Biomedical subjects
Y Yaginuma
Publications and source records attributed to Y Yaginuma.
Overexpression of N-acetylglucosaminyltransferase III enhances the epidermal growth factor-induced phosphorylation of ERK in HeLaS3 cells by up-regulation of the internalization rate of the receptors.
N-Acetylglucosaminyltransferase III (GnT-III) is a key enzyme that inhibits the extension of N-glycans by introducing a bisecting N-acetylglucosamine residue. In this study we investigated the effect of GnT-III on epidermal growth factor (EGF) signaling in HeLaS3 cells. Although the binding of EGF to the epidermal growth factor receptor (EGFR) was decreased in GnT-III transfectants to a level of about 60% of control cells, the EGF-induced activation of extracellular signal-regulated kinase (ERK) in GnT-III transfectants was enhanced to approximately 1.4-fold that of the control cells. A binding analysis revealed that only low affinity binding of EGF was decreased in the GnT-III transfectants, whereas high affinity binding, which is considered to be responsible for the downstream signaling, was not altered. EGF-induced autophosphorylation and dimerization of the EGFR in the GnT-III transfectants were the same levels as found in the controls. The internalization rate of EGFR was, however, enhanced in the GnT-III transfectants as judged by the uptake of (125)I-EGF and Oregon Green-labeled EGF. When the EGFR internalization was delayed by dansylcadaverine, the up-regulation of ERK phosphorylation in GnT-III transfectants was completely suppressed to the same level as control cells. These results suggest that GnT-III overexpression in HeLaS3 cells resulted in an enhancement of EGF-induced ERK phosphorylation at least in part by the up-regulation of the endocytosis of EGFR.
alpha1,6fucosyltransferase is highly and specifically expressed in human ovarian serous adenocarcinomas.
An elevated level of alpha1,6fucosylation in N-glycans represents one of the cancer-related alterations of oligosaccharides and is associated with the metastatic potential of hepatoma cells. However, expression of alpha1,6fucosyltransferase (alpha1,6FucT), which is involved in this aberrant glycosylation, has not been intensively explored in other malignant tumors. We report on a study of the expression of alpha1,6FucT in various types of epithelial ovarian carcinoma tissue, as well as normal ovary, benign and borderline ovarian tumors. The activity assay showed that alpha1,6FucT is highly and specifically elevated in serous adenocarcinomas but not in normal and other ovarian tumor tissues. This elevation was due to enhancement of mRNA expression, as evidenced by Northern blot analysis. Furthermore, we have shown immunohistochemically that alpha1,6FucT expression is localized predominantly in cancer cells. Lectin blot analysis using Lens culinaris agglutinin, which preferentially recognizes alpha1,6fucose residue, suggested that several glycoproteins were likely targets for modification by alpha1, 6fucosylation in serous adenocarcinoma tissues. These findings suggest that the elevated expression of alpha1,6FucT and the resulting modification of N-glycans are distinctive features of this type of ovarian cancer and may be related to the progression of this malignancy.
Abnormal structure and expression of PTEN/MMAC1 gene in human uterine cancers.
The PTEN/MMAC1 gene, located on human chromosome 10q23, has recently been implicated as a candidate tumor suppressor gene in human cancers. In the present study, 12 uterine cancer cell lines and 87 uterine cancers of various grades and histological type were analyzed for PTEN/MMAC1 gene. Three of 44 endometrial carcinoma (7%) showed no PTEN/MMAC1 mRNA expression by RT-PCR analysis. Sequencing analysis of entire coding region of PTEN/MMAC1 gene revealed mutations in three of six endometrial cancer cell lines (50%) and 17 of 44 endometrial cancer tissues (39%). In contrast, for cervical cancers, only one of six cancer cell lines (2%) showed mutation, and one of 43 cancer tissues (2%) had an abnormality. Overall, 36% of the abnormal spots were located in exon 5, 24% were in exon 8, 16% were in exon 3, and 8% were in exon 6, and single cases of abnormality were found in exons 1, 4, and 7. Our results revealed that, in total, 60% of abnormalities were clustered in exons 5 and 8. Exon 5 is a functional domain of the PEN/MMAC1 gene, and therefore, abnormalities in this region may be important for loss of PTEN/MMAC1 gene function. Finally, we found a high frequency of PTEN/MMAC1 gene abnormalities in endometrial carcinomas but a low frequency in cervical carcinomas. These findings suggest that disruption of PTEN/MMAC1 by mutation or absence of expression may contribute to the pathogenesis or neoplastic evolution in a large proportion of endometrial carcinomas but in a small proportion of cervical carcinomas.
Diffuse malignant mesothelioma of the uterus.
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Different expression patterns of nitric oxide synthase isozymes in various gynecological cancers.
The expression of nitric oxide synthase (NOS) in human gynecological cancers, including ovarian cancers, uterocervical cancers, and endometrial cancers for example, was examined by the reverse transcriptase/polymerase chain reaction, coupled with Southern hybridization and by immunohistochemistry. Nitric oxide synthase II (NOS II), an inducible form, was expressed in more than 90% of the cancers. Nitric oxide synthase I (NOS I), a neuronal form, was expressed in 58% of all the ovarian cancers, in which the serous type is found more frequently (5 out of 7) than the mucinous type (2 out of 6), and in all clear-cell cancers. The frequency of NOS I expression in uterocervical cancers and endometrial cancers was relatively low. Nitric oxide synthase III (NOS III), an endothelial form, was detected in 25% of ovarian and 33% of endometrial cancers, while no expression was detected in uterocervical cancers. In terms of cancer types, all clear-cell adenocarcinomas and most of the serous-type adenocarcinomas expressed both NOS I and NOS II, while most uterine squamous carcinomas and endometrial adenocarcinomas expressed only NOS II. However, there was no correlation between the frequency of NOS expression and patients' age or the clinical stage of the disease. Since NO increases vascular permeability and blood flow, the high frequency of NOS expression in gynecological cancers may serve to stimulate and promote tumor growth.
Codon 72 polymorphism of p53 as a risk factor for patients with human papillomavirus-associated squamous intraepithelial lesions and invasive cancer of the uterine cervix.
Squamous intraepithelial lesions (SIL) and invasive cancer of the uterine cervix are thought to be a series of lesions derived from normal cervical squamous tissue. Infection by high risk human papillomavirus (HPV) and integration of viral DNA may initially lead normal cervical cells to become pre-malignant cells in SIL and result in cervical malignancies later on. High risk HPVs, including types 16 and 18, produce a viral protein, E6, which is required for viral replication in host cells. The E6 protein is able to bind to host p53 causing inactivation of its function through the mechanism of ubiquitin-dependent degradation. It has recently been reported that the extent of p53 dysfunction caused by HPVs depends on the status of a polymorphism at codon 72 of p53, Pro or Arg. In that study, it was demonstrated that a patient homozygous for the Arg allele had about a seven times higher risk of developing cervical cancer than a patient homozygous for Pro. In an attempt to confirm this result and elucidate whether this allelic deviation of the Arg genotype seen in invasive cervical cancer occurs in the pre-malignant lesion SIL, we analyzed 219 SIL and 101 invasive cancer samples from Japanese patients using a PCR-based assay. Samples from 88 SIL and 76 invasive cancers were identified as HPV-infected samples and used for further analyses. In these, the frequencies of Arg homozygotes were 31.8, 33.0 and 36.8% in controls, SIL and invasive cancer, respectively. The distributions of the different alleles of codon 72 (Pro/Pro, Pro/Arg and Arg/Arg) did not show significant differences between either control and SIL groups or control and invasive cancer groups. Also, no difference in the frequency of Arg/Arg genotype was detected even between the control and HSIL groups or control and invasive cancer infected with high risk HPVs groups. In conclusion, there was no obvious relationship between the Arg genotype at codon 72 of p53 and predisposition to HPV-associated cervical neoplasia.
Bilateral oophorectomy in asymptomatic women over 50 years old selected by ovarian cancer screening.
The purpose of this study was to evaluate bilateral oophorectomy in women over 50 years old found to have an adnexal mass using transvaginal ultrasonography (TVS) as a mass screening. With TVS a total of 23,451 women without symptoms were examined for ovarian cancer at annual screening for uterine cervical cancer. Two hundred fifty-eight women over 50 years old persistently had abnormal TVS results and 95 women gave informed consent for surgical tumor removal. In the 95 women operated, 7 malignant ovarian cancers were found. Especially adnexal masses which were thought to be benign were treated by laparoscopic surgery.
Analysis of Bcl-2, Bax and Survivin genes in uterine cancer.
To investigate the role of the apoptosis-related genes, Bcl-2, Bax and Survivin genes were analyzed. For the Bax gene, abnormality was detected in 1 of 7 cervical and 1 of 6 endometrial cancer cell lines, 1 of 25 cervical cancer tissues and none of 17 endometrial cancer tissues using PCR-SSCP. In 4 cervical and 2 endometrial cancer cell lines, the ratio of Bcl-2 to Bax expression was higher than the control ratio using Western blotting. Survivin mRNA was detectable in all cell lines and all cancer tissues. The data suggested that these apoptosis-related genes may play important roles in the pathway of carcinogenesis of human uterine cancer.
[New practical sizer for ATS medical open pivot valve].
The sewing cuff of the ATS Medical valve is made from double velour polyester, making the sewing cuff diameter larger than the tissue anulus diameter of this prosthetic heart valve. The ATS valve sizer, with the diameter marked in millimeters, has a ring which allows for an easy measurement of the patient's tissue anulus. However, the diameters of this ring and the prosthetic valve (tissue anulus diameter) are made to equal in size. Therefore, if the valve size is determined by using this sizer, the sewing cuff diameter will be considerably larger than the patient's tissue anulus diameter. In order to also take into account the diameter of the sewing cuff, we added a flange around the sizer in the shape of the sewing cuff. The new and more practical sizer allows us to avoid sizing trouble in valve replacement surgery.
A SacII polymorphism in the human ASCL2 (HASH2) gene region.
The mouse achaete-scute homolog-2 gene (Ascl2 or Mash2) encodes a transcription factor playing a role in the development of the trophoblast. The Ascl2 gene is paternally imprinted in the mouse, but whether this applies to its human homolog is unknown. In the present study, we found a SacII polymorphism in the possible 3' untranslated region (UTR) of the gene. It would be very useful to determine definitively whether the gene is imprinted, as well as to analyze the allelic methylation status of the gene.
Telomerase activity and human papillomavirus (HPV) infection in human uterine cervical cancers and cervical smears.
Telomerase activity and human papillomavirus (HPV) infection were investigated in uterine cervical samples using molecular biology techniques. Thirteen cervical carcinomas and corresponding normal tissue from the same patient, and 102 cervical swabs were examined. Telomerase activity was detected in 12 of 13 cervical cancer tissues (92%). Of the 12 cases that showed telomerase activity, all were HPV positive, and the one case that did not show telomerase activity was HPV negative. A telomeric repeat amplification protocol assay detected telomerase activity in one out of seven normal cervical tissues (14%), and this one case was HPV positive. In cervical smear samples, telomerase activity was detected in two out of 36 normal smears (6%; both HPV positive), in 10 of 32 (31%) CIN1 (cervical intra-epithelial neoplasia) cases (three HPV positive), in four of five (80%) CIN2 cases (two HPV positive), in 15 of 21 (71%) CIN3 cases, (seven HPV positive) and in seven of eight (88%) squamous cell carcinoma cases (six HPV positive). These results suggest that telomerase activity may play some role in cervical carcinogenesis, and telomerase activity is associated with HPV infection in uterine cervical lesions.
Analysis of the Rb gene and cyclin-dependent kinase 4 inhibitor genes (p16INK4 and p15INK4B) in human ovarian carcinoma cell lines.
In the present study, we analyzed human ovarian carcinoma cell lines for abnormalities in the tumor suppressor gene Rb (retinoblastoma) and in cyclin-dependent kinase 4 (CDK4) inhibitor genes (p16INK4 and p15INK4B) using molecular biology techniques. For the Rb gene, in all six cell lines (PA-1, Caov-3 and -4, OVCAR-3, SK-OV-3, and Kuramochi), Rb gene abnormality was not detected using Southern blotting. In the Caov-3 cell line transcripts were not detectable by either Northern blot or polymerase chain reaction. Sequence analysis of the entire coding region of the Rb gene revealed point mutations (AAC to GAC) resulting in codon 123 (Asn to Asp) changes in the Caov-4 cell line. In the PA-1 cell line both wild-type Rb and mutant-type Rb (codon 798: CGG to TGG) were expressed, and in the OVCAR-3 cell line both wild-type Rb and mutant-type Rb (codon 704: ATG to GTG) were expressed. In four of six human ovarian carcinoma cell lines Rb gene abnormality was detected. For the p16INK4 and p15INK4B genes, only the SK-OV-3 cell line had abnormalities. There was a gene rearrangement or minor deletion of the p16INK4 gene in the SK-OV-3 cell line, while the p15INK4B gene was deleted in this cell line. In the SK-OV-3 cell line no mRNAs of p16INK4 and p15INK4B were expressed. At the point of Rb gene inactivation, we can explain five cell lines of six: four cell lines had abnormalities in the Rb gene itself, which is another mechanism by which the Rb gene is inactivated, while one cell line (SK-OV-3) had abnormalities in CDK4 inhibitor genes, another of the inactivation mechanisms of the Rb gene. These data suggest that abnormalities of Rb and CDK4 inhibitor genes (p16INK4, p15INK4B) may be involved in human ovarian carcinogenesis.
Analysis of the retinoblastoma gene in human endometrial carcinoma.
OBJECTIVE: To examine the Rb gene that controls the cell cycle in human endometrial carcinoma. METHODS: Six endometrial carcinoma cell lines (Ishikawa, Hec1-A, Hec1-B, KLE, RL95-2, and AN3 CA) and 48 human endometrial carcinoma tissues were studied by Southern blotting, Northern blotting, polymerase chain reaction (PCR), and DNA sequencing. RESULTS: Southern blotting analysis did not reveal any abnormalities at the DNA level in the endometrial carcinoma cell lines. Size and quantity of Rb transcripts also appeared normal in these cell lines, as evidenced by Northern blotting and reverse transcription-PCR. Sequence analysis of Rb cDNA revealed that the Ishikawa cell line had an abnormality. In human endometrial carcinoma, 20 of 48 cases (42%) were informative and only two cases of 20 (10%) showed loss of heterozygosity at the Rb locus. CONCLUSION: An Rb gene abnormality was found in some human endometrial carcinomas. Therefore, our results suggest that Rb gene abnormalities may be involved in some human endometrial carcinogenesis.
Peripheral CD4+ CD8- gammadelta T cell lymphoma: a case report with multiparameter analyses.
A 72-year-old Japanese man presented with CD4+ T cell receptor (TCR) gammadelta T cell lymphoma involving bilateral cervical lymph nodes. No involvement by tumor was observed in the liver, spleen, nasal cavity, or bone marrow throughout his clinical course. Although the tumor adequately responded to chemotherapy and irradiation, he relapsed with short remission and a slowly aggressive clinical course, and died 24 months after onset. Simultaneous expression of TCR gammadelta with other T-cell antigens on the lymphoma cells was analyzed by 3-color flow cytometry (3-FCM), and showed a unique phenotype CD3+ CD4+ CD8- CD7- CD5+ CD2++ TCR alphabeta (WT31)- betaF1-TCR gammadelta1 (11F2)+ TCR delta1+. Cytogenetic analysis showed 79-81 and structural abnormalities consisting of del(1)(p11) and i(17)(q10). But no abnormality was identified in chromosome 7. DNA analysis revealed gene rearrangements of TCRgamma and delta, while a nongerm line band in TCRbeta was aberrantly seen. These observations suggest a new subtype of gammadelta T-cell lymphoma, which is characterized by CD4 positivity and by a clinical course not as aggressive as other predominant subtypes.
Landry-Guillain-Barre-Strohl syndrome in pregnancy.
We report here a case of Landry-Guillain-Barre-Strohl syndrome (LGBSs) in pregnancy. The patient had rubella viral infection, and the patient's inspiratory ability rapidly weakened. In the end, aggressive plasmapheresis prevented the need for respiratory support and the inherent risk it poses in terms of maternal morbidity and mortality.
Incidence of sniff-related cholesteatomas.
High negative middle ear pressure created by habitual sniffing in patients with insufficient closure of the Eustachian tube has been claimed by Magnuson and colleagues to be an important causative factor of acquired cholesteatomas. The present study was conducted to ascertain the rate and types of cholesteatomas in which habitual sniffing is involved. Among 105 consecutive patients with acquired cholesteatomas (112 ears: 93 flaccida type, 15 tensa type, 4 extensive type), 27 patients (31 ears) were diagnosed as having a habitual sniff in response to aural discomfort resulting from insufficient closure of the Eustachian tube. This corresponds to 25.7% of the patients, which is significantly higher than the prevalence of habitual sniffing in normal subjects, being 2 out of 130 (1.5%) (p < 0.005: chi2-test). Habitual sniffing was found to be statistically more common in flaccida-type than in the tensa-type cholesteatomas. Habitual sniffing in response to aural discomfort was thus found to be an important risk factor for cholesteatomas. However, investigations into other pathogeneses of cholesteatomas should be continued, since the sniff-related cases reported here were limited to one-fourth of the cases of acquired cholesteatomas studied.
[Predictive value of electrogustometry in the preoperative diagnosis of severity of middle ear pathology].
The chorda tympani nerve (CTN) is frequently damaged in various inflammatory middle ear disorders. To determine the validity of electrogustometry in the diagnosis of preoperative severity of a middle ear lesion of the posteosuperior portion of the mesotympanum, the threshold determined by electrogustometry was examined preoperatively and was correlated with the intraoperative findings. One hundred and six ears of 97 patients with various middle ear diseases were examined. The patients ranged in age from 5 to 70 years (average, 39.4) : 55 of them were male and 42 were female. In 80 of them the appearance of the tympanic membrane on the opposite side was normal. The disorders were classified as follows: A : Non-inflammatory diseases including middle ear anomalies, posttraumatic perforation of the tympanic membranes and congenital cholesteatoma without infection (n = 10) ; B : chronic otitis media without cholesteatoma (n = 14) ; C : pars flaccida retraction type cholesteatoma (n = 34) ; D : pars tensa retraction type cholesteatoma and adhesive otitis media (n = 15) ; E : surgically treated ears (n = 33). The average threshold +/- S.D.(dB) of each group according to the above classification was as follows : A : -1.0 +/- 4.4, B : -1.5 +/- 6.2; C : 7.4 +/- 13.7; D : 9.6 +/- 18.2; E : 20.9 +/- 16.8. The rates of abnormal threshold of electrogustometry (more than 8dB) of A, B, C, D and E were 0%, 7.1%, 44.1%, 46.7% and 72.7%, respectively. The intraoperative findings around the CTN were retrospectively classified according to the following 5 groups : I : No pathological tissue was attached to the CTN (n = 44); II : the Granulation tissue or matrix of the cholesteatoma was attached to the CTN (n = 19) ; III : the CTN was surrounded by granulation or a matrix of cholesteatoma (n = 3) ; IV : The CTN was not identifiable due to the severe pathological condition of the middle ear cavity, in either surgically treated or untreated ears (n = 16), V : Surgically treated ears in which the CTN was identifiable (n = 24). The average threshold +/- S.D.(dB) for I, II, III, IV and V were 1.9 +/- 9.6, 2.0 +/- 11.7, 16.0 +/- 20.3, 32.0 +/- 7.4, 16.0 +/- 17.0, respectively. The rates of abnormal threshold of electrogustometry (more than 8dB) of I, II, III, IV and V were 27.3%, 31.6%, 66.7%, 100% and 62.5%, respectively. In both the above classification by the disorders and that by the intraoperative findings around the CTN, differences in the average thresholds between the surgically treated sides and the opposite sides with normally appearing tympanic membranes showed a tendency similar to that of the thresholds of the treated sides. In the present study, the threshold of electrogustometry was correlated with the disease and the intraoperative findings during middle ear surgery, and it was higher in adhesive otitis media and cholesteatoma of the pars tensa type. Electrogustometry is a useful preoperative examination to predict the condition of the posterosuperior portion of the mesotympanum.