Although some studies have indicated that endometriosis may increase the risk of developing ovarian cancer, there are no data from epidemiologic studies in Japan. We prospectively analyzed all cases of ovarian endometrioma enrolled in the prefecture-wide Shizuoka Cohort Study on Endometriosis and Ovarian Cancer Programme, which was initiated in 1985. To evaluate the risk of ovarian cancer by time periods subsequent to ovarian endometrioma diagnosis, a cohort of 6,398 women with a clinically documented ovarian endometrioma in Shizuoka between 1985 and 1995 was identified from the Shizuoka Cancer Registry (SCR), with follow-up through 2002. Ovarian cancer incidence among cohort members was ascertained by linkage to the SCR using a unique person-identification number. Standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed by a use of prefecture-wide rates of ovarian cancer, adjusted for age and calendar year. During follow-up of up to 17 years of the ovarian endometrioma cohort, 46 incident ovarian cancers were identified, yielding that the ovarian cancer risk was elevated significantly among patients with ovarian endometrioma (SIR = 8.95, 95% CI = 4.12-15.3). The SIR did not increase with increasing follow-up duration. The risk increased with increasing age at ovarian endometrioma diagnosis, with a SIR equal to 13.2 (95% CI = 6.90-20.9) in women above 50 years of age. Our findings for the first time support the hypothesis that ovarian endometrioma increases the subsequent risk of developing ovarian cancer in Shizuoka, Japan.
Summary. We experienced three cases and four successful deliveries with congenital afibrinogenaemia and propose the following guidelines for the prenatal and peripartum management: (i) genital bleeding usually begins at 5 weeks' gestation and spontaneous abortion always occurs at 6±8 weeks' gestation without fibrinogen infusion; (ii) the fibrinogen level must be at least 0´60 g/l and, if possible, higher than 1´0 g/l during the pregnancy; (iii) the necessary amounts of fibrinogen increase as the pregnancy progresses and the preterm labour occurs; (iv) the fibrinogen level under the continuous infusion of fibrinogen during labour must be at least 1´5 g/l and, if possible, higher than 2´0 g/l to prevent placental abruption; (v) the puerperium is usually uneventful with a reduced dose of fibrinogen infusion.
Urokinase-type plasminogen activator (uPA) has been implicated in tumor cell invasion and metastasis. We reported previously that transforming growth factor (TGF)-1 induces a dose-and time-dependent up-regulation of uPA mRNA and protein in highly invasive human ovarian cancer cell line HRA, leading to invasion. To further elucidate the mechanism of the invasive effect of TGF-1, we investigated which signaling pathway transduced by TGF-1 is responsible for this effect. Here, we show that 1) nontoxic concentrations of TGF-1 activated Src kinase; 2) TGF-1 rapidly phosphorylates ERK1/2 and Akt, but not p38; 3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment reduced TGF-1-induced phosphorylation of ERK1/2 and Akt by 85-90% compared with controls; 4) pharmacological inhibition of MAPK by PD98059 abrogated TGF-1-mediated Akt stimulation, whereas TGF-1-induced ERK1/2 stimulation was not inhibited by PI3K inhibitor LY294002 or AS-PI3K ODN transfection; 5) up-regulation of uPA mRNA in response to TGF-1 was almost totally blocked by PP2 and PD98059 and partially (ϳ55%) by LY294002; 6) TGF-1-induced uPA mRNA up-regulation was inhibited by treatment with AS ODNs to c-Src or PI3K by 90 or 60%, respectively, compared with control ODN treatment; and 7) blockade of the release of the transcription factor NF-B by pyrrolidinedithiocarbamate reduced the TGF-1-induced activation of the uPA gene by ϳ65%. In addition, curcumin, a blocker of the transcriptional factor AP-1, partially (35%) canceled this effect. Taken together, these data support a role for TGF-1 activation of two distinct pathways (Src-MAPK-PI3K-NF-B-dependent and Src-MAPK-AP-1-dependent) for TGF-1-dependent uPA up-regulation and promotion of invasion.The processes of ovarian cancer dissemination are characterized by altered local proteolysis, cellular proliferation, cell attachment, and invasion, suggesting that the urokinase-type plasminogen activator (uPA) 1 could be involved in the pathogenesis of peritoneal dissemination (1). uPA is a serine protease associated with various pathological conditions including tumor invasion and metastasis (2). One of the factors regulating the metastatic process is considered to be transforming growth factor- (TGF-), which is a multifunctional cytokine that elicits numerous cellular effects pertinent to the metastatic process (1). TGF- regulates a wide range of physiological and pathological cellular processes, including cell growth, differentiation, invasion, migration, mesenchymal transition, extracellular matrix synthesis, and cell death in many cell types including ovarian cancer cells (3). Recent data demonstrated that TGF- specifically stimulates up-regulation of uPA mRNA and protein in certain types of neoplastic cells (1). The cellular mechanism(s) of the TGF--induced uPA-dependent tumor invasion and metastasis has been extensively studied. The identity of the signaling pathway(s) involved in the TGF--induced uPA up-regulation (4) remains less known. In a well...
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