Safety and efficacy of preoperative autologous blood donation for high-risk pregnant women: experience of a large university hospital in Japan.

AIM: Preoperative autologous blood donation (PAD) has the advantages over allogeneic blood transfusion of theoretically no risk of viral infection and alloimmunization. However, there are some concerns regarding PAD in pregnant women, as they sometimes become anemic and adverse effects such as low blood pressure could be harmful to fetuses. In our hospital, the PAD program was implemented in 2006 and has been used in pregnant women at high risk of massive hemorrhage. In this study, the safety of PAD in pregnant women and its efficacy for avoiding allogeneic blood transfusion were investigated. METHODS: The hospital records of pregnant women who delivered at our hospital from January 2009 to June 2012 were reviewed and those who were enrolled in the PAD program for predicted massive hemorrhage were analyzed. RESULTS: Among the total of 3095 deliveries, 69 cases enrolled in the PAD program were analyzed. Blood donation was performed 189 times for the 69 cases. The median donated blood volume was 1200 mL (range, 400-2000). The mean blood loss during delivery was 1976 ± 1654 mL. Autologous blood was transfused in 64 cases. Allogeneic blood transfusion was required in five cases of massive blood loss exceeding 5000 mL. In the other 64 cases, no additional allogeneic blood transfusion was required. No adverse events were observed in either the pregnant women or fetuses. CONCLUSION: For pregnant women at a high risk of massive hemorrhage, our PAD program was safe and effective for avoiding allogeneic blood transfusion.

The role of bone morphogenetic protein 6 in accumulation and regulation of neutrophils in the human ovary.

Bone morphogenetic protein (BMP) cytokine is known to regulate ovulation, as BMP-6 null mice exhibit a decrease in the number of ovulatory follicles without effect on either the morphology or the dynamics of follicular development. In the present study, the role of BMP-6 in ovulatory process was investigated using human granulosa-lutein cells (GCs). Granulosa-lutein cells, obtained from in vitro fertilization patients, were cultured with BMP-6 followed by RNA extraction. The neutrophil-chemotactic activity of the supernatant of cultured GC was investigated. Bone morphogenetic protein 6 significantly increased growth-regulated oncogene α (GRO-α) messenger RNA (mRNA) and protein expression in GC. In the neutrophil-chemotaxis assay, the GC supernatant cultured with BMP-6 attracted more neutrophils than control samples, which was negated with anti-GRO-α neutralizing antibody. Bone morphogenetic protein 6 also suppressed the relative expression of the protease inhibitors, secretory leukocyte peptidase inhibitor, and whey acid protein 14 mRNA in GC. Bone morphogenetic protein 6 might play a role in ovulation by increasing the accumulation of neutrophils in the ovulatory follicle and suppressing the effect of protease inhibitors.

Individualized management of umbilical endometriosis: a report of seven cases.

AIM: The aim of this study was to review diagnostic/therapeutic strategies of umbilical endometriosis managed in our department and evaluate the effectiveness of these strategies. METHODS: Medical records for patients with diagnosis of endometriosis managed from 1999 through 2011 in the University of Tokyo Hospital were retrospectively reviewed. Cases with diagnosis of umbilical endometriosis were identified. Clinical information of age, gravida, parity, histories of surgery and oral contraceptive (OC), management for the disease prior to the first visit, symptoms, patients' desire for pregnancy, diagnostic/therapeutic methods and prognosis were reviewed and summarized. RESULTS: During the period, 2530 patients with diagnosis of endometriosis were identified. Seven patients had diagnosis of umbilical endometriosis, giving an incidence of 0.29% of all endometriosis cases and 5.6% of extragenital endometriosis cases. A definitive diagnosis was made by histological examination following a biopsy (two cases) or a resection (three cases). A clinical diagnosis was made by empirical treatment with OC (one case) or dienogest (one case). With regard to therapy, three patients chose expectant management and did not require therapeutic intervention. Three patients began OC and symptoms were well controlled in all patients. One patient who wished to conceive chose a wide resection followed by umbilical reconstruction. She became pregnant afterwards and recurrence was not reported. CONCLUSION: There are various options of diagnostic/therapeutic strategies, such as empirical treatments and OC that can provide individualized management of umbilical endometriosis, congruent with the severity of patient symptoms, age and desire for pregnancy.

Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells.

The formation of an individual capillary network in the theca cell layer is required for ovarian folliculogenesis. Although vascular endothelial growth factor (VEGF) is critical for this process, the regulation of VEGF has been unclear. In the present study, the relationship between VEGF and intraovarian cytokine, bone morphogenetic protein 7 (BMP-7) was investigated. Granulosa cells (GC), obtained from in vitro fertilization patients, were cultured with BMP-7 followed by RNA extraction. Human umbilical vein endothelial cells (HUVECs) were also cultured with BMP-7 followed by RNA extraction, tube formation assay, or cell count analysis. The BMP-7 stimulated VEGF messenger RNA (mRNA) and protein expression in GC significantly. In HUVEC, BMP-7 increased an approximately 1.8-fold in the cell number and induced the tube formation significantly compared to control. The BMP-7 also induced a 2-fold increase in VEGF receptor mRNA transcript relative abundance in HUVEC. The BMP-7, a theca cell-derived factor, may stimulate endothelial cell to form vasculature in the follicle via 2 distinct mechanisms, induction of VEGF expression in GC and increased sensitivity of endothelial cells to VEGF.

Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: a possible role of the sirtuin 1 pathway.

AIM: Endometriosis is a chronic inflammatory disease. Sirtuin 1 (SIRT1) plays a role in regulation of inflammation. The role of SIRT1 in endometriosis remains unknown. We here addressed the anti-inflammatory effects of SIRT1 on endometriosis. METHODS: The expression of SIRT1 in human ovarian endometriomas and eutopic endometria were examined using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Endometriotic stromal cells (ESC) obtained from endometriomas were exposed to either resveratrol or sirtinol, an activator or inhibitor of sirtuins, respectively, and tumor necrosis factor (TNF)-α-induced interleukin (IL)-8 release from the ESC was assessed at mRNA and protein levels. RESULTS: Both immunochemistry and RT-PCR demonstrated that SIRT1 was expressed in ESC and normal endometrial stromal cells. Resveratrol suppressed TNF-α-induced IL-8 release from the ESC in a dose-dependent manner while sirtinol increased IL-8 release. CONCLUSION: These opposing effects of SIRT1-related agents suggest that IL-8 release from the ESC is modulated through the SIRT1 pathway. Resveratrol may have the potential to ameliorate local inflammation in endometriomas.

Factors that predict poor clinical course among patients hospitalized with pelvic inflammatory disease.

AIM: The aim of this study was to identify factors that can predict clinical course among patients hospitalized with pelvic inflammatory disease (PID). METHODS: Ninety-three patients who needed hospitalization with a diagnosis of PID were retrospectively studied. Patients who were discharged within 7 days by conservative treatment were defined as favorable course cases (n = 44). Patients who needed more than 7 days of hospitalization and/or surgery were defined as poor course cases (n = 49). Twenty variables were evaluated by univariate and logistic regression analysis: age, history of pregnancy/delivery, gynecological open/laparoscopic surgery, PID, oral contraceptives/intrauterine device use and intrauterine operation before onset, body temperature, signs of peritoneal irritation, vomiting/diarrhea, abnormal vaginal discharge, endometriosis/fibroid/adenomyosis/any cystic lesion detected by ultrasonography, white blood cell counts/C-reactive protein (CRP) levels . The cut-off value was calculated by receiver-operator curve (ROC) analysis. RESULTS: Factors associated with poor clinical course were advanced age (P < 0.01), history of gynecological open surgery (P < 0.05), any cystic lesion detected by ultrasonography (P < 0.05) and high CRP levels (P < 0.05). High CRP levels and intrauterine operation before onset were independently associated with poor clinical course. The cut-off value for CRP was 4.4 mg/dL. CONCLUSION: This study identified variables that can predict poor clinical course of PID. These results can assist gynecologists with identifying patients at risk and optimizing the choice of management.

High-risk human papillomavirus correlates with recurrence after laser ablation for treatment of patients with cervical intraepithelial neoplasia 3: a long-term follow-up retrospective study.

AIM: The purpose of our study was to evaluate the efficacy of laser ablation as a conservative treatment for cervical intraepithelial neoplasia 3 (CIN3) and assess whether the human papillomavirus (HPV) test is useful to predict recurrence after treatment. MATERIALS AND METHODS: A total of 134 patients who received laser ablation for treatment of CIN3 were enrolled in this study. During the follow-up period, patients were followed with cytological and colposcopic evaluations. Recurrence of CIN3 was regarded as the primary end-point. HPV genotype was tested before and after treatment. Post-treatment cumulative recurrence rates were estimated and comparisons by both patient age and HPV genotype were performed. RESULTS: Overall cumulative recurrence rate of CIN3 in the first year after treatment was 22.6% for all patients. No significant correlation was shown between patient age and recurrence. Patients infected by specific genotypes (16, 18, 31, 33, 52, and 58) frequently failed to clear the infection after treatment. The 1-year recurrence-free survival in those positive after treatment for eight high-risk genotypes (16, 18, 31, 33, 35, 45, 52, and 58) was significantly lower (66.7%), compared to that in those positive for other high-risk types (78.6%). The recurrence-free survival of those who remained HPV-positive after treatment was significantly lower than those who turned negative. CONCLUSION: Laser ablation should be performed prudently with appropriate patient counseling about recurrence rate. Considering its minimal invasiveness, laser ablation is effective, especially for young patients who are negative for eight high-risk genotypes. With regard to HPV testing, although genotyping has significant value for predicting recurrence, screening for all genotypes warrants further evaluation.

Placental abnormalities detected by ultrasonography in a case of confined placental mosaicism for trisomy 2 with severe fetal growth restriction.

Clinical outcome of confined placental mosaicism (CPM) is varied, from normal pregnancy to intrauterine fetal death. It has been suggested that CPM for trisomy 2 is less likely to cause serious adverse effect on pregnancy. We hereby report a case of CPM for trisomy 2, which presented severe fetal growth restriction (FGR) and placental abnormalities. A 30-year-old woman was referred to our hospital at 17⁺² weeks because of marked FGR. Ultrasonography demonstrated prominent placental hypertrophy with multiple focal defects without any fetal structural abnormalities. Amniocentesis at 18⁺³ weeks revealed normal karyotype. Fetal growth rate worsened with gestational weeks, reaching -7 standard deviation at 36 weeks. At 37 weeks, the fetal condition suddenly deteriorated, ending in a stillbirth of a 756-g female baby. Postnatal cytogenetic analysis by array comparative genomic hybridization revealed trisomy 2 of the chorionic villi, and CPM for trisomy 2 was suggested as the cause of FGR and placental abnormalities.

Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth.

Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1ß in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth.

Omega-3 polyunsaturated Fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE), derived from eicosapentaenoic acid (EPA), and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX)-knockout (KO) and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6) expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy.

In human pregnancy, CD14⁺ decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20-30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD-1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7-H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-γ, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-γ production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-γ production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy.

Predictive factors for recurrence of ovarian mature cystic teratomas after surgical excision.

OBJECTIVE: To study the recurrence rate and predictive factors for recurrence after surgical excision of ovarian mature cystic teratomas (MCT). STUDY DESIGN: Retrospective study of 382 patients who underwent surgical excision of MCT and whose post-surgical follow-up data were available over six months. Patients who underwent concomitant oophorectomy or had a history of oophorectomy were excluded. Medical records were reviewed for evidence of recurrence. The Cox-hazard model was used for the estimation of predictive factors for recurrence. Categorical data were compared using the Chi-square and Fisher's exact tests. RESULTS: There were 16 recurrences within a mean follow-up period of 43.0 months, with a recurrence rate of 4.2%. Young age (<30 years old, Y) (hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.04-8.62, P=0.043), large cyst (≥8 cm in diameter, L) (HR 2.75; 95% CI 1.03-7.37, P=0.044), and bilaterality (B) (HR 2.88; 95% CI 1.07-7.76, P=0.036) were shown to be significant predictive factors. When a patient had all these three factors, the recurrence rate was 21.0%, otherwise 3.4% (P<0.01). Patients with Y+L, Y+B, and B+L also showed significantly higher recurrence rate (21.4%, 15.9%, and 11.4%, respectively). CONCLUSION: The long-term recurrence rate after surgical excision of MCT in this study is 4.2%. A patient with young age (<30 years old) or large cyst (≥8 cm in diameter) or bilateral cysts is at high risk of recurrence, which is even higher when a patient has more than one of these factors.

Laparoscopic ovarian-sparing surgery for a young woman with an exophytic ovarian fibroma.

Ovarian fibroma can occur in young women of reproductive age. Despite its benign feature, most surgical removals are done in open surgery with oophorectomy. However, an ovarian-sparing tumor resection can be an option, especially for an exophytic type of fibroma, which accounts for more than half of ovarian fibromas. Here we report a case of exophytic ovarian fibroma in a young woman treated by laparoscopic ovarian-sparing surgery. A 27-year-old woman presented with a pelvic mass. Magnetic resonance imaging revealed an 11 cm × 8 cm solid mass connected to the normal-appearing left ovary by a pedicle-like structure. A clinical diagnosis of an exophytic ovarian fibroma was made, and laparoscopic ovarian-sparing surgery with an intraoperative pathological examination was planned. The tumor was resected by cutting the pedicle, morcellated in a pouch and removed. All procedures were performed laparoscopically and the affected ovary was completely preserved. Having confirmation of its benign characteristics by the intraoperative examination, no further excision was performed. The patient conceived 3 months after the surgery and no recurrence was reported. We propose that gynecologists should consider laparoscopic ovarian-sparing surgery for exophytic ovarian fibroma in women of reproductive age.

Laparoendoscopic single-site concomitant surgery for gallstones and a giant ovarian teratoma.

Laparoendoscopic single-site (LESS) technique has gained popularity in several fields of surgery. Our patient had multiple gallstones and a left ovarian mature cystic teratoma 12 cm in diameter. She underwent concomitant laparoscopic cholecystectomy and adnectomy using LESS technique. Using a transient gasless technique resulted in the extraction of a giant ovarian tumor through the umbilical incision with no leakage into the abdominal cavity. Concomitant LESS surgery is feasible and has many benefits both for patients and doctors - cosmetics, possibly less pain, avoidance of multiple surgeries and cost-effectiveness. LESS technique is also useful for extracting a giant tumor with the transient gasless technique. This novel method might be applied to the removal of a tumor suspicious for malignancy.

Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer.

Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr286 by GSK3ß triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.

The significance of serum anti-Müllerian hormone (AMH) levels in patients over age 40 in first IVF treatment.

PURPOSE: Although studies of serum anti-Müllerian hormone (AMH) in predicting ovarian reserve are numerous, many studies utilized patients under age 40. However, the assessment of ovarian reserve is especially critical in older infertile women. This study evaluates the significance of AMH level in patients over age 40 at the time of their first in vitro fertilization (IVF) treatment. METHODS: Forty-nine women over age 40 were studied. Although serum samples were taken prior to their IVF treatments, the data of serum AMH of patients were not taken into consideration to determine the therapy strategy, including follicle induction in which clomiphene citrate and human menopausal gonadotropin were used. RESULT(S): Twelve out of 49 patients achieved a clinical pregnancy (24.4 %). There was a positive correlation between serum AMH levels and the number of oocytes retrieved (P < 0.0001). The ROC curve analysis for prediction of poor ovarian response, ≤3 retrieved oocytes, showed that the optimum cut-off level was < 1.0 ng/mL for AMH. The lower AMH group (AMH < 1.0 ng/ml) showed less chance of undergoing embryo transfer than the higher AMH group (AMH ≥1.0 ng/ml). There was no difference in pregnancy rate between the two groups. Five out of 12 pregnant women exhibited AMH levels of less than 0.4 ng/ml. CONCLUSION(S): Assessment of serum AMH concentration in older patients is useful for the prediction of oocytes numbers which may be obtained in IVF. A cut-off level of 1.0 ng/ml AMH can be used to predict poor ovarian response. This cut-off level of AMH of 1.0 ng/ml might be useful to predict whether patients could have an embryo transfer, but had no power to predict achieving pregnancy. On the other hand, our data also showed that patients over age 40 with extreme low levels of AMH still had a chance of pregnancy.

Interleukin-4 and prostaglandin E2 synergistically up-regulate 3ß-hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells.

CONTEXT: Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease. OBJECTIVE: The objective of the investigation was to study the effect of IL-4 on the expression of 3ß-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay. RESULTS: IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA. CONCLUSIONS: IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease.

Cyclic stretch augments production of neutrophil chemokines and matrix metalloproteinases-1 (MMP-1) from human decidual cells, and the production was reduced by progesterone.

PROBLEM: The purpose of this study was to evaluate the impact of mechanical stretch caused by uterine contraction and progesterone (P4) on decidual cells (DC), neutrophil chemokines, and MMP-1 expression. METHOD OF STUDY: DC were cultured, and cyclic stretch was applied using a computer-operated cell stretch system. Interleukin (IL)-8, growth-regulated oncogene (GRO) α, matrix metalloproteinase (MMP)-1, and mRNA and/or protein expression/activity was measured using RT-PCR and ELISA. Neutrophil chemotactic activity in conditioned media was evaluated using migration assays. The effect of P4 was also studied. RESULTS: Cyclic mechanical stretch increased IL-8, GROα, mRNA and protein, and MMP-1 production and activity level. Supernatant from stretched cells induced neutrophil chemotactic activity significantly. P4 suppressed the effect of stretch. CONCLUSION: The current study demonstrates that cyclic mechanical stretch stimulates the production of neutrophil chemokines and MMP-1 from human decidual cells, and the production was reduced by progesterone. These findings suggest that decidual cells are responding to mechanical and endocrine signals and induce biochemical factors and thereby contribute to the regulation of human labor.

A novel interaction between hScrib and PP1γ downregulates ERK signaling and suppresses oncogene-induced cell transformation.

Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.

The influence of infertility treatment on the prognosis of endometrial cancer and atypical complex endometrial hyperplasia.

INTRODUCTION: Many patients with endometrial cancer have no children when diagnosed, and thus are reluctant to undergo hysterectomy, hoping to preserve their fertility. Their requirement is met, at least partially, with high-dose medroxyprogesterone acetate that brings good response rate in the treatment of endometrial cancer in the early stage and atypical complex endometrial hyperplasia (EC/ACEH). Actually, a number of successful pregnancies after the conservative treatment have been reported. To conceive, many of them need infertility treatment because of ovulation disorders which might have induced the cancer with unopposed estrogens. However, on the other side, hyperestrogenic status caused by ovulation induction or controlled ovarian stimulation might promote the progression and the recurrence of the disease. OBJECTIVE: This study aimed to assess the effectiveness and safety of infertility treatment after conservative therapy for EC/ACEH, to confirm the significance of fertility-sparing therapy. METHODS: The patients with EC/ACEH who achieved complete response after high-dose medroxyprogesterone acetate were eligible for this retrospective study. Characteristics of the patients, whether they underwent infertility treatment, conceived, or relapsed, and the interval from complete response to conception or recurrence were retrospectively analyzed. RESULTS: The clinical outcomes of 36 patients were investigated. Twenty-six of them desired to conceive soon after complete response. All of them underwent infertility treatment, and 16 women delivered healthy babies. Kaplan-Meyer curve and log-rank test analysis revealed that women who achieved live birth had a significantly lower risk of recurrence than those without live birth. There was not a significant difference between the patients with and without infertility treatment. CONCLUSIONS: Use of ovulation induction drugs after conservative treatment of endometrial cancer did not increase the recurrence of the disease. Moreover, resulting pregnancy seems to have an advantageous effect on the oncologic outcome.