Transforming growth factor-B (TGF-B) is thought to play a role in the pathobiological progression of ovarian cancer because this peptide hormone is overexpressed in cancer tissue, plasma, and peritoneal fluid. In the current study, we investigated the role of the TGF-B/ Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-B1, TGF-B2, and TGF-B3 induced pro -matrix metalloproteinase (MMP) secretion, loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and acquisition of a fibroblastoid phenotype, consistent with an epithelial-tomesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-B -mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-B1, TGF-B2, and TGF-B3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-B -stimulated invasion and MMP secretion. Analysis of Smad3 nuclear expression in microarrays of serous benign tumors, borderline tumors, and cystadenocarcinoma revealed that Smad3 expression could be used to distinguish benign and borderline tumors from carcinoma (P = 0.006). Higher Smad3 expression also correlated with poor survival (P = 0.031). Furthermore, a direct relationship exists between Smad3 nuclear expression and expression of the mesenchymal marker N-cadherin in cancer patients (P = 0.0057). Collectively, these results implicate an important role for the TGF-B/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential. (Mol Cancer Res 2008;6(5):695 -705)
Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize that activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the betaA-subunit of activin A and phospho-GSKalpha/beta (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that betaA expression in epithelia did not correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared with benign tumors. Phospho-GSKalpha/beta (Ser9/21) staining was more intense in mitotically active carcinoma cells and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSKalpha/beta (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P=0.046). Our data are consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.
OBJECTIVE:To determine if a decrease in the episiotomy rate over time is associated with a corresponding decrease in the anal sphincter laceration rate. METHODS: Our institution began use of restrictive episiotomy in 1998, with decreasing rates over 4 consecutive academic years (1998 -99 to 2001-02). We obtained data from all women delivered during this period, and excluded cesarean and vaginal twin or breech deliveries. Rates of episiotomy, anal sphincter laceration (3 rd and 4 th degree tears), and other confounding variables were compared between 1998 -99 and 2001-02. Logistic regression was used to estimate the odds ratio of anal sphincter lacerations due to episiotomy and other variables in the first and last years of the study. RESULTS: The episiotomy rate decreased each of the 4 years, from 37.4% in 1998 -99 to 16.5% in 2001-02 (pϽ0.001). Similarly, the anal sphincter laceration rate decreased from 9.7% to 5.4% (pϽ0.001). There were no changes in age, race, nulliparity, duration of the second stage of labor, birthweight, or macrosomia, but oxytocin use decreased (37% to 31%, pϭ0.002), epidural use decreased (80% to 76%, pϭ0.02), and operative vaginal deliveries increased (8.9% to 11.2%, pϭ0.03). At spontaneous vaginal delivery, the episiotomy and anal sphincter laceration rates decreased over four years from 33% to 14% (pϽ0.001), and from 6.6% to 2.8% (pϽ0.001), respectively. Similarly, at operative vaginal delivery, the episiotomy and anal sphincter laceration rates decreased from 81% to 37% (pϽ0.001), and from 42% to 27% (pϭ0.007), respectively. Between the first and last years of the study, the adjusted odds ratio of anal sphincter laceration due to episiotomy decreased from 6.5 (95% CI 3.8, 11.1) to 2.9 (95% CI 1.7, 5.0). Conversely, the adjusted odds ratio for operative vaginal delivery increased from 4.4 (95% CI 2.7, 6.9) to 6.3 (95% CI 3.6, 11.1), but did not change for the other independent risk factors for anal sphincter laceration: nulliparity (from 2.9 to 2.9), prolonged second stage (from 2.0 to 2.1), and macrosomia (from 1.9 to 2.6). CONCLUSION: With restricted use of episiotomy, our episiotomy rate at vaginal delivery decreased by 56%, and our anal sphincter laceration rate decreased by 44%. These decreases occurred for spontaneous vaginal delivery as well as operative vaginal delivery. In addition, the risk of anal sphincter laceration due to episiotomy was reduced OBJECTIVE: To determine the prevalence, risk factors and impact upon quality of life of anal incontinence (AI) in women aged 18 to 65. METHODS: Consecutive women presenting for general gynecologic care to one of 6 tertiary centers were given a self-administered, anonymous bowel function questionnaire. Women responding positively to the question "Have you had any accidental leakage of bowel movements or gas in the last 12 months?" were prompted to complete the Fecal Incontinence Severity Index (FISI, 51 point scale) and the Fecal Incontinence Quality of Life Scale (FIQL, 0 -5 point scales). A higher score on the FISI indicates wor...
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