Nobuya Sano

Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling.

Nucling is a novel apoptosis-associated molecule, which is involved with cytochrome c /Apaf-1/caspase-9 apoptosome induction following pro-apoptotic stress. In the present study, we show first that Nucling is able to interact with galectin-3. Galectin-3 is known to participate in many biological processes, including apoptotic cell death. Nucling was found to down-regulate the expression level of galectin-3 mRNA/protein. Nucling-deficient cells, in which galectin-3 expression is up-regulated, appeared to be resistant to some forms of pro-apoptotic stress as compared with wild-type cells. In addition, the preputial gland from Nucling-deficient mice expressed a significant level of galectin-3 and exhibited a high incidence of inflammatory lesions, indicating that Nucling plays a crucial role in the homoeostasis of this gland by interacting with the galectin-3 molecule and regulating the expression level of galectin-3. Up-regulation of galectin-3 was also observed in the heart, kidney, lung, testis and ovary of the Nucling-deficient mice. In order to confirm the functional interaction between Nucling and galectin-3, a well-documented candidate for the mediator of galectin-3 expression, NF-kappaB (nuclear factor kappaB), was investigated as well. Nucling was shown to interfere with NF-kappaB activation via the nuclear translocation process of NF-kappaB/p65, thus inhibiting the expression of galectin-3. Taken together, we propose that Nucling mediates apoptosis by interacting and inhibiting expression of galectin-3.

Problems in histological grading of malignancy and its clinical significance in patients with operable Breast Cancer

Although the histological grading of malignancy in patients with operable breast cancer, typically consisting of three factors: tubular formation, mitotic counts, and nuclear atypia, plays an important role in identifying patients at high risk of recurrence, the most effective combination of factors is still not completely clear. In assessing prognosis, the problems of clinical application of the grade of malignancy are not only related to the assemblage of the factors employed, but also to the heterogeneity within the tumor and interobserver variations. In a review of the correlation between the histological grading system for malignancy in operable breast cancer patients and the recurrence rate, only the grade of nuclear atypia statistically correlated with the rate of recurrence. Furthermore, a grading system consisting of mitotic counts and nuclear atypia was more significantly correlated to the risk of recurrence than was the system based on the three factors described above. Concerning the heterogeneity of histologic features within the primary tumor, a system based on the grade of mitotic counts or nuclear atypia showed a high degree of heterogeneity, but a system based on the grade of tubular formation showed low heterogeneity and bimodal distribution.

Potential pathophysiological role of d-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain

Abstractd-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of d-amino acids. Among the possible substrates of DAO in vivo, d-serine is proposed to be a neuromodulator of the N-methyl-d-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant d-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate d-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia.

Cathepsin G: the significance in rheumatoid arthritis as a monocyte chemoattractant.

Human cathepsin G (EC 3.4.21.20) has been reported to have the in vitro chemotactic activity for human monocytes. In this study, we examined the role of cathepsin G in monocyte involvement in joint inflammation of rheumatoid arthritis (RA) as a monocyte chemoattractant. Eighteen patients with RA and four patients with osteoarthritis (OA) were used in this study. Thiobenzylester substrate, Succ-Phe-Leu-Phe-S-Bzl, was used to measure the activity of cathepsin G in synovial fluids. Monocyte migration induced by cathepsin G and synovial fluids was assessed by a 48-well microchemotaxis chamber technique. Immunohistochemical staining was performed to determine the cellular origin of cathepsin G in RA synovial tissue. A very low activity of cathepsin G was detected in synovial fluids from patients with OA. On the other hand, significantly increased activity of cathepsin G was detected in patients with RA when compared with the value of OA patients. A considerable monocyte chemotactic activity was detected in the synovial fluid of RA patients, and the activity was partially decreased by the treatment with inhibitors for cathepsin G, α1-antichymotrypsin and phenylmethylsulfonyl fluoride. The activity of cathepsin G was significantly correlated with the neutrophil counts in synovial fluids and the concentration of interleukin-6. Immunohistochemical studies showed that cathepsin G was strongly expressed by synovial lining cells, and weakly expressed by macrophages and neutrophils in synovial tissues. This study indicates that the monocyte chemotactic activity of cathepsin G may have a role in the pathogenesis of RA synovial inflammation.

Gastric inverted hyperplastic polyp. Report of four cases and relation to gastritis cystica profunda

Gastric inverted hyperplastic polyp (IHP) is a rare type of gastric polyp, and is characterized by downward growth of the hyperplastic mucosal components into the submucosa. To the best of our knowledge, 16 gastric IHP cases have been described in the English literature, but the pathogenesis has not been established. We report the clinical and pathological findings of four gastric IHP cases. The lesions were mainly composed of hyperplastic foveolar‐type glands with focal cystic dilatation. Pyloric type glands, endocrine cells, acinic cell metaplasia, and smooth muscle bundles were also seen as components of the polyp. Two cases (cases 1 and 4) coexisted with multifocal gastritis cystica profunda (GCP) and gastric adenocarcinoma. Case 4 furthermore exhibited an intermediate form between IHP and GCP. We suggest that IHP may be GCP associated with exaggeratedly hyperplastic and metaplastic changes. In case 4, the coexisting gastric carcinoma was mainly located in the submucosa, whilst the mucosal component was minimal. Five out of twenty reported gastric IHP cases, including our cases, coexisted with gastric adenocarcinoma. These facts would lead us to further investigate the relation between gastric IHP and carcinoma.

cDNA microarray analysis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma

Intrarenal pheochromocytoma (paraganglioma) is a very rare tumour. Its diagnosis is often difficult to establish because of its rarity and its histological similarity to renal cell carcinoma (RCC). Recently, we examined the molecular signatures of different subtypes of kidney tumours by using cDNA microarray. The signature pattern for one tumour, which was originally diagnosed as granular cell RCC, was clearly distinct from that of any other subtype of kidney tumour, and led us to re-evaluate the case. Haematoxylin and eosin staining revealed histological features suggestive of pheochromocytoma, and immunohistochemical studies showed positive staining for neuroendocrine markers but not for keratin. A germline missense mutation, D119E, in the familial paraganglioma related gene succinate dehydrogenase subunit D (SDHD), was subsequently identified. The treatment modality was revised and radiotherapy was given, to which the patient responded, leading to a reduction in tumour size of 25% within the first month. To our knowledge, this is the first report of an intrarenal pheochromocytoma that was diagnosed with the assistance of cDNA microarray analysis.

Influence of large intrahepatic blood vessels on the gross and histological characteristics of lesions produced by radiofrequency ablation in a pig liver model

Abstract: Aims: To determine whether the presence of large intrahepatic blood vessels (≥3 mm) affect radiofrequency (RF)‐induced coagulation necrosis, the gross and histological characteristics of RF‐ablated areas proximal to or around vessels were examined in normal pig livers.

Non-carcinogenicity of capsaicinoids in B6C3F1 mice

The carcinogenicity of a mixture of capsaicinoids (64.5% capsaicin and 32.6% dihydrocapsaicin) was examined in B6C3F1 mice. In a 13-week toxicity study, renal toxicity was observed in 1% capsaicinoid-treated males. Next, groups of 50 mice of each sex were given 0, 0.025, 0.083 or 0.25% capsaicinoids in powdered diet for 79 weeks and killed in week 83. Food intake was reduced in mice of all capsaicinoid-treated groups, especially females, because of the pungency of capsaicinoids, and inhibition of body weight gain was apparent in females. The numbers of tumour-bearing females in the high-dose groups were significantly lower than that in the controls, and the incidences of hepatocellular neoplasms in both sexes were negatively correlated with the dose of capsaicinoids (Cochran-Armitage trend test). Renal cell adenomas developed in one mouse each of 0.025 and 0.25% capsaicinoid-treated males. The incidences of other tumours were similar in the treated and control groups. Thus, the present study indicated that a mixture of capsaicinoids is not carcinogenic in B6C3F1 mice.

Familial hyperparathyroidism associated with jaw fibroma: case report and literature review

A 53‐year‐old female suliering from renal stones and hypercalcaemia was diagnosed as having primary hyperparathyroidism caused by hyperplasia of the parathyroid glands. She underwent total parathyroidectomy and implantation of parathyroid tissue. After one year, she underwent surgery for a jaw tumour. The pathological findings indicated it to be a cementifying fibroma. Jackson et al. (1990) reported the familial association of hyperparathyroidism with Jaw tumours, and they suggested that this condition represents a new clinical syndrome. We believe that our case belongs to this syndrome.

So-called mesothelial/monocytic incidental cardiac excrescences obtained during valve replacement surgery: report of three cases and literature review.

Abstract We present three cases of so-called mesothelial/monocytic incidental cardiac excrescences (MICE) of the heart and a brief review of related literature. Case 1 was a 51-year-old woman who underwent mitral- and aortic-valve replacement. A tissue sample was submitted as a thrombus attached to the left atrial endocardium. Case 2 was a 69-year-old woman who underwent mitral-valve replacement. The sample was incidentally obtained as whitish clot-like fragments, but its exact origin was not known. Case 3 was a 68-year-old woman who underwent mitral-valve replacement for suspected infective endocarditis. The sample adherent to the pericardium was removed after valvular surgery. Histologically, these lesions were composed of a mixture of plump histiocytoid cells, a papillary arrangement of cuboidal cells, various sized vacuoles, and fibrin. The nests of cuboidal cells resembled cancer cells but showed features of mesothelial cells and no proliferative activity, immunohistochemically or ultrastructurally. In all cases, a suction tube placed in the left atrium was occasionally used to remove overflowing intrapericardial fluid during the surgery. The tip of the suction tube was covered with spiral wire, which is likely to transfer the stripped pericardial mesothelial cells to the left atrium. The significance of MICE is their possibility of being misdiagnosed as metastatic carcinoma by pathologists and a risk of arterial embolization by mesothelial debris clinically.