Isamu Kodani

Expression of Minichromosome Maintenance 2 (MCM2), Ki-67, and Cell-Cycle-Related Molecules, and Apoptosis in the Normal-Dysplasia-Carcinoma Sequence of the Oral Mucosa

Objective: We examined cell cycle and cell death biomarker trends with the normal-dysplasia-carcinoma sequence of the oral epithelia analyzing the pathological significance of a new biomarker, minichromosome maintenance 2 (MCM2). Methods: This study analyzed 12 patients with normal oral epithelia, 69 with dysplasia, and 35 with squamous cell carcinoma (SCC); in 13 patients, SCCs were preceded by dysplasia. The sections were immunostained for MCM2, Ki-67, P53, P27Kip1 and P21CIP1/WAF1, and conducted by TUNEL methods. Western blot analysis of MCM2 was performed in the 4 human cultured oral SCCs, all of which showed the expression. Results: Significantly higher labeling indices (LI; %) of MCM2, Ki-67, and P53, as well as lower LI of TUNEL indices (TI; %), P27, and P21 were noted in the SCCs than in the dysplasias. The 13 dysplasias developed SCC with significantly higher LI of MCM2 and P53, and lower LI of P21 than the other dysplasias (each p < 0.05). The LI of MCM2, P21 and the TI were not correlated with P53 expression. Conclusions: Oral dysplasia was characterized by lower cell proliferation and a higher frequency of cell death compared to SCCs. The higher LI of MCM2 and P53 and the lower LI of P21 might predict malignant transformation of oral dysplasia. MCM2 is regulated via a P53-independent pathway, and a useful biomarker of proliferating cells.

Effects of oral consumption of the green tea polyphenol EGCG in a murine model for human Sjogren's syndrome, an autoimmune disease.

SIGNIFICANCE Protection of glandular cells from autoimmune-induced damage would be of significant clinical benefit to Sjogrens syndrome (SS) patients. Epigallocatechin-3-gallate (EGCG) possesses anti-apoptotic, anti-inflammatory, and autoantigen-inhibitory properties. AIMS To investigate if EGCG protects against certain autoimmune-induced pathological changes in the salivary glands of the non-obese diabetic (NOD) mouse model for SS. MAIN METHODS Animals were provided with either water or water containing 0.2% EGCG. At the age of 8, 16 and 22 weeks, submandibular salivary gland tissue and serum samples were collected for pathological and serological analysis. KEY FINDINGS Significant lymphocyte infiltration was observed in the salivary glands of the water-fed group at the age of 16 weeks, while the EGCG group showed reduced lymphocyte infiltration. By 22 weeks of age, water-fed animals demonstrated elevated levels of apoptotic activity within the lymphocytic infiltrates, and high levels of serum total anti-nuclear antibody, compared to EGCG-fed animals. Remarkably, proliferating cell nuclear antigen (PCNA) and Ki-67 levels in the salivary glands of water-fed NOD mice were significantly elevated in comparison to BALB/c control mice; in contrast, PCNA and Ki-67 levels in EGCG-fed NOD animals were similar to BALB/c mice. These results indicate that EGCG protects the NOD mouse submandibular glands from autoimmune-induced inflammation, and reduces serum autoantibody levels. Abnormal proliferation, rather than apoptosis, appears to be a characteristic of the NOD mouse gland that is normalized by EGCG. The evidence suggests that EGCG could be useful in delaying or managing SS-like autoimmune disorders.

Expression of Fas and Fas ligand in human gastric adenomas and intestinal-type carcinomas: correlation with proliferation and apoptosis

Background. Fas (APO-1/CD95), a member of the tumor necrosis factor/nerve growth factor receptor superfamily, mediates apoptosis in response to agonistic antibodies or Fas ligand (FasL) binding. Previous reports indicated an upregulation of FasL in gastric carcinomas to evade host immune attack. Fas/FasL expression, however, has not been analyzed in terms of apoptosis and proliferation in gastric adenoma and carcinoma. Methods. This study was conducted on seven human gastric carcinoma cell lines, 47 gastric adenomas, and 75 intestinal-type adenocarcinomas (48 early and 27 advanced carcinomas). Fas/FasL expression was examined by immunohistochemistry, apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method, and Fas gene mutation by a reverse transcriptase (RT) polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing method. Results. Fas and FasL expressions were noted in 18 (38.3%) and 17 (36.2%) adenomas, in 21 (43.8%) and 33 (68.8%) early carcinomas, and in 10 (37.0%) and 19 (70.4%) advanced carcinomas, respectively. The frequency of FasL expression was significantly higher in advanced carcinomas than in the early carcinomas and adenomas; in contrast, there was no significant difference in Fas expression among the three groups. The mean apoptotic index (AI) was 4.96 ± 0.51 in the adenomas, 2.96 ± 0.23 in the early carcinomas, and 1.67 ± 0.17 in the advanced carcinomas. A significantly higher AI was noted in the lesions with Fas expression than in those without Fas expression in all three groups. No missense mutations of the Fas gene were detected in any of the gastric carcinoma cell lines, or in the gastric adenomas or carcinomas. Conclusions. Upregulation of FasL may correlate with the progression of gastric carcinoma. Apoptosis in gastric adenoma and carcinoma cells may occur via Fas-dependent and -independent pathways, but further clarification is needed.

Intraosseous Schwannoma of the Mandible

Abstract This report is of a patient with intraosseous Schwannoma of the mandible, which is extremely rare and must be cautiously diagnosed. A 45-year-old woman had a radiolucent figure at the right ramus of the mandible. The enucleated tumour consisted of spindle-shaped cells with palisading and collagenous fibres, and demonstrated a clear borderline and encapsulation by a coat. Schwannoma was discriminated from neurofibroma, leiomyoma, and fibroma using Elastica van Gieson stain, Massons trichrome stain, and the immunostains anti-S 100 protein antibody, anti-glial fibrillary acidic protein antibody, anti-α-SMA antibody, and anti-desmine antibody.

PITX1 is a reliable biomarker for predicting prognosis in patients with oral epithelial dysplasia

Paired-like homeodomain 1 (PITX1) genes are essential in human development. In the present study, PITX1 protein expression was evaluated in human normal oral mucosa, oral epithelial dysplasia and oral squamous cell carcinoma (OSCC), with the aim of examining the expression patterns of these critical genes during the multi-stage transformation of oral epithelial dysplasia to OSCC. PITX1 and Ki-67 expression were assessed by immunohistochemistry in 26 individuals with normal oral mucosa, 106 patients with oral epithelial dysplasia and 97 OSCC patients. The labeling indices (LIs) of PITX1 and Ki-67 were calculated and their correlation with the incidence of malignancy was evaluated. The PITX1 LI of the dysplasia specimens was significantly lower than that of the normal oral mucosa samples, but significantly higher than that of the OSCC samples. The oral epithelial dysplasia patients that exhibited low PITX1 expression showed a significantly higher incidence of malignant transformation than those exhibiting high PITX1 expression, regardless of the histological grades of their oral epithelial dysplasias. On the other hand, no correlation was observed between the Ki-67 LI and the incidence of malignancy. These results suggested that PITX1 suppression is associated with malignant transformation in the oral epithelium and that PITX1 expression may serve as a novel biomarker for predicting prognosis in oral epithelial dysplasia.

A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism.

Clinico-immunohistochemical Study of Oral Verruciform Xanthomas

Abstract Objective: To elucidate the immunohistochemical characteristics of oral verruciform xanthomas and the aetiology of foam cells. Patients and Methods: Oral verruciform xanthomas surgically extirpated from 5 patients were examined using immunohistochemistry. Results: The verruciform xanthomas revealed an accumulation of foam cells with clear cytoplasm in the connective tissue around the elongated epithelial rete pegs. The foam cells were intensely positive for CD-68, lysozyme, and vimentin, and were weakly positive for α-1-antitrypsin, but were negative for total keratin and S-100 protein. A small number of dendritic cells were found among the foam cells and were positive for S-100 protein. Conclusions: The findings suggest that the foam cells in oral verruciform xanthomas are of monocytemacrophage lineage and are associated with a local inflammatory immune mechanism similar to verruciform xanthomas of other organs.