PubMed Health⌕ Search

Biomedical subjects

Fumitaka Kikkawa

Publications and source records attributed to Fumitaka Kikkawa.

At least 19 recordsLinked to original sources
PubMed2006

Preferable correlation to blastocyst development and pregnancy rates with a new embryo grading system specific for day 3 embryos.

PURPOSE: To investigate the cleavage stage embryo quality by the correlation between the morphological features and blastocyst development rate to develop a new embryo grading system. METHODS: A retrospective analysis, including 216 cycles of cleavage stage embryo transfer and 251 cycles of blastocyst transfer. The correlation with blastocyst development of the embryo cleavage stage, fragmentation and uniformity of blastomeres was evaluated. RESULTS: There were significant differences in the blastocyst development rate between > or =7 cells and < or=6 cells (68.8% vs. 30.7%), <50% fragmentation and > or =50% fragmentation (51.9% vs. 25.7%), and evenly sized blastomeres and unevenly sized blastomeres (48.7% vs. 30.1%) on day 3. The new grading system defined by these 3 parameters showed a preferable correlation to the pregnancy rate. CONCLUSIONS: The new grading system specific for day 3 embryos is useful for the selection of good quality embryos and may improve the pregnancy rate.

Adult↗
PubMed2006

Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide.

To improve the therapeutic efficacy of herpes simplex virus type 1 (HSV-1) thymidine kinase (tk)/ganciclovir (GCV) therapy, we have made recombinant tk chimeras fused with the arginine-rich (RXP) repeat of herpes simplex virus type 2 (HSV-2) US11 and examined their activity of intercellular trafficking and cytotoxicity. When examined the immunofluorescence staining patterns of RXP/tk fusion proteins in transfected COS7 cells, the RXP chimeras revealed a conservation of the trafficking activity of RXP. We also found that transfection of tkC Delta 6-RXP (lacking the C-terminal six amino residues of tk), tk-RXP, and tkN Delta 66-RXP (lacking the N-terminal 66 amino residues of tk) induced apoptosis even in the absence of GCV. The results suggest that these tk/RXP chimeras themselves have apoptosis-inducing activity, and that the HSV tk nucleoside-binding domain may be involved in the induction of apoptosis. Furthermore, treatment with 5 muM GCV induced efficient cell death in cells tranfected with tk-RXP in comparison to the cells transfected with tk (P < 0.0001).

Animals↗
PubMed2006

Neutral endopeptidase expressed by decidualized stromal cells suppresses akt phosphorylation and deoxyribonucleic acid synthesis induced by endothelin-1 in human endometrium.

Endothelin-1 (ET-1) in human endometrium has been proposed to have a potential paracrine role, for its receptors are also present within this tissue. In addition, the expression of ET-1 varies during the menstrual cycle, and therefore, ET-1 may be involved in the cyclic change of the human endometrium, such as proliferation and decidualization. However, neither the inactivation of ET-1 in the endometrium nor the paracrine effect of ET-1 on endometrial cells has been determined. We investigated the production of ET-1 and the presence of neutral endopeptidase (NEP), which cleaves and inactivates ET-1, in primary cultured human endometrial cells. We found primary cultured endometrial epithelial cells, not stromal cells, to be the major source of ET-1. Western blot analysis and RT-PCR demonstrated that NEP was predominantly expressed by endometrial stromal cells. We also demonstrated that ET-1 stimulated the phosphorylation of Akt and DNA synthesis in endometrial stromal cells via the ET(A) receptor and phospahtidylinositol-3 kinase signaling pathways. The effect of ET-1 was regulated by NEP expressed by stromal cells. We also found that conditioned medium containing ET-1 from endometrial epithelial cell culture stimulated phosphorylation of Akt via the ET(A) receptor. In conclusion, ET-1 has a paracrine effect of Akt phosphorylation and cell proliferation on endometrial stromal cells, which occurs via the ET(A) receptor and phospahtidylinositol-3 kinase signaling pathways, and is regulated by cell-surface NEP.

Cell Proliferation↗
PubMed2006

Long-term follow-up and prognostic factor analysis in clear cell adenocarcinoma of the ovary.

BACKGROUND AND OBJECTIVES: There were a few reports of a large number of patients with clear cell adenocarcinoma (CCA) of the ovary because of the low incidence of CCA. This study compared the clinical factors affecting long-term survival of patients with CCA to those with serous cystadenocarcinoma (SCA). METHODS: One hundred and seventy-eight CCA and 311 SCA patients treated between 1987 and 2000 were retrospectively evaluated. Differences in survival rates were calculated using log-rank test and Cox's proportional hazards analysis was used to identify independent prognostic factors. RESULTS: The ratio of stage I was significantly higher than that of SCA. There was no significant difference of 8-year survival rate in each stage between CCA and SCA. However, the patients with stage IIIb or IIIc CCA showed significantly worse prognosis than those with SCA. Positive peritoneal or ascitic cytology, the presence of residual tumor, more than 100 ml ascites were demonstrated to have the significant impact on survival by univariate analysis. Multivariate analysis demonstrated that stage, more than 100 ml ascites, and the presence of residual tumor were significant prognostic factors of CCA overall survival. CONCLUSIONS: Distribution of stage and substage differed between CCA and SCA in this study. Thus, substaging is quite important for comparison of prognoses between histologies, and CCA showed poorer prognoses than serous adenocarcinoma in stages IIIb and IIIc.

Adenocarcinoma, Clear Cell↗
PubMed2006

Localization of angiotensin II, the AT1 receptor, angiotensin-converting enzyme, aminopeptidase A, adipocyte-derived leucine aminopeptidase, and vascular endothelial growth factor in the human ovary throughout the menstrual cycle.

OBJECTIVE: To assess the expression and cellular distribution of angiotensin II (Ang II), angiotensin type 1 receptor (AT1R), angiotensin-converting enzyme (ACE), aminopeptidase A (APA), adipocyte-derived leucine aminopeptidase (A-LAP), and vascular endothelial growth factor (VEGF) in human ovarian tissue during the menstrual cycle. DESIGN: Ovarian tissues (n = 52) and corpora lutea (n = 34) were obtained from patients undergoing hysterectomy/oophorectomy, and tissue sections were immunostained for each antigen. SETTING: University hospital. PATIENT(S): Patients undergoing hysterectomy or oophorectomy for benign conditions. INTERVENTION(S): Immunostaining of tissue sections using antibodies to each antigen. MAIN OUTCOME MEASURE(S): Microscopic evaluation to assess the presence, distribution, and cellular localization. RESULT(S): The luteal tissue is the major site of Ang II, ACE, AT1R, and VEGF, with highest staining intensity found during the midluteal phase and at pregnancy. The AT1R was found in theca cells. The APA was strongly immunolocalized in pericytes. Immunolocalization of AT1R was almost similar to that of VEGF including oocytes in the primordial and intermediate follicles. CONCLUSION(S): The expression and distinct pattern of the cellular localization of Ang II and its related proteins in human ovarian tissue during folliculogenesis and in the luteal tissue suggest their roles in the growth and differentiation of theca, granulose, and luteal cells.

Aminopeptidases↗
PubMed2006

Possible involvement of crosstalk cell-adhesion mechanism by endometrial CD26/dipeptidyl peptidase IV and embryonal fibronectin in human blastocyst implantation.

When human blastocysts hatch through the zona pellucida, gaining the ability to adhere to the endometrium, crosstalk between the embryo and the uterus may represent a successful outcome of their synchronized development and differentiation. CD26/dipeptidyl peptidase IV is known as a marker molecule of the implantation phase endometrium. To study the role of CD26 in implantation, 35 human hatched blastocysts were prepared by enzymatic treatment of expanded blastocysts that had been grown on schedule from frozen-thawed surplus embryos at the 2- or 4-cell stage. The blastocysts were placed on CD26-overexpressing or mock-transfected control monolayer cell cultures. The CD26-overexpression caused significantly higher blastocyst adhesion rate (53.3% versus 25.0%, P < 0.05) and significantly larger outgrowth area of trophectoderm (1.7-fold, P < 0.05). The second part of the present study was to show the expression of fibronectin, a CD26 ligand, in human preimplantation embryos, using the same donated resources. Fibronectin mRNA was detected by RT-PCR from the single hatched blastocyst (2/2) and from the single early blastocyst (3/6) but not from the single morula (0/5) samples. An indirect immunofluorescence technique verified the localization of fibronectin on the surface of the blastocyst. These results indicate that the adhesion mechanism by endometrial CD26 and embryonal fibronectin may be involved in human blastocyst implantation.

Blastocyst↗
PubMed2006

Clinical characteristics and prognosis of mucinous tumors of the ovary.

OBJECTIVE: Ovarian mucinous tumors consist of benign, borderline, and carcinomatous tumor, but the clinical characteristics of these 3 types have not been investigated in detail. In this study, we compared the clinical characteristics and prognosis among these 3 types of mucinous tumors. METHODS: One hundred sixty-one patients with mucinous cystadenocarcinoma and 143 patients with mucinous borderline tumor were registered between 1986 and 2003. All patients were reviewed by two pathologists, then the mixed type and cases showing other organized malignant tumors were excluded from this study. Patients with mucinous carcinoma staged Ib or more were treated postoperatively with 6 cycles of platinum-based chemotherapy. Survival probability was analyzed by the Kaplan-Meier method and differences in survival rates were calculated using log-rank test. RESULTS: Mean patient ages were 43.9, 44.7, and 49.7 years in patients with benign, borderline, carcinomatous tumor, respectively. The ratio of early stage (I, II) to advanced stage (III, IV) was significantly lower in carcinoma than in borderline tumor. The levels of tumor markers tended to increase with the level of malignancy. CA72-4 is the most useful discriminating marker according to ROC analysis. In borderline tumor, 5 patients died of disease, and all of these patients had stage III disease with residual tumor after the initial surgery. Patients with borderline tumor showed significantly better prognosis than those with carcinoma; however, there were no significant differences in prognosis between borderline tumor and carcinoma in patients with stage III tumor or residual tumor. CONCLUSIONS: In mucinous tumors, measurement of CA72-4 is recommended to distinguish malignant from benign tumors. Even in borderline tumor, patients with residual tumor showed a poorer prognosis than carcinoma, suggesting that complete resection is necessary for a good prognosis.

Adenocarcinoma, Mucinous↗
PubMed2006

A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells.

In several recent studies, we have shown that P-LAP can be a poor prognostic factor and a factor of chemoresistance in endometrial carcinoma, especially in the advanced patients. In our study, we investigated whether P-LAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells displayed a 1.8-fold, 2.0-fold and 1.7-fold increase in IC(50) against paclitaxel, carboplatin and cisplatin respectively. Translational downregulation by siRNA2 to P-LAP on A-MEC-LAP cells demonstrated 60%, 51% and 58% decrease in IC(50). To investigate the mechanism of P-LAP-induced chemoresistance, we also assessed whether P-LAP transfection had an effect on carboplatin-induced apoptotic death of A-MEC cells. A-MEC and A-MEC-pc (transfected with vector alone) cells exhibited a strong apoptotic response to carboplatin, while A-MEC-LAP cells exhibited a weak apoptotic response. In an attempt to identify the mechanism of the inhibitory effect on apoptotic response to carboplatin, we next assessed the expression of cleaved caspases and PARP cleavage. While treatment of A-MEC-pc cells with carboplatin exhibited increased levels of cleaved caspase 3, caspase 7 and caspase 9 compared to that after no treatment, A-MEC-LAP cells did not show any expression of these caspases. These results suggest that P-LAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance.

Antineoplastic Agents↗
PubMed2006

Endoplasmic reticulum aminopeptidase-1 mediates leukemia inhibitory factor-induced cell surface human leukocyte antigen-G expression in JEG-3 choriocarcinoma cells.

Maternal immune tolerance is required for extravillous trophoblasts (EVTs) to invade the decidua without rejection. Endoplasmic reticulum aminopeptidase-1 (ERAP1) generates human leukocyte antigen (HLA) class I-adapted antigenic peptides, but its function in trophoblasts lacking classical HLA class I molecules remains undetermined. Leukemia inhibitory factor (LIF) is produced from decidua during the implantation period and plays a necessary role in establishing pregnancy. This study is intended to investigate the location and the function of ERAP1 in trophoblastic cells, focusing on LIF. Immunohistochemistry showed strong ERAP1 expression in cultured EVTs. In choriocarcinoma cell lines used as a model for trophoblasts, ERAP1 was expressed more intensively in JEG-3 than BeWo cells. Immunoblot analysis and immunocytochemistry localized ERAP1 to the endoplasmic reticulum (ER) in JEG-3 cells. Flow cytometry with HLA-G antibody to monitor the supply of antigenic peptides presenting to HLA-G in the ER showed that reducing ERAP1 transcripts by RNA interference did not affect cell surface expression of membrane HLA-G1 (mHLA-G1) in JEG-3 cells under basal conditions. In LIF-treated JEG-3 cells, cell surface mHLA-G1 expression was increased along with ERAP1 protein and promoter activities. In contrast to nonstimulated cells, eliminating ERAP1 from LIF-treated JEG-3 cells reduced the cell surface mHLA-G1 expression and soluble HLA-G1 secretion. This study provides the first evidence showing that ERAP1 is localized in the ER of trophoblasts and is involved in regulating cell surface HLA-G expression in the presence of LIF. Consequently, ERAP1 would function to present antigenic peptides to HLA-G in trophoblasts.

Aminopeptidases↗
PubMed2006

Methods for myometrium closure and other factors impacting effects on cesarean section scars of the uterine segment detected by the ultrasonography.

OBJECTIVE: Ultrasound examination is an objective method for assessment of uterine scar defects. The present study was conducted to compare single-layer interrupted sutures (Group A) with double-layer interrupted sutures (Group B) and our new method (Group C) as well as other perioperative parameters in relation to risk of wedge defects in scars. METHODS: We have introduced a new myometrium closure procedure consisting of continuous suture with decidual closure followed by interrupted myometrium suture. In this prospective study, women undergoing cesarean operation (n = 137) were examined by transvaginal ultrasound one month after surgery to assess the appearance of lower uterine scars. Multivariate logistic regression analysis was performed to identify associations of perioperative parameters and methods for lower myometrium closure with abnormal wedge formation. RESULTS: Wedge defects were observed in a total of 27 patients (19.7%). The analysis revealed Groups B and C to have reduced risks with odds ratios of 0.28 and 0.077, respectively, as compared to Group A. Furthermore, increasing gestational week at delivery, plural fetal pregnancies, premature rupture of membranes and pre-eclampsia were also linked with an increased risk, with odds ratios of 1.4-8.9. CONCLUSION: The incidence of uterine scar defects 1 month after cesarean sections varies with the method applied for myometrial suture and perioperative variables. The data suggest that methods for myometrium closure as well as other factors influence the condition of myometrial healing.

Adult↗
PubMed2006

Involvement of DPPIV/CD26 in epithelial morphology and suppressed invasive ability in ovarian carcinoma cells.

Dipeptidyl peptidase IV (DPPIV) is a multifunctional cell surface aminopeptidase with ubiquitous expression and it has a variety of functional properties in the development of human malignancies. In the present study, we showed the possible correlation between DPPIV/CD26 expression and less migratory potential with decreased MMP-2 expression in ovarian carcinoma cells. Moreover, induction of DPPIV/CD26 resulted in reduced expressions of MMP-2 and mesenchymal markers such as vimentin and SMA, with a less invasive potential and an epithelial morphologic change. This evidence implies that DPPIV/CD26 may play a crucial role in the antimetastatic potential in ovarian carcinoma.

Animals↗
PubMed2006

Manipulating the angiotensin system--new approaches to the treatment of solid tumours.

Angiotensin II (Ang II), a main effector peptide in the renin-angiotensin system (RAS), plays a fundamental role as a vasoconstrictor in controlling cardiovascular function and renal homeostasis. Ang II also acts as a growth promoter or angiogenic factor via type 1 angiotensin II receptors (AT1Rs) in certain tumour cell lines. Recent studies have shown the activation of the local RAS in various tumour tissues, including the abundant generation of Ang II by angiotensin-converting enzyme (ACE) and the upregulation of AT1R expression. Thus, considerable attention has been paid to the role of the RAS in cancer and its blockade as a new approach to the treatment of cancer. There is increasing evidence that the Ang II-AT1R system is involved in tumour growth, angiogenesis and metastasis in experimental models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker, both of which have been used as antihypertensive drugs. In addition, specific Ang II-degrading enzymes are expressed in tumours and play a regulatory role in cell proliferation and invasion. This review focuses on the role of the Ang II-AT1R system in solid tumours, particularly in the progression of gynaecological cancer, and presents the clinical potential of manipulating the angiotensin system as a novel and promising strategy for cancer treatment.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Advances in treatment of epithelial ovarian cancer.

Since most cases of epithelial ovarian cancer are advanced at diagnosis, this disease is one of the most lethal malignancies of the female genital tract. In recent years, aggressive cytoreductive surgery and chemotherapy have been employed in an attempt to improve the survival rate in patients with epithelial ovarian cancer. Introduction of platinum anticancer drugs increased survival rate, and several randomized studies have been tried to establish the better combination of anticancer drugs. As a result, the combination of paclitaxel and carboplatin was considered as standard regimen for the first-line treatment of patients with advanced ovarian cancer. Since International Federation of Gynecology and Obstetrics (FIGO) accepted a postoperative staging system in 1988, staging laparotomy needs hysterectomy, bilateral adnexectomy, omentectomy, and pelvic and para-aorta lymphadenectomy. However, the influence of lymphadenectomy on survival still remains controversial. Complete resection of the tumor is often difficult since the disease has spread to the abdominal cavity. In such cases, interval debulking surgery is performed after chemotherapy to remove tumors completely. The effectiveness of neoadjuvant chemotherapy and interval debulking surgery still remains unclear. This review will describe the advances in surgical procedures and chemotherapy in treatment of ovarian cancer patients.

Female↗
PubMed2006

Impaired insulin-regulated membrane aminopeptidase translocation to the plasma membrane in adipocytes of Otsuka Long Evans Tokushima Fatty rats.

Insulin-regulated membrane aminopeptidase (IRAP) translocates to the plasma membrane with glucose transporter-4 (GLUT4) on insulin stimulation. However, this may be impaired in patients at risk of diabetes. Recently a novel technique has been developed to assess cell surface IRAP activity dynamically using a fluorogenic membrane impermeable substrate. In this study we measured the cell surface IRAP activity and 3-O-[methyl-14C]-D-Glucose uptake in adipocytes isolated from Otsuka Long Evans Tokushima Fatty rats (OLETF), developed as a model of type 2 diabetes mellitus, to evaluate whether the translocation of GLUT4/IRAP vesicles is affected. On the addition of insulin, the cell surface IRAP activity promptly increased to reach equilibrium in a hormone dose-dependent manner. OLETF rats showed significantly lower equilibrium activity than control rats (P<0.01). Time to reach the equilibrium was also significantly longer in the OLETF case, and adipocytes isolated from OLETF rats demonstrated both a delay and a reduction in 3-O-[methyl-14C]-D-Glucose uptake. This impairment in all parameters was alleviated by treatment with pioglitazone. Continuous measurement of cell surface IRAP activity allowed accurate evaluations of GLUT4/IRAP vesicle translocation and of the establishment of defects in OLETF rats.

Adipocytes↗
PubMed2005

Anti-progressive effect of neutral endopeptidase 24.11 (NEP/CD10) on cervical carcinoma in vitro and in vivo.

OBJECTIVES: Neutral endopeptidase 24.11 (NEP) is known to play important roles in the maintenance of homeostasis or in neoplastic transformation and tumor progression in certain human malignancies through the enzymatic inactivation of bioactive peptides such as endothelin-1 (ET-1), angiotensin-II, and bombesin. METHODS: In this study, we first investigated NEP expression in cervical carcinoma by immunohistochemical staining and Western blot analysis. Next, we examined NEP functions in vitro and in vivo by generating NEP-overexpressing cervical carcinoma cells. RESULTS: We found a significant decrease in cellular proliferative and invasive abilities with a reduced ET-1 concentration in the conditioned medium by NEP overexpression in cervical carcinoma CaSki cells, which have an ET-1 autocrine loop. In addition, these potentials were cancelled by blockade of NEP activity with a specific inhibitor. Although vector-transfected CaSki cells could grow even in serum-free media, NEP-overexpressing cells failed to proliferate in these media. Furthermore, we demonstrated that NEP suppressed tumor formation of subcutaneous xenografts using nude mice. CONCLUSIONS: Our results indicated that NEP functions as a tumor-suppressor gene in cervical carcinoma cells, and its expression may have prognostic significance. Further elucidation of the mechanism underlying the observed effect of NEP will contribute to a better understanding of its role in the pathophysiology of cervical carcinoma.

Animals↗
PubMed2005

Gene regulation and physiological function of placental leucine aminopeptidase/oxytocinase during pregnancy.

Human pregnancy serum and placenta have the ability to degrade uterotonic peptide oxytocin (OT). Placental leucine aminopeptidase (P-LAP), which is also called cystine aminopeptidase, is the only membrane aminopeptidase known to functionally degrade OT as oxytocinase (OTase). P-LAP/OTase hydrolyzes several peptides other than OT including vasopressin and angiotensin III. P-LAP/OTase predicted from cDNA sequence is a type II integral membrane protein, which is converted to a soluble form existing in maternal serum by metalloproteases, possibly ADAM (a disintegrin and metalloproteinase) members. P-LAP/OTase activity increases with normal gestation, while decreases in the patients with preterm delivery and severe preeclampsia. In placenta, P-LAP/OTase is predominantly expressed in differentiated trophoblasts, syncytiotrophoblasts. Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. P-LAP/OTase may be involved in maintaining pregnancy homeostasis via metabolizing peptides such as OT and vasopressin.

Cystinyl Aminopeptidase↗