Immunohistochemical detection of a specific receptor for lipocalin2 (solute carrier family 22 member 17, SLC22A17) and its prognostic significance in endometrial carcinoma

Background: We previously reported the overexpression of lipocalin2 (LCN2), a 25 kDa secretory protein involved in iron-transportation, in endometrial carcinoma and its possible contribution to endometrial carcinogenesis. Recently, a specific receptor for LCN2, solute carrier family 22 member 17 (SLC22A17), was identified. The present study was undertaken to investigate the expression of SLC22A17 in endometrial carcinoma. Methods: The expression of the SLC22A17 and LCN2 proteins was examined immunohistochemically using 69 cases of endometrial carcinoma and adjacent normal endometrial tissues. Immunoreactivity was evaluated according to the percentage of positive cells and described as a positivity index (PI, full score 100). Results: The expression of SLC22A17 was negligible in normal endometria, but positive staining for SLC22A17 (PI 1) was observed in 35 cases of endometrial carcinoma. The PI for SLC22A17 was significantly higher in cases with histological grade 3 (P < 0.0005), advanced FIGO stage (P=0.002), deep myometrial invasion (P=0.029), positive lymph-vascular space invasion (P = 0.029), positive intraperitoneal cytology (P = 0.020) and adnexal metastasis (P= 0.029). The expression of SLC22A17 and LCN2 was positively correlated with a significant difference (P= 0.002), and the patients who overexpressed both SLC22A17 and LCN2 showed poorer survival than those without the expression of SLC22A17 or LCN2 (P= 0.002). Moreover, the overexpression of both SLC22A17 and LCN2 was indicated to be an independent prognostic factor by multivariable analysis. Conclusions: These results suggested that SLC22A17, in cooperation with LCN2, to be involved in the acquisition of aggressive behavior among endometrial carcinoma cells.ArticleEXPERIMENTAL AND MOLECULAR PATHOLOGY. 91(2):563-568 (2011)journal articl

Immunohistochemical expression of keratan sulfate: a possible diagnostic marker for carcinomas of the female genital tract

Aims The authors previously reported the expression of keratan sulfate (KS), a glycosaminoglycan, in the epithelium of normal and neoplastic endometria. The aim of this study was to evaluate its potential use as a diagnostic marker, and the expression of KS was investigated in other human epithelial tissues. Methods Expression was examined immunohistochemically using 102 samples of normal epithelia and 110 samples of carcinomas from the female genital tract (FGT; cervix, endometrium, ovary, fallopian tube), digestive organs (gastrointestinal tract, pancreas, liver), urinary tract, lung, mammary gland, thyroid and mesothelium. Results In normal tissues, KS was consistently detected in the FGT and ectopic endometrium (25/26), but was not found in the digestive organs (1/42) and urinary tract (0/6), and was only partly detected in the lung (7/10), mammary gland (3/9) and thyroid (4/4). In malignant tissues, KS was consistently observed in carcinomas of the endometrium, ovary and fallopian tube (29/32), and was partly detected in carcinomas of the lung, mammary gland, thyroid, pancreas and mesothelium, but was absent in carcinomas of the gastrointestinal tract (0/17), liver (0/5) and urinary tract (0/11). Among carcinomas of the FGT, digestive organs and urinary tract, KS positivity suggested the possibility of FGT carcinomas, with 79.5% (31/39) sensitivity and 92.9% (39/42) specificity. Conclusions KS is a potentially useful marker for the supportive diagnosis of the primary site of metastatic carcinomas or unknown primary carcinomas, especially in the abdominal cavity.ArticleJOURNAL OF CLINICAL PATHOLOGY. 64(12):1058-1063 (2011)journal articl

Laser-captured microdissection-microarray analysis of the genes involved in endometrial carcinogenesis: stepwise up-regulation of lipocalin2 expression in normal and neoplastic endometria and its functional relevance

Endometrial carcinoma often arises from normal endometrial glandular cells via a precursor, atypical endometrial hyperplasia. However, the genetic changes involved in this carcinogenetic process are not fully understood. Differentially expressed genes were selected from glandular cells of normal proliferative-phase endometria, atypical endometrial hyperplasia, and endometrial carcinoma using laser-captured microdissection and microarray. The microarray analysis revealed a total of 51 genes to be up-regulated and 23 genes to be down-regulated in neoplastic endometrial epithelia. We focused on lipocalin2 (LCN2), which showed the largest magnitude of up-regulation. Immunostaining for lipocalin2 confirmed a stepwise increase in its expression in endometrial hyperplasia and carcinoma. In addition, elevated expression of lipocalin2 was correlated with the poor outcome of endometrial carcinoma patients. The subcellular distribution of lipocalin2 was both cytoplasmic and nuclear, despite reports that lipocalin2 is a secretory protein. Treatment of endometrial carcinoma cells with 5-azacytidine increased the expression of lipocalin2, suggesting the expression to be controlled by methylation of the promoter. The forced expression of lipocalin2 resulted in the enhanced cell proliferation and invasion in vitro. The expression of lipocalin2 increased with the endometrial carcinogenesis, and accumulation of the protein conferred biological aggressiveness to endometrial carcinoma cells. These results suggest lipocalin2 to be a novel target in the treatment of endometrial carcinoma.ArticleHUMAN PATHOLOGY. 42(9):1265-1274 (2011)journal articl

Verification of Japanese language classes that foster logical thinking skills

In this study, based on the hypothesis that it is effective to develop logical thinking ability in the Japanese language department, we will examine the reading comprehension and instruction of "strategy" at low, middle and high levels. By conducting lessons based on these hypotheses, the types of logical thinking and the characteristics of developmental stages were clarified. One is logical thinking as a process of interpreting the logic contained in the content of the story. The other is the logic of linguistic expression, or logical thinking as a process of interpreting the narrator or author of a story

Inverse correlation between Skp2 and p27(Kip1) in normal endometrium and endometrial carcinoma

Copyright (c) 2010 Taylor & Francis. This is an electronic version of an article published in "GYNECOLOGICAL ENDOCRINOLOGY, Volume 26, Issue 3, pages 220-229 (2010)". GYNECOLOGICAL ENDOCRINOLOGY is available online at: https://doi.org/10.3109/09513590903215482Cyclin-dependent-kinase (cdk) inhibitor, p27<SUKip1</SU (p27), has been shown to participate in progestin-induced growth suppression of normal endometrial glands. To analyse the molecular mechanisms regulating p27 protein, we examined immunohistochemical expression of the SCF<SUSkp2</SU (Skp1-Cullin-F-box protein) complex factors, i.e. Skp1, Cul1 and Skp2, and compared them with that of p27, steroid receptors and Ki-67. In normal endometrial glands, the expression of Skp2 was observed in the proliferative phase, whereas that of p27 was observed in the secretory phase. Cultured normal endometrial glandular cells showed that progesterone induced the down-regulation of Skp2 along with up-regulation of p27. In endometrial carcinomas, the inverse topological correlation between Skp2 and p27 was evident in 39/66 (59%) cases, and the expression of Skp2 showed a strong correlation with Ki-67. These findings suggest that the expression of SCF<SUSkp2</SU complex changes during the menstrual cycle in normal endometrium and the SCF<SUSkp2</SU ubiquitin-proteasome pathway may also work in endometrial carcinomas.</.ArticleGYNECOLOGICAL ENDOCRINOLOGY. 26(3):220-229 (2010)journal articl

Complexity and Conservation of Thermospermine-Responsive uORFs of SAC51 Family Genes in Angiosperms

ACAULIS5 (ACL5) encodes thermospermine synthase in Arabidopsis and its loss-of-function mutant acl5 shows excess xylem differentiation and severe dwarfism. SAC51 encodes a basic helix-loop-helix (bHLH) protein and was identified from sac51-d, a dominant suppressor mutant of acl5, which restores the wild-type phenotype without thermospermine. The 5′ leader of the SAC51 mRNA contains multiple upstream open-reading frames (uORFs) and sac51-d has a premature stop codon in the fourth uORF. This uORF is conserved among SAC51 family genes in vascular plants. According to the GUS reporter assay, the SAC51 promoter was not responsive to thermospermine but the SAC51 5′ leader fused to the constitutive 35S promoter enhanced the GUS activity in response to thermospermine. Disruption experiments of each start codon of the SAC51 uORFs revealed that uORF4 and uORF6 whose start codon corresponds to the second methionine codon of uORF4 had an inhibitory effect on the main ORF translation while the other four uORFs rather had a stimulatory effect. The response of the 5′ leader to thermospermine was retained after disruption of each one of six start codons of these uORFs but abolished by mutating both uORF4 and uORF6 start codons, suggesting the importance of the C-terminal sequence shared by these uORFs in the action of thermospermine. We introduced GUS fusions with 5′ leaders of SAC51 family genes from other angiosperm species into Arabidopsis and found that all 5′ leaders responsive to thermospermine, so far examined, contained these two conserved, and overlapping uORFs

Prognosis factors in the treatment of bisphosphonate-related osteonecrosis of the jaw - Prognostic factors in the treatment of BRONJ -

Objectives: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a relatively rare but serious side effect of bisphosphonate (BP)-based treatments. This retrospective study aimed to investigate the risk factors and predictive markers in cases where patients were refractory to a recommended conservative treatment offered in our hospital. Patients and Methods: This single-center study collated the medical records of all patients treated for BRONJ between 2004 and 2011. A complete medical history, including detailed questionnaires, was collected for all patients, focusing on identifying underlying risk factors, clinical features, location and bone marker levels of BRONJ. Results: The mean BRONJ remission rate was 57.6%, and the median duration of remission was seven months. Eighteen patients (34.6%) had persistent or progressive disease with a recommended conservative treatment for BRONJ. Notably, urinary cross-linked N-terminal telopeptide of type 1 collagen (NTX) levels in those resistant to conservative treatment tended to be lower than in patients that healed well. Conclusions: We confirm that a significant proportion of BRONJ sufferers are refractory to a recommended conservative treatment and find that anticancer drugs, periodontal disease, the level of bone exposure and the dosage of intravenous BPs (e.g. zoledronate) represent specific risk factors in BRONJ that may determine the success of a recommended conservative treatment. Additionally, the NTX levels might be able to be a prognostic factor for the conservative treatment of BRONJ; additional research is necessary

Verification of Japanese language classes that foster logical thinking skills

In this study, based on the hypothesis that it is effective to develop logical thinking ability in the Japanese language department, we will examine the reading comprehension and instruction of "strategy" at low, middle and high levels. By conducting lessons based on these hypotheses, the types of logical thinking and the characteristics of developmental stages were clarified. One is logical thinking as a process of interpreting the logic contained in the content of the story. The other is the logic of linguistic expression, or logical thinking as a process of interpreting the narrator or author of a story

Immunohistochemical expression of keratan sulfate: a possible diagnostic marker for carcinomas of the female genital tract

Aims The authors previously reported the expression of keratan sulfate (KS), a glycosaminoglycan, in the epithelium of normal and neoplastic endometria. The aim of this study was to evaluate its potential use as a diagnostic marker, and the expression of KS was investigated in other human epithelial tissues. Methods Expression was examined immunohistochemically using 102 samples of normal epithelia and 110 samples of carcinomas from the female genital tract (FGT; cervix, endometrium, ovary, fallopian tube), digestive organs (gastrointestinal tract, pancreas, liver), urinary tract, lung, mammary gland, thyroid and mesothelium. Results In normal tissues, KS was consistently detected in the FGT and ectopic endometrium (25/26), but was not found in the digestive organs (1/42) and urinary tract (0/6), and was only partly detected in the lung (7/10), mammary gland (3/9) and thyroid (4/4). In malignant tissues, KS was consistently observed in carcinomas of the endometrium, ovary and fallopian tube (29/32), and was partly detected in carcinomas of the lung, mammary gland, thyroid, pancreas and mesothelium, but was absent in carcinomas of the gastrointestinal tract (0/17), liver (0/5) and urinary tract (0/11). Among carcinomas of the FGT, digestive organs and urinary tract, KS positivity suggested the possibility of FGT carcinomas, with 79.5% (31/39) sensitivity and 92.9% (39/42) specificity. Conclusions KS is a potentially useful marker for the supportive diagnosis of the primary site of metastatic carcinomas or unknown primary carcinomas, especially in the abdominal cavity.ArticleJOURNAL OF CLINICAL PATHOLOGY. 64(12):1058-1063 (2011)journal articl