-
[show abstract]
[hide abstract]
ABSTRACT: 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.
International Journal of Gynecological Cancer 01/2013; · 1.65 Impact Factor
-
Kazunori Nagasaka,
Takayuki Seiki,
Aki Yamashita,
Paola Massimi,
Vanitha Krishna Subbaiah,
Miranda Thomas,
Christian Kranjec,
Kei Kawana,
Shunsuke Nakagawa,
Tetsu Yano,
Yuji Taketani,
Tomoyuki Fujii, Shiro Kozuma,
Lawrence Banks
[show abstract]
[hide abstract]
ABSTRACT: 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.
PLoS ONE 01/2013; 8(1):e53752. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Uterine arteriovenous fistula (AVF) is a rare entity, but may lead to life-threatening hemorrhage. Although transcatheter embolization, surgical ligation, or hysterectomy would be considered for treatment of uterine AVF, there is poor knowledge as to how gynecologists can manage the uterine AVF with multiple large inflow arteries. Herein we report a uterine AVF successfully treated using multiple-step transcatheter embolization. The patient, a 58-year-old postmenopausal woman with a history of dilation and curettage, had intermittent massive uterine bleeding. Radiologic imaging revealed the presence of a large vasculature mass. The mass occupied the entire pelvis, and the source of hemorrhage was identified as an accompanying AVF. We thought that surgical intervention was contraindicated because of the potential risk of uncontrollable intraoperative bleeding. Multiple-step transcatheter embolization was performed, with complete resolution of the AVF. Thereafter, the patient had no further uterine bleeding. Multiple-step transcatheter embolization might be the most beneficial and efficient treatment option for a uterine AVF with multiple large inflow arteries.
Journal of Minimally Invasive Gynecology 11/2012; 19(6):780-4. · 1.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION AND HYPOTHESIS: The aim of this study was to translate the Pelvic Floor Distress Inventory-Short Form 20 (PFDI-20) into Japanese and test its reliability and validity among Japanese women. METHODS: Fifty-nine women with and without pelvic floor disorders (age 55.8 ± 16.8 years, mean ± SD) completed the Japanese PFDI-20 (J-PFDI-20) questionnaire at baseline and 2 weeks later. Intraclass correlation coefficients (ICC) and the Bland and Altman method for test-retest reliability and Cronbach's alpha for internal consistency of the J-PFDI-20 were used. Scores of total and subscales were compared between women with and without pelvic floor disorders for known-groups validity. Spearman's correlation coefficients between the J-PFDI-20 and the severity of pelvic floor disorders and Urinary Incontinence Quality of Life Scale (I-QOL) were used for construct validity. RESULTS: The PFDI-20 was successfully translated from English into Japanese with face validity through rigorous cross-cultural validation. Test-retest reliability of the J-PFDI-20 and three subscales was good to excellent (ICC = 0.77-0.90). The Bland and Altman analysis showed that differences between the first and second scores of total J-PFDI-20 and its subscales were not significantly different from 0 and largely fell within the range of 0 ± 1.96 SD. Cronbach's alpha values were 0.52-0.83. Analysis of known-groups validity showed differences in scores of the J-PFDI-20 between women with and without pelvic floor disorders. Acceptable construct validity was found in J-PFDI-20 total and subscale scores with positive correlations to severity of pelvic floor disorders (ρ > 0.35) and negative correlations to I-QOL (ρ < -0.39). CONCLUSIONS: The results suggest that the J-PFDI-20 is a reliable and valid condition-specific quality of life instrument for women with pelvic floor disorders.
International Urogynecology Journal 10/2012; · 1.83 Impact Factor
-
Satoko Kojima,
Kei Kawana,
Kensuke Tomio,
Aki Yamashita,
Ayumi Taguchi,
Shiho Miura,
Katsuyuki Adachi,
Takeshi Nagamatsu,
Kazunori Nagasaka,
Yoko Matsumoto,
Takahide Arimoto,
Katsutoshi Oda,
Osamu Wada-Hiraike,
Tetsu Yano,
Yuji Taketani,
Tomoyuki Fujii,
Danny J Schust, Shiro Kozuma
[show abstract]
[hide abstract]
ABSTRACT: PROBLEM: Local adaptive cervical regulatory T cells (Tregs) are the most likely direct suppressors of the immune eradication of cervical intraepithelial lesion (CIN). PD-1 expression on T cells induces Tregs. No studies have quantitatively analyzed the Tregs and PD-1+ cells residing in CIN lesions. METHOD OF STUDY: Cervical lymphocytes were collected using cytobrushes from CIN patients and analyzed by FACS analysis. Comparisons were made between populations of cervical Tregs and PD-1+ CD4+ T cells in CIN regressors and non-regressors. RESULTS: A median of 11% of cervical CD4+ T cells were Tregs, while a median of 30% were PD-1+ cells. The proportions of cervical CD4+ T cells that were Tregs and/or PD-1+ cells were significantly lower in CIN regressors when compared with non-regressors. CONCLUSIONS: The prevalence of cervical tolerogenic T cells correlates inversely with spontaneous regression of CIN. Cervical Tregs may play an important role in HPV-related neoplastic immunoevasion.
American Journal Of Reproductive Immunology 10/2012; · 2.17 Impact Factor
-
Yuichiro Miyamoto,
Shunsuke Nakagawa,
Osamu Wada-Hiraike,
Takayuki Seiki,
Michihiro Tanikawa,
Haruko Hiraike,
Kenbun Sone,
Kazunori Nagasaka,
Katsutoshi Oda,
Kei Kawana,
Keiichi Nakagawa,
Tomoyuki Fujii,
Tetsu Yano, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: Although the prognosis of uterine cervical cancer has improved due to the advances of treatment modalities, survival of recurrent or metastatic cervical cancer remains poor. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer is disappointing. Inactivation of tumor suppressors through ubiquitin-mediated degradation by human papillomavirus is known to be a critical step in the carcinogenesis of uterine cervix. Bortezomib, a selective inhibitor of the proteasome, has been shown to inhibit the growth of several solid tumors. To determine the role of bortezomib in cervical cancer as a chemotherapeutic agent, we studied its biological properties. Bortezomib efficiently inhibited the proteasomal activities in cervical cancer cells, and an increased expression of tumor suppressors such as p53, hDlg and hScrib became evident. In addition, sequential or concomitant treatment of bortezomib and cisplatin stimulated the expression of p53, hScrib and p21 and the stimulation was markedly influenced by the order of drugs in HeLa cells. We further confirmed that the concomitant use of bortezomib and cisplatin has synergistic inhibitory effects on the growth of xenograft tumors derived from HeLa cells. Our data establish the possibility that the concomitant use of bortezomib and cisplatin could be an alternative choice in cases resistant to conventional chemotherapy, and sequential effects must be considered for advanced and therapy-resistant cervical cancer patients.
Oncology Reports 10/2012; · 1.84 Impact Factor
-
Masanori Ito,
Tomohiko Urano,
Hisahiko Hiroi,
Mikio Momoeda,
Mayuko Saito,
Yumi Hosokawa,
Ryo Tsutsumi,
Fumiko Zenri,
Minako Koizumi,
Hanako Nakae,
Kuniko Horie-Inoue,
Tomoyuki Fujii,
Tetsu Yano, Shiro Kozuma,
Satoshi Inoue,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: Members of the 14-3-3 family are intracellular dimeric phosphoserine-binding proteins that can associate with and modulate the activities of many proteins. In our efforts to isolate the genes regulated by progesterone (P(4)) using suppressive subtractive hybridization, we previously found that 14-3-3τ is one of the genes upregulated by P(4). In this study, we demonstrated by quantitative RT-PCR (qRT-PCR), western blot analyses, and immunohistochemistry that 14-3-3τ mRNA and protein levels were increased in the rat uterus after P(4) treatment. Furthermore, qRT-PCR indicated that P(4) increased 14-3-3τ mRNA levels in human endometrial epithelial cells and endometrial stromal cells (ESCs). Western blot and qRT-PCR analyses revealed that in vitro decidualization using cAMP and medroxyprogesterone 17-acetate increased levels of 14-3-3τ mRNA and protein in ESCs. We have shown by qRT-PCR and western blot analyses that P(4) increased the mRNA and protein levels of 14-3-3τ in Ishikawa cells that stably express P(4) receptor-B (PR-B). Immunocytochemistry revealed that 14-3-3τ colocalizes with PR and translocates from the cytoplasm to the nucleus in response to P(4). Moreover, by luciferase reporter assay, we demonstrated that 14-3-3τ enhances the transcriptional activity of PR-B. Taken together, we propose that 14-3-3τ is a P(4)-responsive gene in uterine cells that modulates P(4) signaling.
Journal of Molecular Endocrinology 09/2012; 49(3):193-202. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease that affects the right side of the heart and causes ventricular arrhythmias. It is considered as the most common cause of sudden cardiac death in young adults. However, risk and optimal management of ARVC during pregnancy and delivery remain unclear due to the small number of reported cases. Here we report a case of successful management of pregnancy and delivery in a patient with ARVC, who had a history of sustained ventricular tachycardia from her previous pregnancy.
Journal of Obstetrics and Gynaecology Research 08/2012; · 0.94 Impact Factor
-
Akira Shirane,
Osamu Wada-Hiraike,
Michihiro Tanikawa,
Takayuki Seiki,
Haruko Hiraike,
Yuichiro Miyamoto,
Kenbun Sone,
Mana Hirano,
Hajime Oishi,
Katsutoshi Oda,
Kei Kawana,
Shunsuke Nakagawa,
Yutaka Osuga,
Tomoyuki Fujii,
Tetsu Yano, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: Sirtuin 1 (SIRT1), originally found as a class III histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. We examined the role of SIRT1 in the regulation of uterine receptivity using Ishikawa and RL95-2 endometrial carcinoma cell lines. Exogenous expression of SIRT1 significantly enhanced E-cadherin expression, while small interfering RNA-mediated depletion of endogenous SIRT1 resulted in a significant reduction of E-cadherin expression. A SIRT1 activator resveratrol elevated E-cadherin expression in a dose dependent manner, while SIRT1 repressors nicotinamide and sirtinol exhibited a dose dependent reduction of E-cadherin expression. We also showed that both forced expression of SIRT1 and activation of SIRT1 promote E-cadherin-driven reporter gene constructs, and SIRT1 is localized at E-cadherin promoter containing E-box elements in Ishikawa cells. Using an in vitro model of embryo implantation, we demonstrate that exogenous expression of SIRT1 and stimulation of SIRT1 activity resulted in the Ishikawa cell line becoming receptive to JAR cell spheroid attachment. Furthermore, resveratrol enhanced E-cadherin and Glycodelin protein expression at sites of intercellular contact, suggesting an additive role of resveratrol in promoting implantation. The initial step of human reproduction depends on the capacity of an embryo to attach and implant into the endometrial wall, and these results revealed the novel mechanism that activation and increased expression of SIRT1 play an important role in uterine receptivity.
Biochemical and Biophysical Research Communications 07/2012; 424(3):604-10. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Japanese herbal medicines, Juzen-taiho-to (JTT) and Hochu-ekki-to (HET), have been shown to enhance humoral immune responses to vaccine antigen when used as adjuvants for prophylactic vaccines. However, their adjuvant effect on mucosal cellular immune responses remains unstudied. The precursor lesion of cervical cancer, high-grade CIN that expresses HPV E7 oncoprotein ubiquitously is a target for HPV therapeutic vaccines that elicit mucosal E7-specific type 1 T cell responses. We have demonstrated that oral immunization with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) is more effective in eliciting mucosal E7-specific IFNγ-producing cells than subcutaneous or intramuscular antigen delivery. Here we report the synergistic effect of an oral Lactobacillus-based vaccine and Japanese herbal medicines on mucosal immune responses. Oral immunization of mice with LacE7 plus either a Japanese herbal medicine (JTT or HET) or a mucosal adjuvant, heated-labile enterotoxin T subunit (LTB), promotes systemic E7-specific type 1 T cell responses but not mucosal responses. Administration of LacE7 plus either Japanese herbal medicine and LTB enhanced mucosal E7-specific type 1 T cell response to levels approximately 3-fold higher than those after administration of LacE7 alone. Furthermore, secretion of IFNγ and IL-2 into the intestinal lumen was observed after oral administration of LacE7 and was enhanced considerably by the addition of Japanese herbal medicines and LTB. Our data indicated that Japanese herbal medicines, in synergy with Lactobacillus and LTB, enhance the mucosal type 1 immune responses to orally immunized antigen. Japanese herbal medicines may be excellent adjuvants for oral Lactobacillus-based vaccines and oral immunization of LacE7, HET and LTB may have the potential to elicit extremely high E7-specific mucosal cytotoxic immune response to HPV-associated neoplastic lesions.
Vaccine 06/2012; 30(36):5368-72. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm that is generally estrogen-receptor- and progesterone-receptor-positive and develops in premenopausal women. Although tamoxifen treatment is associated with an increased risk of ESS, the effect of other selective estrogen receptor modulators, including toremifene, on the risk of ESS is not clear. A 61-year-old postmenopausal woman was treated with toremifene as an adjuvant therapy for breast cancer. A cystic mass developed during the treatment, with gradual growth in the uterine myometrium. The patient was treated with hysterectomy and bilateral salpingo-oophorectomy, and the tumor was diagnosed as low-grade ESS (stage IA) with estrogen-receptor and progesterone-receptor. The patient discontinued toremifene and has been progression-free for 21 months. Our data suggest that toremifene might be associated with the development of ESS in certain patients through its estrogen-like effects in the uterus.
Journal of Obstetrics and Gynaecology Research 06/2012; · 0.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aim: Platinum is a milestone drug against gynecologic malignancies. The purpose of this retrospective study was to investigate the feasibility of replacing carboplatin with nedaplatin in patients who had developed a hypersensitivity reaction to carboplatin. Material and Methods: Fifteen patients with recurrent gynecologic cancer (12 ovarian, 1 fallopian tube, 1 endometrial and 1 cervical cancer) who had experienced a hypersensitivity reaction to carboplatin and a possible clinical indication for continuing treatment with platinum were treated with nedaplatin (80 mg/m(2) )-containing regimen. Results: The total number of nedaplatin cycles given was 137 (range 1-29). Four (27%) patients developed hypersensitivity reactions on the second, second, fourth, and ninth administration, respectively. The severities of all the hypersensitivity reactions were grade 3 or less. The other 11 patients (73%) had no nedaplatin-associated hypersensitivity reactions. The incidence of hypersensitivity reactions in the paclitaxel and nedaplatin group (three of four, 75%) was more frequent than the docetaxel and nedaplatin group (none of seven, P = 0.024). The objective response rate in eleven patients with measurable disease was 36% (complete response at 9% and partial response at 27%), and the disease control rate was 73% (stable disease at 36%). Conclusion: Nedaplatin-associated hypersensitivity reactions are not rare in patients who developed allergic reactions to carboplatin. Retreatment of carboplatin-allergic patients with nedaplatin cannot be recommended without careful consideration of the potential risks and benefits.
Journal of Obstetrics and Gynaecology Research 06/2012; · 0.94 Impact Factor
-
Yuji Ikeda,
Katsutoshi Oda,
Shunsuke Nakagawa,
Satsuki Murayama-Hosokawa,
Shogo Yamamoto,
Shumpei Ishikawa,
Linghua Wang,
Yutaka Takazawa,
Daichi Maeda,
Osamu Wada-Hiraike,
Kei Kawana,
Masashi Fukayama,
Hiroyuki Aburatani,
Tetsu Yano, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: Synchronous carcinomas in the endometrium and ovaries can be a single primary tumor with metastasis (SPM) or dual primary tumors (DP). Although the prognosis of DP without any metastases is significantly better than that of SPM, pathological diagnosis is difficult in tumors with similar histological features.
In 10 tumors from 5 patients with synchronous endometrial and ovarian carcinomas, 250K single nucleotide polymorphism arrays were performed. The patients were genetically diagnosed according to the pattern of copy number alterations (CNAs), in addition to microsatellite status and mutational analysis of PIK3CA, PTEN, K-Ras, and CTNNB1.
Of the 5 patients, 3 exhibited identical CNA patterns, including type, loci, and degree of each alteration in the endometrial and ovarian carcinomas. The other 2 exhibited CNAs only in either endometrial or ovarian carcinoma. All 5 tumors had 1 or more genetic mutations in the genes examined. One patient exhibited mutations both in PIK3CA and PTEN at discordant sites between endometrial and ovarian carcinomas, whereas the other 4 exhibited concordant mutations. Overall, 4 of the 5 patients were genetically diagnosed with SPM, and the remaining 1 with DP. The pathological diagnosis was not in agreement with the genetic diagnosis in 4 of the 5 patients.
Genome-wide genotyping diagnosis may represent a useful approach for distinguishing between SPM and DP in synchronous endometrial and ovarian carcinomas.
International Journal of Gynecological Cancer 06/2012; 22(5):725-31. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The perinatal mortality rate of vasa previa is high if it is not prenatally diagnosed. In this report, a case of vasa previa
diagnosed prenatally is presented. Antepartum hemorrhage at 24weeks of gestation prompted a close investigation of the uterine
cervix, internal os, and placenta. We detected a low-lying bilobed placenta with umbilical cord insertion in the lower uterine
segment. Furthermore, one of the connecting vessels of the bilobed placenta passed directly above the internal os. Vasa previa
was suspected and confirmed with color Doppler and MRI. The fetus was delivered uneventfully by planned Cesarean section at
38weeks of gestation. It should be considered that placenta previa (including low-lying placenta), bilobed placenta, and
umbilical cord insertion in the lower uterine segment are associated with high risk of vasa previa. Ultrasound screening for
cord insertion and placenta around the internal os enables efficient and certain detection of vasa previa.
KeywordsVasa previa-Lobed placenta-Transvaginal ultrasound
Journal of Medical Ultrasonics 04/2012; 38(1):41-45. · 0.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cervical cancer is the second largest cause of cancer-related death in women worldwide, and it occurs following persistent infection, sometimes for decades, with a specific subset of human papillomavirus (HPV) types; the approximately 13 oncogenic subtypes. Prophylactic vaccines against HPV infections hold promise for cost-effective reductions in the incidence of cervical cancer, but this may not be enough. Two prophylactic HPV vaccines are presently available and both contain L1 virus-like particles (VLPs) derived from the HPV subtypes most frequently associated with cervical cancer, HPV-16 and -18. Since the L1-VLP vaccines can only effectively prevent infection by the specific HPV subtype against which the vaccine was developed, cervical cancers caused by high-risk HPV subtypes other than HPV-16 and -18 may still occur in recipients of the current HPV vaccines. Furthermore, HPV vaccination coverage for adolescents is insufficient in most countries and therefore even HPV-16 and -18 infections are unlikely to be fully eradicated using the existing strategies. The development of HPV therapeutic vaccines remains essential. Many therapeutic vaccines aimed at clearing HPV-related cervical lesions have been developed and tested in patients with HPV16-positive cervical intraepithelial lesions (CIN) or cervical cancers. To date, definitive clinical efficacy and appropriate immunological responses have never been demonstrated for cervical neoplasia although promising results have been reported in patients with vulvar intraepithelial neoplasia. Here we discuss shortcomings of previous HPV therapeutic vaccine candidates and propose a novel vaccination strategy that leverages newly gained knowledge about mucosal immunity and the induction of mucosal immune responses.
The Open Virology Journal 01/2012; 6:264-9.
-
Keiko Shoji,
Katsutoshi Oda,
Tomoko Kashiyama,
Yuji Ikeda,
Shunsuke Nakagawa,
Kenbun Sone,
Yuichiro Miyamoto,
Haruko Hiraike,
Michihiro Tanikawa,
Aki Miyasaka,
Takahiro Koso,
Yoko Matsumoto,
Osamu Wada-Hiraike,
Kei Kawana,
Hiroyuki Kuramoto,
Frank McCormick,
Hiroyuki Aburatani,
Tetsu Yano, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.
PLoS ONE 01/2012; 7(5):e37431. · 4.09 Impact Factor
-
Akiko Masuda,
Tomoyuki Fujii,
Yuki Iwasawa,
Kazuhiro Nakamura,
Ryunosuke Ohkawa,
Koji Igarashi,
Shinichi Okudaira,
Hitoshi Ikeda, Shiro Kozuma,
Junken Aoki,
Yutaka Yatomi
[show abstract]
[hide abstract]
ABSTRACT: The bioactive lipid lysophosphatidic acid (LPA) exerts multiple effects in the female reproductive system. Serum/plasma LPA is mainly produced by the lysophospholipase D activity of autotaxin (ATX). Previous studies have suggested that ATX has critical roles in cancer, reproduction, and vascular development. In the present study, we evaluated the usefulness of serum ATX measurements in pregnant women.
We measured the serum ATX antigen levels in 32 normal pregnant women, 15 patients with pregnancy-induced hypertension (PIH), and 7 patients with preterm delivery using a recently developed automated enzyme immunoassay.
The serum ATX antigen levels in normal pregnant women were significantly higher than those in non-pregnant women (P<0.001). The serum ATX antigen levels in normal pregnant women were significantly and positively correlated with the gestational week (r=0.809, P<0.001). During the third trimester, the serum ATX antigen levels of the patients with PIH (3.299 ± 1.720 mg/l) were significantly lower than those of the normal pregnant women (4.915 ± 2.323 mg/l) (P=0.04).
The serum ATX antigen level increases with the progression of pregnancy. The serum ATX level may be a serological marker for the prediction of PIH.
Clinica chimica acta; international journal of clinical chemistry 10/2011; 412(21-22):1944-50. · 2.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS).
By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed.
The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) ∗ 100, odds = e(X) and X = 8.18 + 1.23 ∗ BW (kg)- 7.74 ∗ MH (m)- 0.253 ∗ BS.
This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome.
Journal of Obstetrics and Gynaecology Research 07/2011; 37(12):1784-91. · 0.94 Impact Factor
-
Satoko Kojima,
Kei Kawana,
Tomoyuki Fujii,
Terufumi Yokoyama,
Shiho Miura,
Kensuke Tomio,
Ayako Tomio,
Aki Yamashita,
Katsuyuki Adachi,
Hidetaka Sato,
Takeshi Nagamatsu,
Danny J Schust, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: Mucosal T cells are the most likely direct effectors in host anti-human papillomavirus adaptive immunity and regression of cervical intraepithelial neoplasia (CIN) lesions. There are no studies addressing intraepithelial lymphocytes (IELs) in CIN lesions.
Cervical lymphocytes were collected using cytobrushes from patients with CIN and analyzed by FACS analysis. Comparisons were made between populations of cervical T cells in CIN regressors and non-regressors.
A median of 74% of cervical lymphocytes were CD3(+) T cells. Populations of integrin αEβ7(+) IEL in CIN lesions varied markedly among patients (6-57%). Approximately half of integrin β7(+) T cells were CD45RA-negative memory T cells. The number of integrin αEβ7(+) cells among cervical T cells was significantly higher in CIN regressors when compared to non-regressors.
Higher cervical IEL numbers are associated with spontaneous regression of CIN. Accumulation of cervical integrin αEβ7(+) IEL may be necessary for local adaptive effector functions.
American Journal Of Reproductive Immunology 07/2011; 66(5):435-43. · 2.17 Impact Factor
-
Yuki Iwasawa,
Kei Kawana,
Tomoyuki Fujii,
Danny J Schust,
Takeshi Nagamatsu,
Yukiko Kawana,
Seisuke Sayama,
Shiho Miura,
Junko Matsumoto,
Katsuyuki Adachi,
Hironobu Hyodo,
Takahiro Yamashita, Shiro Kozuma,
Yuji Taketani
[show abstract]
[hide abstract]
ABSTRACT: PROBLEM β(2) glycoprotein1 (β(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-β(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound β(2) GP1. Anti-β(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-β2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-β2GP1 mAbs. CONCLUSIONS β(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.
American Journal Of Reproductive Immunology 06/2011; 67(1):54-65. · 2.17 Impact Factor
