ERß- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis.

In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-ß (ERß) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERß binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERß target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERß at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERß and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention.

Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis.

Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and identifies a novel role for the GATA family as key regulators of uterine physiology-aberrant DNA methylation in endometriotic cells correlates with a shift in GATA isoform expression that facilitates progesterone resistance and disease progression.

FER kinase promotes breast cancer metastasis by regulating α6- and ß1-integrin-dependent cell adhesion and anoikis resistance.

Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating α6- and ß1-integrin-dependent adhesion. Conversely, the overexpression of FER in non-metastatic breast cancer cells induces pro-invasive features. FER drives anoikis resistance, regulates tumour growth and is necessary for metastasis in a mouse model of human breast cancer. In human invasive breast cancer, high FER expression is an independent prognostic factor that correlates with high-grade basal/triple-negative tumours and worse overall survival, especially in lymph node-negative patients. These findings establish FER as a promising target for the prevention and inhibition of metastatic breast cancer.

Changes in the ovarian stromal blood flow in patients treated with laparoscopic salpingostomy for ectopic pregnancy.

This study is aimed to evaluate the impact of laparoscopic salpingostomy on ovarian stromal blood flow indices in patients with ectopic pregnancy, and to compare the ovarian stromal blood flow indices with matched paired healthy women. We included 37 patients who underwent laparoscopic salpingostomy and 37 age- and parity-matched women as controls. The main outcome was the differences in ovarian volume, antral follicle count (AFC), and ovarian stromal blood flow indices between the study group participants after the surgery and the healthy controls. Comparison of the ovarian parameters between the study group after the surgery and the control group revealed no significant differences in terms of ovarian volume (p = 0.783), AFC (p = 0.253), ovarian stromal S/D ratios (p = 0.054), pulsatility index (PI; p = 0.938) and resistance index (RI; p = 0.041). In addition, comparison of the ovarian parameters before and after the surgical treatment revealed no significant differences in the ovarian volume (p = 0.141), AFC (p = 0.084), ovarian stromal S/D ratios (p = 0.187), PI (p = 0.102) and RI (p = 0.108). In conclusion, laparoscopic salpingostomy does not affect ovarian function in terms of ovarian stromal blood flow indices, ovarian volume, and AFC.

Sexual dysfunction assessment and hormonal correlations in patients with polycystic ovary syndrome.

In this controlled study, we aimed to evaluate the sexual dysfunction of patients with polycystic ovary syndrome (PCOS) in comparison to healthy controls. We enrolled 64 sexually active women in our study. The PCOS group consisted of 32 women who met the Rotterdam diagnostic criteria, and the control group was composed of 32 age-matched, healthy females. In addition to the demographic and clinical characteristics of the participants, the hormonal and biochemical parameters were also studied. All patients were invited to fill out the female sexual function index (FSFI) and Beck's Depression Inventory questionnaires. The prevalence of sexual dysfunction in the PCOS group was similar to controls (25% vs 19%; P=0.54). No significant difference was found according to each domain score of FSFI. Significant negative correlations were found between the total FSFI scores of the PCOS group and the total (r=-0.278) and free testosterone (r=-0.493) levels. Although depressive scores of PCOS patients were higher, they did not show greater impaired sexual functions than age-matched controls according to their FSFI scores. Considering the multifactorial state of female sexual dysfunction, further studies are needed to clarify the impact of PCOS upon sexuality.

Comparison of risk of malignancy indices; RMI 1-4 in borderline ovarian tumor.

PURPOSE: The aim of this study was to evaluate prognostic values of the risk of malignancy index (RMI)/1-4 in patients with borderline ovarian tumors (BOTs). METHODS: The study consisted of 50 patients with BOT diagnosed and treated between 2005-2010 and 50 patients with benign adnexal massses between 2009-2010 as a control comparison group in the retropsective study. Preoperative serum CA125, U score, tumor size (S), and menopausal status were recorded. The RMI 1-3 was calculated according to the formula; UxMxCA125 and RMI4 formulation was; UxMxCA125xS. S equaled 1 for tumor size <7 cm and was 2 when size a 7 cm. The RMI 1-4 indices were calculated for all patients together with the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy (DA). The performances of RMI indices were evaluated by McNemar's test and determined the best score cutoff value by the receiver operating characteristic (ROC) curve. RESULTS: The mean age, median value of CA125, ultrasound score, menopausal status, median values of RMI 1-4 of BOTs were statistically higher than benign adnexal masses. The sensitivity of RMI 1-4 was 26, 36, 62, and 60% at cutoff 200 level, respectively. The areas under curve of RMI 1-4 were found to be 0.676, 0.665, 0.668 and 0.734, respectively. DA of RMI 1-4 was found to be 56, 59, 50, and 71, respectively. When RMI 1-4 indices were compared with each other RMI 4 was the best RMI for BOTs. CONCLUSION: RMI 4 was the best predictive RMI for preoperative discrimination of BOT at a cutoff level of 200.

Comparison of tumor markers and clinicopathological features in serous and mucinous borderline ovarian tumors.

OBJECTIVE: The aim of this study was to assess tumor markers and clinicopathological findings of patients with serous and mucinous borderline ovarian tumor (BOT) features. METHODS: The study consisted of 50 patients that were diagnosed with and treated for BOT between 2005-2010 in three centers. CA125, CA19-9, and CA125+CA19-9 levels and clinicopathological features were compared in serous and mucinous histotypes. In serous and mucinous BOTs, correlations between tumor markers and demographics such as age, menopausal status, parity, clinical findings (stage, relapse, adjuvant chemotherapy, cytology, lymph node involvement and tumoral morphology (cystic-solid content, papilla, septation) were evaluated. RESULTS: There were no significant differences between serous and mucinous tumors in the clinicopathological features such as stage, tumor markers, age, menopausal status, or cytology. In serous BOTs we found a significant relation between elevated CA125+ CA19-9, CA19-9 and recurrence (p < 0.05). Also there was a significant relation between elevated CA125+ CA19-9, CA19-9 and cytology positivity (p < 0.05). We found a significant relation in serous BOTs between elevated CA125+CA19-9, adjuvant chemotherapy and lymph node metastases (p < 0.05). Also In mucinous BOTs with papilla formation we found a significant relation between elevated CA125 and CA125+ CA19-9 (p < 0.05). There was significant relation between cytology positivity and elevated CA19-9 in mucinous BOTs (p < 0.05). CONCLUSION: Serum tumor markers of serous and mucinous BOTs were different in relation to their clinicopathological features. This may reflect differences of serous and mucinous BOTs.

Mammary development and breast cancer: the role of stem cells.

The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often found deregulated in breast cancer. Here we provide an overview on the functional and molecular identification of mammary stem cells in the context of both normal breast development and breast cancer. We discuss the contribution of some key signaling pathways with an emphasis on Notch receptor signaling, a cell fate determination pathway often deregulated in breast cancer. A further understanding of the biological roles of the Notch pathway in mammary stem cell behavior and carcinogenesis might be relevant for the development of future therapies.

Lidocaine spray in addition to paracervical block reduces pain during first-trimester surgical abortion: a placebo-controlled clinical trial.

BACKGROUND: A variety of anesthetic and analgesic techniques have been used for uterine aspiration, and most clinicians use a paracervical block with or without additional analgesia. We intended to evaluate whether the addition of 10% lidocaine spray to a paracervical block decreases pain during cervical dilation and uterine aspiration. STUDY DESIGN: Seventy-seven patients were divided into two groups: paracervical blocks (PCB) (n = 30) and PCB plus 10% lidocaine spray (n = 47). Anticipated and overall perceived pain scores were measured with a standard Visual Analog Scale (VAS). RESULTS: Anticipated pain VAS scores of two groups were similar, however overall perceived pain VAS scores demonstrated a significant difference. PCB with Lidocaine only group had 6.56 ± 1.43 cm mean VAS score, whereas lidocaine plus lidocaine spray group had 2.35 ± 1.39 cm, the difference being statistically significant (p < .01). CONCLUSION: We found that 10% lidocaine spray safely decreases perceived pain during first-trimester surgical abortion, when used in addition to PCB with lidocaine HCl.

Rubella seroprevalence in an unvaccinated pregnant population in Malatya, Turkey.

BACKGROUND: Controlling congenital rubella by 2010 is one of the targets of the World Health Organization. Most European countries currently include rubella vaccine in their national immunization programmes, but not yet in Turkey. OBJECTIVES: To define rubella seroprevalence in pregnancy in Malatya, Turkey. STUDY DESIGN: A cross-sectional interview survey was conducted among pregnant women living in Malatya province from November 2003 to May 2004, together with a follow-up component. METHODS: Stratified probability proportional to size sampling methodology. A total of 824 pregnant women from 60 clusters were enrolled. After obtaining informed consent, participants' socio-demographic and fertility characteristics were collected by interview questionnaire. Various blood samples were drawn. After storing serum samples at -20 degrees C for 6 months, anti-rubella IgM and IgG titres were studied by micro ELISA. Only 803 sera were eligible for serological study. RESULTS: Of the 803 samples tested for rubella antibodies, 753 cases (93.8%) had anti-rubella IgG positivity, indicating past infection. Five of the pregnant women (0.6%) had both anti-rubella IgM and IgG positive results, suggesting a recent infection. The remaining 45 women (5.6%) were seronegative for both antibodies. Seroprevalence was not associated with age or urban/rural residency. All the five anti-rubella IgM positive women were in the second trimester of pregnancy. CONCLUSIONS: As 5.6% of pregnant women were susceptible to rubella during pregnancy, and five of them had already had a recent infection, immunization efforts should be directed at babies and adolescents.

Evaluation of the immune response to hepatitis B vaccination in children aged 1-3 years in Malatya, Turkey.

By the end of 1998, Turkey had launched the routine vaccination of infants against hepatitis B. The purpose of the study is to evaluate the immune response in a sample of vaccinated children aged 1-3 years in the city of Malatya. A total of 210 vaccinated children 12 to 48 months old were selected for the study with 30 cluster sampling in the city of Malatya, Turkey. The children were visited at their homes during January-April 2002. The information on demographic characteristics, family's and child's medical history was gathered, childrens' weight and height were measured and blood samples were taken. Anti-HBs, HbsAg and anti-HBc titers were assayed by micro-ELIZA from the sera. The mean age of the children was 26.3 months, 100 (47.6%) were male and 110 (52.4%) were female. Overall, 203 (96.7%) children had protective anti-HBs levels (> or = 10 IU/l), 0.5% showed evidence of natural infection (with positive anti-HBc and anti-HBs titers), 0.5% had acute or chronic infection (with positive HbsAg and anti-HBc titers) and 2.3% were seronegative. Geometric mean titer of anti-HBs among vaccinated children except those who had positive anti-HBc titers was 138.7 mIU/ml (95% CI:124.7-154.2) and seroconversion rates did not differ by age, sex, anthropometric measurements, time after third dose and place of vaccine administered (P > 0.05). The high seroprotection rate over 95% showed that routine infant vaccination program for hepatitis B was successfully carried out in the city Malatya.