibroids (66 ± 17%; n = 5). Treated myometrium (40 ± 30% collagen; n = 3) was similar to control myometrium (53 ± 8%; n = 2). Picrosirius staining demonstrated loss of collagen fibers in treated fibroids. Treated fibroids were less stiff (3630 ± 2410 Pa; n = 4) than controls (5930 ± 830 Pa; n = 4). Treated and control myometrium had similar stiffness (2149 ± 927 Pa; n = 3 and 3314 ± 494 Pa; n = 2, respectively) and were never liquefied. In conclusion, injections of CHC into encapsulated fibroids are feasible and effective. Heterogeneity of collagen types and quantities within individual fibroids may contribute to varied responses and need additional investigation. Further study of collateral effects on myometrium is indicated. Injected CHC has potential for treatment of fibroids.
- Rare case of endometrioid adenocarcinoma arising from cystic adenomyosis. [JOURNAL ARTICLE]
- J Obstet Gynaecol Res 2014 Oct 20.
Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.
- Knowledge of uterine fibroid symptoms and presentation among African-American women: a pilot study. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- J Reprod Med 2014 Sep-Oct; 59(9-10):448-54.
To assess awareness and knowledge of fibroid symptoms and presentation among African-American women.This was a cross-sectional survey study completed by a convenience sample of African-American women attending a community fair. Questions covered demographics, medical history, technology use, and fibroid knowledge. A total of437 surveys were distributed, 320 were returned, and 199 met eligibility criteria.Participants' mean age was 48.8 +/- 12.9 years. Of them, 65.8% lacked college degrees and 43.2% had annual household incomes of < $25,000. The prevalence of inadequate health literacy was 14.1%. Most knew that fibroids are more common in African-American women (74.9%), can cause menorrhagia (80.9%), and can increase odds of miscarriage (74.4%). Many thought that fibroids are cancerous (47.2%), increase the risk of heart disease (32.7%), or are diagnosable via blood test (46.2%). Internet usage and education had highest correlations with fibroid awareness. Health literacy status showed no significant correlation with cumulative fibroid knowledge.African-American women's knowledge of the symptoms of fibroids is intact; however, they are less familiar with the systemic impact of the tumors. Additional research is needed to further assess women's knowledge offibroids and to develop interventions for patient education.
- Quantitative Proteome Profiling of human Myoma and Myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention. [JOURNAL ARTICLE]
- Proteomics 2014 Oct 18.
Uterine leiomyomas are benign tumors affecting a large proportion of the female population. Despite the very high prevalence, the molecular basis for understanding the onset and development of the disease are still poorly understood. In this study, we profiled the proteomes and kinomes of leiomyoma as well as myometrium samples from patients to a depth of >7000 proteins including 200 kinases. Statistical analysis identified a number of molecular signatures distinguishing healthy from diseased tissue. Among these, nine kinases (ADCK4, CDK5, CSNK2B, DDR1, EPHB1, MAP2K2, PRKCB, PRKG1 and RPS6KA5) representing a number of cellular signaling pathways showed particularly strong discrimination potential. Preliminary statistical analysis by receiver operator characteristics plots revealed very good performance for individual kinases (area under the curve, AUC of 0.70 to 0.94) as well as binary combinations thereof (AUC 0.70 to 1.00) which might be used to assess the activity of signaling pathways in myomas. Of note, the receptor tyrosine kinase DDR1 holds future potential as a drug target owing to its strong links to collagen signaling and the excessive formation of extracellular matrix typical for leiomyomas in humans. This article is protected by copyright. All rights reserved.
- Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. [JOURNAL ARTICLE]
- Mol Genet Genomics 2014 Oct 18.
Although somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been reported previously in uterine fibroids in women from Finland, South Africa, and North America, the status of these mutations was not reported in the Southern United States women. The aim of this study is to determine the MED12 somatic mutations in uterine fibroids of women from Southern Unites States, which will help to better understand the contribution of MED12 mutations in fibroid tumor biology. Herein, we determined the frequency of MED12 gene exon 2 somatic mutations in 143 fibroid tumors from a total of 135 women from the Southern United States and in 50 samples of the adjacent myometrium using PCR amplification and Sanger sequencing. We observed that the MED12 gene is mutated in 64.33 % (92/143) of uterine fibroid cases in the exon 2 (including deletion mutations). These mutations include 107T > G (4.3 %), 130G > C (2.8 %), 130G > A (7.0 %), 130G > T (2.8 %), 131G > C (2.1 %), 131G > A (20.2 %), and 131G > T (2.1 %). Interestingly, we identified four novel mutations in these patients: 107 T > C (12.8 %), 105A > T (2.1 %), 122T > A (2.1 %), and 92T > A (2.1 %). As expected, we did not observe any mutations in the normal myometrium. Moreover, we found a higher rate of deletion mutations (17.5 %, 25/143) in the above fibroid tumors. Our results clearly demonstrate that the MED12 gene exon 2 is frequently mutated in human uterine fibroids in Southern United States women. These results highlight the molecular pathogenesis of human uterine fibroids with the central role of MED12 somatic mutations.
- Inflammatory Myofibroblastic Tumor of the Uterus: Clinical and Pathologic Review of 10 Cases Including a Subset With Aggressive Clinical Course. [JOURNAL ARTICLE]
- Am J Surg Pathol 2014 Oct 15.
Inflammatory myofibroblastic tumor is currently regarded as a neoplasm with intermediate biological potential and a wide anatomic distribution. Inflammatory myofibroblastic tumors of the female genital tract are rare, and to date reported cases behaved indolently. We describe, herein, 10 cases of uterine inflammatory myofibroblastic tumor, 3 of which had an aggressive clinical course. Subject age ranged from 29 to 73 years. Tumors were composed of spindle and epithelioid myofibroblastic cells admixed with lymphoplasmacytic infiltrates in a variably myxoid stroma. Two growth patterns, myxoid and fascicular (leiomyoma-like), were noted. All tumors were positive for ALK expression by immunohistochemistry, which was stronger in the myxoid areas. Smooth muscle marker and CD10 expression was variable in extent, but typically positive. Fluorescence in situ hybridization for ALK rearrangements was positive in both fascicular and myxoid areas in all 8 cases tested. Three subjects showed clinical evidence of tumor aggressiveness as defined by extrauterine spread, local recurrence, or distant metastasis. Aggressive tumors were larger, had a higher proportion of myxoid stroma, and higher mitotic activity than indolent tumors. Tumor cell necrosis was seen only in cases with adverse outcome. This is the first report to describe aggressive biological behavior in uterine inflammatory myofibroblastic tumor. This diagnosis is often underappreciated and merits inclusion in the differential diagnosis of myxoid mesenchymal lesions of the uterus, particularly because patients with an aggressive course may benefit from targeted therapy.