Biomedical subjects

Ikuo Konishi

Publications and source records attributed to Ikuo Konishi.

At least 19 recordsLinked to original sources

PubMed2007

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: it's inhibition leads to growth suppression and apoptosis.

The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro the expression and functional role of Hh signal molecules in epithelial ovarian tumors and normal ovarian surface epithelial (OSE) cells. The expression of Shh, Dhh, Ptch, Smo and Gli1 proteins was not observed in normal OSE, but was increased stepwise in benign, borderline and malignant neoplasms. In addition, immunoreactivity for Shh, Dhh, Ptch, Smo and Gli1 was highly correlated with cell proliferation assessed by Ki-67. Blocking the Hh signal using either the Hh pathway inhibitor cyclopamine or Gli1 siRNA led to remarkably decreased cell proliferation in ovarian carcinoma cells. Treatment with cyclopamine induced not only G, arrest but also apoptosis along with the downregulation of cyclin A and cyclin D1, and the upregulation of p21 and p27. Among the Hh signal molecules, Dhh expression was correlated with poor prognosis of ovarian carcinoma patients. These findings suggest that the Hh signal pathway plays an important role in ovarian tumorigenesis as well as in the activation of cell proliferation in ovarian carcinomas. Thus, the Hh signal pathway is a possible molecular target of new treatment strategies for ovarian carcinoma.

Apoptosis↗

PubMed2006

Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas.

Semaphorins (SEMAs) compete with vascular endothelial growth factor (VEGF) for receptor neuropilin 1 (NP1) and 2 (NP2) and suppress angiogenesis. To clarify the involvement of SEMA and VEGF in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expression of SEMA, VEGF, NP1, and NP2 in 105 epithelial ovarian tumors. In addition, loss of heterozygosity at SEMA gene loci was examined. Strong expression of SEMA was found in 48% of benign, 33% of borderline tumors, and 13% of carcinomas (P < .05). Positivity for SEMA was significantly decreased in stage IV carcinomas and the expression of SEMA was significantly lower in peritoneal metastases than in primary lesions. Expression of SEMA showed a weak inverse correlation with microvessel density, but the correlation was not statistically significant. Loss of heterozygosity at SEMA3B or SEMA3F was demonstrated in none of the benign tumors, 8% of borderline tumors, and 29% of carcinomas. Expression of NP1 and NP2 was significantly higher in carcinomas than in benign tumors (P < .0001 and .0002, respectively). Patients with ovarian carcinoma with a high VEGF/SEMA ratio showed poorer survival than those with a low VEGF/SEMA ratio (P = .005). Decreased expression of SEMA and increased expression of NP1 and NP2 are characteristics of ovarian carcinomas, and loss of SEMA expression may play an important role in ovarian carcinoma progression. A high VEGF/SEMA ratio has adverse prognostic significance in patients with ovarian carcinoma.

Female↗

PubMed2006

Wavelet analysis for detecting body-movement artifacts in optical topography signals.

We have developed a wavelet-based method of detecting body-movement artifacts in optical topography (OT) signals. Although OT, which is a noninvasive imaging technique for measuring hemodynamic response related to brain activation, is particularly useful for studying infants, the signals occasionally contain undesirable artifacts caused by body movements, so data corrupted by body-movement artifacts must be eliminated to obtain reliable results. For this purpose, we applied a wavelet transform to automatically detect body-movement artifacts in OT signals. We measured OT signals from nine healthy infants in response to speech stimuli. After the continuous signals had been divided into blocks (a block is a time series of OT signal in a 30-s period including a 10-s stimulation period), they were classified into two groups (movement blocks and non-movement blocks) according to whether the participants moved or not by video judgment. Using those data, we developed a wavelet-based algorithm for detecting body-movement artifacts at a high discrimination rate being consistent with the actual body-movement state. The wavelet method has two parameters (scale and threshold), and a Monte Carlo analysis gave the mean optimal parameters as 9+/-1.9 (mean+/-standard deviation) for the scale and as 42.7+/-1.9 for the threshold. Our wavelet method with the mean optimal parameters (scale=9, threshold=43) achieved a higher discrimination rate (mean+/-standard deviation: 86.3+/-8.8%) for actual body movement than a previous method (mean+/-standard deviation: 80.6+/-8.7%) among different participants (paired t test: t(8)=2.92, p<0.05). These results demonstrate that our wavelet method is useful in practice for eliminating blocks containing body-movement artifacts in OT signals. It will contribute to obtaining reliable results from OT studies of infants.

Artifacts↗

PubMed2006

Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells.

Impaired mismatch repair (MMR) is reportedly crucial in the early stages of endometrial carcinogenesis. Although estrogen exposure is considered an important risk factor for endometrial carcinoma, the relationship between estrogen and MMR activity remains undetermined. The present study was undertaken to elucidate the effect of estrogen on MMR activity in normal and malignant endometrial cells. The expression of MMR proteins, hMLH1 and hMSH2, and its correlation with estrogen was examined using immunohistochemical and immunofluorescent techniques. The effect of estradiol (E2) on the expression of hMLH1/hMSH2 protein/mRNA and in vitro MMR activity using two types of heteroduplex (G/T mismatches, 2-base insertion-deletion loops) was examined in cultured normal endometrial glandular cells and estrogen receptor-positive endometrial carcinoma Ishikawa cells. Immunohistochemical expression of hMLH1 and hMSH2 in normal endometrial glands was positively correlated with the serum E2 levels. The expression of hMLH1/hMSH2 protein and mRNA was increased in normal endometrial glandular and Ishikawa cells by E2 treatment. In vitro MMR activity was up-regulated by E2 in both types of cell and heteroduplex. Immunofluorescent analysis demonstrated that E2 enhanced proliferation and hMLH1/hMSH2 expression in both cells; however, proliferating cells without hMLH1/hMSH2 expressions implying high-risk cells were more frequently observed under low E2 concentrations. Collectively, the E2-induced up-regulation of MMR activity in endometrial cells suggests that high estrogen levels act as an intrinsic defense against endometrial carcinogenesis, whereas the imbalance between cell growth and MMR under low E2 environment as seen at postmenopause is vulnerable to carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Cystic clear cell tumor of borderline malignancy of the ovary lacking fibromatous components: report of two cases and a possible new histological subtype.

BACKGROUND: All of the ovarian borderline clear cell tumors ever reported had, without exception, an adenofibromatous pattern. CASE: We report two cases of borderline cystic clear cell tumor of the ovary without apparent invasive lesions or adenofibromatous components. CONCLUSION: This is the first report of cystic clear cell tumors of borderline malignancy, indicating a possible new histological subtype.

Adenocarcinoma, Clear Cell↗

PubMed2006

Early endometrial carcinoma: clinicopathology, hormonal aspects, molecular genetics, diagnosis, and treatment.

The number of patients with endometrial carcinoma is markedly increasing in Japan. Therefore, understanding of its biological characteristics and establishment of appropriate treatment are important. In this article, we first describe the clinicopathology of the two types of endometrial carcinoma with their hormonal background and genetic alterations, and then discuss the pathways of early endometrial carcinogenesis. In addition, we also review the diagnostic and therapeutic modalities for early endometrial carcinomas with current controversies, especially regarding postoperative treatment strategies.

Adenocarcinoma↗

PubMed2006

Human amniotic cell sheet harvest using a novel temperature-responsive culture surface coated with protein-based polymer.

Human amniotic epithelial (hAE) and mesenchymal (hAM) cells are believed to have the potential to differentiate into various functional cells, such as neurons, hepatocytes, cardiomyocytes, and pancreatic beta cells. However, cell transplantation has been performed by injection of cell suspensions, and thus it is difficult to control shape, size, location, and functions of differentiated cells. To overcome these problems, we developed a novel temperature-responsive culture surface coated with elastic protein-based polymer. By reducing the temperature using a polyvinylidene difluoride (PVDF) membrane, the primary hAE and hAM cell sheet can detach from the coated surface. The recovered cell sheet can be transferred and can re-adhere and re-proliferate on another surface. This represents the first report of harvesting of primary hAE and hAM cell sheets using the novel temperature- responsive polymer. These findings suggest that this new technique of cell sheet detachment from noncytotoxic, highly biocompatible protein-based polymer-coated surfaces may be useful in tissue engineering, as well as in the investigation of hAE and hAM cell sheets for transplantation.

Amnion↗

PubMed2006

Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression.

Although S100A4 expression has reportedly been associated with metastasis of various malignancies, little is known about its biological significance in ovarian carcinomas. In this study, we investigated expression and secretion of S100A4 and its extracellular function in ovarian carcinoma cells. We first used immunohistochemistry to examine the expression and localization of S100A4 in 113 epithelial ovarian neoplasms (24 benign, 20 borderline, and 69 malignant tumors) and analyzed its prognostic significance in patients with ovarian carcinoma. Then we investigated the expression, subcellular localization, and secretion of S100A4 in four ovarian carcinoma cell lines. Finally, we examined the effect of S100A4 treatment on the cell proliferation and invasiveness of ovarian carcinoma cells, along with activation of small GTPase, RhoA. Both cytoplasmic and nuclear expressions of S100A4 were significantly stronger in carcinomas than those in benign and borderline tumors. Ovarian carcinoma patients with strong nuclear S100A4 expression showed a significantly shorter survival than those without (P = 0.0045). This was not the case for cytoplasmic S100A4 expression. Ovarian carcinoma cell lines were shown to express S100A4, and secrete S100A4 into the culture media. Treatment with recombinant S100A4 resulted in the upregulation of S100A4 expression, translocation of S100A4 into the nucleus, and enhancement of invasiveness, which was associated with the upregulation of small GTPase, RhoA. These findings suggest that the nuclear expression of S100A4 is involved in the aggressive behavior of ovarian carcinoma and S100A4 is an autocrine/paracrine factor that plays an important role in the aggressiveness of ovarian carcinoma cells.

Active Transport, Cell Nucleus↗

PubMed2005

BRAF mutation in endometrial carcinoma and hyperplasia: correlation with KRAS and p53 mutations and mismatch repair protein expression.

PURPOSE: Although several gene abnormalities have been reported in endometrial carcinoma, the genetic alterations have not fully been elucidated. Recent studies have revealed frequent activating mutations of the gene for BRAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies. However, the prevalence and significance of BRAF mutations in endometrial carcinoma remain unclear. EXPERIMENTAL DESIGN: We examined BRAF mutations in exons 11 and 15 in 97 cases of endometrial carcinoma (endometrioid type, 78; nonendometrioid type, 19), 9 cases of atypical endometrial hyperplasia, and 20 cases of normal endometrium by direct sequencing. In addition, mutations of KRAS and p53 and the immunohistochemical expression of hMLH1 and hMSH2 were also examined. RESULTS: Of the 97 carcinomas and 9 hyperplasias, 20 (21%) and 1 (11%) had BRAF mutations, most of them at previously unreported sites. Twenty samples of normal endometrium and 21 samples of normal endometrium obtained from sites adjacent to neoplastic lesions had no BRAF mutations. There was no apparent difference in the prevalence of BRAF mutation among stages, histologic subtypes, or grades. Mutations of KRAS and p53 were found in 18 (19%) and 22 (23%) cases, and 65 (67%) and 92 (95%) cases showed positive immunostaining for hMLH1 and hMSH2, respectively. BRAF mutation was more frequently found in hMLH1-negative cases (12 of 32, 41%) than in hMLH1-positive cases (7 of 65, 11%; P = 0.008), suggesting that it is associated with an abnormal mismatch repair function. CONCLUSIONS: These findings suggest that mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Intratumoral heterogeneous expression of p53 correlates with p53 mutation, Ki-67, and cyclin A expression in endometrioid-type endometrial adenocarcinomas.

To further elucidate the significance of p53 mutation in endometrial carcinoma, we investigated it in endometrioid-type endometrial carcinomas showing intratumoral heterogeneous p53 expression. In addition, we also examined the correlation of p53 mutation and cyclin A expression, because we previously reported a topological correlation between the expression of p53 and cyclin A. The p53 mutation in exons 5-8 in 54 cases of endometrial carcinoma showing immunohistochemical expression of p53 was examined using microdissected tissue DNAs. Of the 54 p53-positive endometrial carcinomas, 23 (43%) had p53 mutation with a tendency in histologically higher grade tumors. Ten of the 54 showed a heterogeneous p53 expression, and in 9 of the 10 cases, p53 mutation was present only in p53-positive sites, which were often found in histologically less differentiated areas with elevated Ki-67 in the same tumor. Cyclin A expression was topologically observed in p53-positive areas; however, it was noted in both tumors with (12/23, 52%) and without (18/31, 58%) p53 mutation. These results suggest that p53 mutation is a late event and plays an important role in the acquisition of malignant potentials in endometrioid-type endometrial adenocarcinomas. Unexpectedly, accumulation of the p53 protein itself may be important in cyclin A overexpression.

Adult↗

PubMed2005

Expression of cyclins, p53, and Ki-67 in cervical squamous cell carcinomas: overexpression of cyclin A is a poor prognostic factor in stage Ib and II disease.

We previously reported the overexpression of cyclins in uterine cervical carcinoma; however, their clinicopathological significance remained undetermined. In the present study, we examined the immunohistochemical expression of cyclins (D1, E, A, B1), p53 and Ki-67 in squamous cell carcinoma (stage Ib+II; 80 cases, stage III+IV; 23 cases). Correlations between the expression of cyclins and clinicopathological parameters and patient survival were statistically evaluated. The results indicated that in the normal squamous epithelium, the expression of cyclins and Ki-67 was sporadically observed in the parabasal layer. Of the 103 cervical carcinomas, overexpression of cyclins D1, E, A, B1 and p53 was observed in 13 (13%), 23 (22%), 25 (24%), 18 (18%) and 23 (22%) cases, respectively, with a slight predominance in advanced stage tumors. The expression of cyclin D1, E, A and p53 significantly correlated with that of Ki-67 (Spearman's rank correlation). Univariate and multivariate analyses revealed that lymph node metastasis and cyclin A overexpression were independent prognostic factors for unfavorable outcomes in stage Ib+II patients. These findings suggest that the overexpression of various cyclins is involved in the acquisition of the vigorous growth potential of cervical carcinoma cells, and that cyclin A is an independent prognosticator of cervical carcinoma in early stages.

Adult↗

PubMed2005

Human amniotic mesenchymal cells have some characteristics of cardiomyocytes.

BACKGROUND: Cellular cardiomyoplasty (CCM) is a major method for the treatment of heart failure because adult cardiomyocytes do not regenerate after ischemic injury, which results in heart failure. There is a great deal of interest in finding suitable new cell sources for use in CCM. Here, we report that human amniotic mesenchymal cells (hAMC), which are multipotent cells derived from fetal mesoderm, may be a suitable cell source for CCM. METHODS: Freshly isolated hAMC were examined to detect the expression of cardiac-specific genes by reverse-transcription polymerase chain reaction and immunocytochemistry. hAMC were cocultivated with neonatal rat heart explants and transplanted into myocardial infarcts in the rat heart. RESULTS: hAMC expressed cardiac-specific transcription factor GATA4, cardiac-specific genes, such as myosin light chain (MLC)-2a, MLC-2v, cTnI, and cTnT, and the alpha-subunits of the cardiac-specific L-type calcium channel (alpha1c) and the transient outward potassium channel (Kv4.3). After stimulation with basic fibroblast growth factor (bFGF) or activin A, hAMC expressed Nkx2.5, a specific transcription factor for the cardiomyocyte and cardiac-specific marker atrial natriuretic peptide. In addition, the cardiac-specific gene alpha-myosin heavy chain was detected after treatment with activin A. Coculture experiments confirmed that hAMC were able to both integrate into cardiac tissues and differentiate into cardiomyocyte-like cells. After transplantation into the myocardial infarcts in rat hearts, hAMC survived in the scar tissue for at least 2 months and differentiated into cardiomyocyte-like cells. CONCLUSION: The results of the present study suggest that hAMC possess some characteristics of cardiomyocytes.

Amnion↗

PubMed2005

Prenatal diagnosis of amniotic sheets by magnetic resonance imaging.

We report prenatal diagnosis of an amniotic sheet by magnetic resonance imaging (MRI) at 28 weeks' gestation. The amniotic sheet divided the uterine cavity into 2 compartments, with the fetus and placenta located in the upper portion of the amniotic cavity. Although prenatal diagnosis of amniotic sheets can be performed with ultrasonography, the wider field of view and excellent tissue contrast provided by MRI may allow better spatial visualization of the amniotic sheet and, therefore, improve the diagnostic accuracy.

Adult↗

PubMed2005

Expression of Aurora kinases A and B in normal, hyperplastic, and malignant human endometrium: Aurora B as a predictor for poor prognosis in endometrial carcinoma.

Aurora kinases such as Aurora A and Aurora B are key regulators of mitosis and have been reported to be overexpressed in various malignancies. However, the expression and localization of Aurora kinases in normal and neoplastic endometrial tissues remain undetermined. In the present study, immunohistochemical expression of Aurora A and B was examined in 40 normal, 30 hyperplastic, and 73 malignant endometria. The data were compared with the expression of Ki-67 and patient survivals. The expression of Aurora A and B at protein and messenger RNA levels was also examined using Western blotting and the reverse transcriptase polymerase chain reaction. The expression of Aurora A in normal endometrium was observed mainly in the proliferative phase and was decreased in the secretory phase. The Aurora A expression was significantly increased in carcinomas compared with normal proliferative endometrium; however, there was no correlation of Aurora A expression with Ki-67 expression or patient survival. The expression of Aurora B in normal endometrium was significantly higher in the proliferative phase than in the secretory phase. In endometrial carcinomas, the expression of Aurora B was correlated with Ki-67 expression and was significantly increased in high-grade tumors. In addition, patients with Aurora B-positive carcinoma showed poor prognosis compared with those with Aurora B-negative carcinoma (P = .0135). Accordingly, the present study indicates the aberrant expression of Aurora A and Aurora B in endometrial carcinomas and the clinical importance of Aurora B expression in relationship to patient prognosis.

Adenocarcinoma↗

PubMed2005

Severe gastrointestinal bleeding during pregnancy in a case of blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by distinctive cutaneous and gastrointestinal venous malformations that usually cause massive or occult gastrointestinal hemorrhage and iron deficiency anemia secondary to the bleeding episodes. Only two reports of BRBNS in pregnant women can be found, according to the MEDLINE search. Both cases did not describe severe complications during pregnancy. This is the first case report of BRBNS with severe intestinal hemorrhage in a pregnant woman. The woman had been symptom-free for 5 years before the pregnancy and remained symptom-free for 2 years after delivery. This suggests that pregnancy induced the hemangiomas of the gastrointestinal tract to bleed. Celiotomy was needed to deal with massive gastrointestinal bleeding. We propose that women with BRBNS should be checked for systemic hemangiomas before pregnancy. However, it is difficult to check the small intestine thoroughly for hemangioma. Therefore, adequate attention needs to be paid to possible gastrointestinal bleeding when caring for patients with this condition. Our experience suggests that when dealing with pregnant women with BRBNS, it is essential to bear in mind the possibility that pregnancy may trigger the symptoms of hemangioma to become manifest, possibly causing life-threatening massive bleeding from the digestive tract.

Adult↗

PubMed2005

Primary retroperitoneal mucinous cystadenoma of borderline malignancy: a case report and review of the literature.

A case of primary retroperitoneal mucinous cystic tumor of borderline malignancy is reported. A 36-year-old, nulliparous woman complained of abdominal fullness. Physical examination revealed a cystic mass 12-cm x 8-cm in size. At laparotomy, a cystic tumor was observed in the right retroperitoneal space. Both ovaries appeared normal and the uterus was almost normal except for small myomatous nodules. Removal of the retroperitoneal tumor, an appendectomy, and a myomectomy were performed. The histologic diagnosis was a primary retroperitoneal mucinous cystic tumor of borderline malignancy, similar to findings for ovarian tumor. There was no evidence of disease 6 months after the surgery.

Adult↗

PubMed2005

Leiomyoma of the ovary presenting with Meigs' syndrome.

Ovarian leiomyoma is a rare tumor. Ovarian leiomyoma accompanied with Meigs' syndrome is extremely rare. We report a case of ovarian leiomyoma presenting with Meigs' syndrome, which was first noted as dyspnea in a 79-year-old woman. A whole-body examination revealed a solid mass of the ovary, accumulation of ascites and pleural effusion, and elevated serum carbohydrate antigen 125. Abdominal hysterectomy and salpingo-oophorectomy were carried out. After the surgery, ascites and pleural effusion disappeared. The pathological diagnosis of the removed tumor was leiomyoma of the left ovary. The patient has been healthy for 24 months after the surgery, with no signs of recurrence. We also review the literature on this disease and the clinicopathologic characteristics of the current case are discussed.

Aged↗

PubMed2004

Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to an AP-1 sequence.

To explore the mechanism of estrogen-induced growth of normal endometrium, the transactivation system of the cyclin D1 gene was analysed using cultured normal endometrial glandular cells. Estradiol (E2) treatment of cultured normal endometrial glandular cells induced upregulation of c-Jun, and then cyclin D1 proteins, followed by serial expressions of cyclins E, A and B1 proteins. Increase in the mRNA expression of cyclin D1 preceded the protein expression of cyclin D1 under E2 treatment. A luciferase assay using deletion constructs of the cyclin D1 promoter indicated that E2-induced increase in transcriptional activity was observed in reporters containing AP-1-binding site sequence, and that in the absence of E2, cotransfection of c-Jun also showed increase of transcriptional activity in the same reporters with AP-1 sequence. A gel shift assay using nuclear extract from E2-treated endometrial glandular cells and AP-1 sequences of the cyclin D1 promoter indicated specific binding between c-Jun protein and the promoter. Transfection of c-jun antisense oligonucleotides to the glandular cells resulted in the suppression of the E2-induced upregulation of cyclin D1 mRNA and protein. These findings suggest that E2-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to the AP-1 sequences.

Adult↗