Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function.

Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extracellular domain of TREM2. However, the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in TREM2 on disease progression remain unknown. In this study, we identified several high-risk nsSNPs in the TREM2 gene using various deleterious SNP predicting algorithms and analyzed their destabilizing effects on the ligand recognizing region of the TREM2 immunoglobulin (Ig) domain by molecular dynamics (MD) simulation. Cumulative prediction by all tools employed suggested the three most deleterious nsSNPs involved in loss of TREM2 function are rs549402254 (W50S), rs749358844 (R52C), and rs1409131974 (D104G). MD simulation showed that these three variants cause substantial structural alterations and conformational remodeling of the apical loops of the TREM2 Ig domain, which is responsible for ligand recognition. Detailed analysis revealed that these variants substantially increased distances between apical loops and induced conformation remodeling by changing inter-loop nonbonded contacts. Moreover, all nsSNPs changed the electrostatic potentials near the putative ligand-interacting region (PLIR), which suggested they might reduce specificity or loss of binding affinity for TREM2 ligands. Overall, this study identifies three potential high-risk nsSNPs in the TREM2 gene. We propose further studies on the molecular mechanisms responsible for loss of TREM2 function and the associations between TREM2 nsSNPs and neurodegenerative diseases.

Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1.

Disruptive neuronal migration during early brain development causes severe brain malformation. Characterized by mislocalization of cortical neurons, this condition is a result of the loss of function of migration regulating genes. One known neuronal migration disorder is lissencephaly (LIS), which is caused by deletions or mutations of the LIS1 (PAFAH1B1) gene that has been implicated in regulating the microtubule motor protein cytoplasmic dynein. Although this class of diseases has recently received considerable attention, the roles of non-synonymous polymorphisms (nsSNPs) in LIS1 on lissencephaly progression remain elusive. Therefore, the present study employed combined bioinformatics and molecular modeling approach to identify potential damaging nsSNPs in the LIS1 gene and provide atomic insight into their roles in LIS1 loss of function. Using this approach, we identified three high-risk nsSNPs, including rs121434486 (F31S), rs587784254 (W55R), and rs757993270 (W55L) in the LIS1 gene, which are located on the N-terminal domain of LIS1. Molecular dynamics simulation highlighted that all variants decreased helical conformation, increased the intermonomeric distance, and thus disrupted intermonomeric contacts in the LIS1 dimer. Furthermore, the presence of variants also caused a loss of positive electrostatic potential and reduced dimer binding potential. Since self-dimerization is an essential aspect of LIS1 to recruit interacting partners, thus these variants are associated with the loss of LIS1 functions. As a corollary, these findings may further provide critical insights on the roles of LIS1 variants in brain malformation.

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function.

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein-protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein-protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders.

Increased number of arginase 1-positive cells in the stroma of carcinomas compared to precursor lesions and nonneoplastic tissues.

Arginase 1 (Arg1) is involved in dampening the response of antitumor T lymphocytes. Arg1 expression has been reported in a variety of cancer cell lines and tumor-associated myeloid-derived cells. However, its examination in situ in tumor microenvironment is poorly investigated. We examined the Arg1-positive cells in tumor microenvironment of gastric carcinomas (GCs), colorectal carcinomas (CRCs) and prostate carcinomas (PCs), and analyzed their clinicopathological significance. Immunohistochemical staining for Arg1 was done in 60 GCs, 38 gastric adenomas, 40 CRCs, 10 colonic adenomas, 36 PCs, and 15 benign prostatic hyperplasia (BPH). Arg1 expression was predominantly localized in tumor microenvironment and the stroma of nonneoplastic tissues. Cells with Arg1 expression were mostly leukocytes, morphologically resembling polymorphonuclear neutrophils, and showed CD15 expression. Arg1 expression was focally expressed in cancer cells of 6 PCs, but not in those of GCs and CRCs. Arg1-positive cells were significantly more infiltrated in tumors than adenomas and nonneoplastic tissues, such as BPH, intestinal metaplasia and adjacent tissues. There were no significant findings between them and clinicopathological parameters, except for the relationship to gender and tumor differentiation in CRCs. These findings suggest that Arg1-positive cells in tumor microenvironment is involved in the occurrence of GCs, CRCs, and PCs. More expansive studies are necessary to better elucidate their clinicopathological significance in carcinomas.

The prevention of TNF-α/IFN-γ mixture-induced inflammation in human keratinocyte and atopic dermatitis-like skin lesions in Nc/Nga mice by mineral-balanced deep sea water.

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by environmental and chemical allergens. Despite the complexity of its pathogenesis, many investigations have shown that substances having anti-inflammatory activities alleviated the pathology of AD. Here, we evaluated the effects of mineral-balanced deep sea water (DSW) on AD-like skin damage in both in vitro and in vivo. The results showed that mineral-balanced DSW regressed inflammatory chemokines, such as macrophage-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC) and regulated on activation, normal T-cell expressed and secreted (RANTES), and cytokines, interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression in HaCaT immortal human keratinocyte treated with tumor necrosis factor (TNF)-α/ interferon (IFN)-γ mixture. Furthermore, increased cyclooxygenase (COX)-2 protein expressions were also reversed, filaggrin gene expression was enhanced and decreased involucrin transcriptions was recovered by mineral-balanced DSW in TNF-α/IFN-γ mixture-treated HaCaT human keratinocyte. Moreover, we revealed that the inhibitory effects of mineral-balanced DSW were mediated with the suppression of signal transducer and activator of transcription (STAT) 1 phosphorylation. In animal experiments, we showed that hardness 2000 of mineral-balanced DSW decreased the serum levels of IgE, IL-4, and histamine, and alleviated the severity score and numbers of scratching in dinitrochlorobezene (DNCB)-treated Nc/Nga mice. Furthermore, increased epidermal thickness and mast cell infiltration by DNCB treatment were reversed by the application of hardness 2000 mineral-balanced DSW. Taken together, the present investigation indicates that mineral-balanced DSW is a potent substance with anti-atopic dermatitis activity.

O-GlcNAcylation is associated with the development and progression of gastric carcinoma.

INTRODUCTION: O-GlcNAcylation occurs via an O-linked ß-N-acetylglucosamine (O-GlcNAc) moiety linked to the side chain hydroxyl of a serine or threonine residue on nucleocytoplasmic proteins. This reaction, which is catalyzed by O-GlcNAc-transferase (OGT), is involved in a variety of human cancers; however, its clinical significance in gastric carcinomas (GC) has been poorly investigated in vivo. MATERIALS AND METHODS: Immunohistochemical staining for O-GlcNAcylation and OGT was performed in 64 primary GCs, 40 gastric adenomas and nonneoplastic tissues adjacent to GCs, including 31 tissues of intestinal metaplasia and 24 normal gastric tissues. Their expressions were also studied in 20 tissues of chronic gastritis according to Helicobacter pylori (H. pylori) infection. RESULTS: O-GlcNAcylation was expressed in the nucleus and both the nuclear rim and cytoplasm. OGT was strongly expressed in the nucleus and weakly expressed in the cytoplasm. O-GlcNAcylation expression levels were significantly correlated with those of OGT. Their expression levels were progressively increased during the carcinogenesis of GC. O-GlcNAcylation expression was higher in GC with intestinal type, higher pT stage and nodal metastasis, while OGT expression was higher in GC with nodal metastasis. Nuclear O-GlcNAcylation expression was more frequently observed in tumors including GC and adenoma than in nonneoplastic tissues including intestinal metaplasia and normal tissue. Nuclear O-GlcNAcylation expression in GC was closely associated with large size, moderate and poor differentiation, higher pT stage, nodal metastasis and higher clinical stage. In addition, the expression of O-GlcNAcylation and OGT was more elevated in H. pylori-infected chronic gastritis than in chronic gastritis without H. pylori infection. CONCLUSIONS: O-GlcNAcylation expression and its nuclear expression were associated with the carcinogenesis and progression of GC.

Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis.

Differential membranous E-cadherin expression, cell proliferation and O-GlcNAcylation between primary and metastatic nodal lesion in colorectal cancer.

INTRODUCTION: O-GlcNAcylation is an O-linked ß-N-acetylglucosamine (O-GlcNAc) moiety linked to the side chain hydroxyl of a serine or threonine residue. The E-cadherin/ß-catenin system, an integral component of epithelial to mesenchymal transition (EMT)/mesenchymal to epithelial transition (MET), is affected through O-GlcNAcylation. The current study examined the status of EMT/MET in both the tumor center and invasive front of the primary colorectal carcinoma (CRC) and metastatic nodal lesions, which were compared to O-GlcNAcylation expression levels in those areas. In addition, the cliniopathological significance of O-GlcNAcylation was studied MATERIAL AND METHODS: Immunohistochemical staining for E-cadherin, ß-catenin, Snail, O-GlcNAc and Ki67 was performed in 40 primary CRC tissues, 40 nonneoplastic colons, and 17 nodal metastatic lesions. Western blot was also conducted in primary CRC tissue RESULTS: Membranous E-cadherin expression was lowest in the invasive front, but showed greater increases in metastatic nodal lesions. Moreover, its expression level was negatively correlated with that of nuclear ß-catenin and Snail. The Ki67 labeling index (LI) was lowest in the invasive front, and increased in metastatic nodal lesions. Primary CRC showed higher expression of O-GlcNAcylation and O-GlcNAc-transferase (OGT) than nonneoplastic colons. O-GlcNAcylation expression decreased in metastatic nodal lesions compared to the invasive front and tumor center, and was inversely correlated with Ki67 LI. However, O-GlcNAcylation expression was only slightly changed between tumor center and invasive front. In addition, there was no correlation between its expression and the level of nuclear ß-catenin, membranous E-cadherin and Snail. No significant relationship was observed between O-GlcNAcylation level and cliniopathological parameters. CONCLUSIONS: Differential membranous E-cadherin expression, cell proliferation and O-GlcNAcylation in metastatic nodal lesion compared to primary CRC may play role in establishing its lesions; however, these findings are not sufficient to show the role of O-GlcNAcylation in the EMT/MET of CRC.

A Case of Rapidly Growing Extraocular Sebaceous Carcinoma.

Sebaceous carcinoma is a rare malignant tumor differentiated from the adnexal epithelium of sebaceous glands and forms less than 1% of all cutaneous malignancies. We present a case of a 93-year-old woman with a rapidly growing mass on the right cheek. Initial histiopathologic finding was basal cell carcinoma. The mass was widely excised and superficial parotidectomy was performed while preserving the facial nerve branches. The resulting defect was covered with a transposition flap from the ipsilateral posterior auricular area and the donor site was closed primarily. However, histopathologic examination of the excised mass showed a poorly differentiated sebaceous carcinoma with a clear resection margin. The diagnosis of sebaceous carcinoma can be difficult to make at initial presentation. This report describes a rare case of a rapidly growing extraocular sebaceous carcinoma, which resulted in a good treatment outcome, and provides a review of relevant literature.

Progressive Increase of Regulatory T Cells and Decrease of CD8+ T Cells and CD8+ T Cells/Regulatory T Cells Ratio during Colorectal Cancer Development.

BACKGROUND: We examined the distribution of CD8+ T cells and regulatory T cells (Tregs), measured the CD8+ T cell/Tregs ratio, investigated the relationship between Tregs and cyclooxygenase-2 (COX-2) expression during colorectal cancer (CRC) development. METHODS: We performed immunohistochemical staining for CD8, forkhead box P3, E-cadherin, and COX-2 in 32 cases of invasive CRC, 10 cases of intramucosal CRC, 27 cases of high-grade tubular adenoma, 22 cases of low-grade tubular adenoma, and 32 cases of non-neoplastic conditions. RESULTS: We observed a progressive increase in Tregs, and a decrease in CD8+ T cells and the CD8+ T cells/Tregs ratio during CRC development. The alterations were most severe in high-grade tubular adenoma and CRC. COX-2 expression was positively associated with Tregs infiltration. The degree of T cell infiltration differed among tumor compartment and the ratio in the tumor center was the lowest of all areas. The ratio and number of CD8+ T cells in the tumor center and the invasive front of invasive CRC were associated with gender, differentiation, node metastasis and tumor budding. CONCLUSIONS: Alteration in the distribution of both CD8+T cells and Tregs may contribute to the generation of an immune environment suitable for the development and progression of CRC.

The Expression of CD10 and CD15 Is Progressively Increased during Colorectal Cancer Development.

BACKGROUND: The aim of this study was to examine the expression of CD10 and CD15 in tumor cells, stromal cells and infiltrating inflammatory cells during colorectal carcinoma (CRC) development and to investigate their expression levels between the tumor center and invasive front and compare them to clinicopathological parameters in invasive CRC. METHODS: We performed immunohistochemical staining for CD10, CD15, and E-cadherin in 42 cases of CRC, 49 of tubular adenoma, 15 of hyperplastic polyp, and 17 of non-neoplastic colon. RESULTS: CD10 was expressed in tumor cells (tCD10), stromal cells (sCD10) and infiltrating inflammatory cells (iCD10), and CD15 was expressed in tumor cells (tCD15) and infiltrating inflammatory cells (iCD15). Their expressions were progressively increased during CRC development and the iCD10 expression level was significantly correlated with the iCD15 expression level in invasive CRC. Invasive front revealed a higher expression level of iCD10 and iCD15 than the tumor center. Moreover, the iCD15 expression level of invasive front was significantly correlated with the degree of tumor budding and tCD15 in whole tissue sections was closely associated with tumor depth. CONCLUSIONS: The present study suggests that the expression of CD10 and CD15 is associated with the development and progression of CRC.

The expression of pigment epithelium-derived factor in bladder transitional cell carcinoma.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). METHODS: We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD). RESULTS: The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. CONCLUSIONS: The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression.

Prostaglandin E(2) and interleukin-1ß reduce E-cadherin expression by enhancing snail expression in gastric cancer cells.

Inflammation is closely related to the progression of cancer as well as tumorigenesis. Here, we investigated the effect of prostaglandin E(2) (PGE(2)) and interleukin-1ß (IL-1ß) on E-cadherin expression in SNU719 gastric cancer cells. E-cadherin expression decreased as the dose or exposure time of PGE(2) and IL-1ß increased, whereas Snail expression increased with dose or time of PGE(2) and IL-1ß. E-cadherin expression reduced by PGE(2) treatment increased after the transfection of Snail siRNA. Neutralization of IL-1ß using anti-IL-1ß antibody blocked the expression pattern of E-cadherin and Snail occurred by IL-1ß treatment. However, there was no synergic effect of IL-1ß and PGE(2) on the expression pattern of E-cadherin and Snail. In conclusion, inflammatory mediators reduced E-cadherin expression by enhancing Snail expression in gastric cancer cells. Inflammation-induced transcriptional regulation of E-cadherin in gastric cancer has implications for targeted chemoprevention and therapy.

A Case Report of Sweet's Syndrome with Parotitis.

Sweet's syndrome is characterized by clinical symptoms, physical features, and pathologic findings which include fever, neutrophilia, tender erythematous skin lesions, and a diffuse infiltrate of mature neutrophils. This is a report of our experience of Sweet's syndrome with parotitis. A 57-year-old man initially presented with tender swelling on the right cheek similar to parotitis. His symptoms relapsed despite the use of an oral antibiotic agent for 3 weeks. He additionally presented with erythematous papules and plaques on the periocular area and dorsum of both hands. Histiopathologic findings on punch biopsy of the right dorsum of the hand showed superficial perivenular histiocytic infiltration without vasculitis. We confirmed this as histiocytoid Sweet's syndrome and used systemic corticosteroid. After initiation of treatment with systemic corticosteroids, there was a prompt recovery from both the dermatosis-releated symptoms and skin lesions. Sweet's syndrome should be considered in patients with therapy-refractory parotitis and unclear infiltrated nodules. We present a confusing case who initially appeared to have parotitis but turned out to have histiocytoid Sweet's syndrome.

Epithelial to mesenchymal transition in cutaneous squamous cell carcinoma is correlated with COX-2 expression but not with the presence of stromal macrophages or CD10-expressing cells.

Epithelial to mesenchymal transition (EMT) is an intricate process by which epithelial cells loose epithelial characteristics and acquire a mesenchymal-like phenotype. EMT and cyclooxygenase 2 (COX-2) expression are related to tumor invasion and metastasis. The tumor microenvironment plays a major role in tumor progression and the induction of EMT. Here, we investigated the relationship between EMT and COX-2 expression as well as tumor-associated macrophages (TAM) and CD10-positive stromal cells during the development of cutaneous squamous neoplastic lesion. We performed immunohistochemical staining for vimentin, E-cadherin, ß-catenin, COX-2, CD68, and CD10 in 41 cases of squamous cell cancers (SCC), 20 of Bowen's disease, 30 of actinic keratosis, and 30 samples of normal skin. SCC cells showed significantly increased vimentin expression and reduced expression of membranous E-cadherin and ß-catenin compared with cells in precursor lesions and in normal skin. COX-2 expression was also markedly increased in SCC cells. E-cadherin expression was positively correlated with ß-catenin expression and inversely correlated with COX-2 expression in SCC cells. The number of TAM and CD10-positive stromal cells increased from the normal skin to precursor lesions and SCC cells. The number of TAM and of CD10-positive stromal cells did not correlate with the expression of E-cadherin, ß-catenin, COX-2, and vimentin in SCC cells. We suggest that cutaneous SCC cells show EMT, which appears to be correlated with COX-2 expression but not with stromal CD10 expression and TAM.

CD10 Is Again Expressed at a Certain Stage during the Neoplastic Process of Bladder Transitional Cell Carcinomas.

PURPOSE: CD10, a membrane-bound zinc-dependent metallopeptidase, is normally expressed in many tissues. Accordingly, the derangement of CD10 expression may be related to development or progression in a variety of tumors. The aim of this study is to examine any association between CD10 expression and clinicopathological parameters in bladder transitional cell carcinomas (TCCs) and the relationship between expression of E-cadherin and CD10. MATERIALS AND METHODS: Immunohistochemical staining was performed for CD10 and E-cadherin in tissues of 94 TCCs and 10 non-neoplastic bladder mucosa. RESULTS: Positive immunoreactivity for CD10 was observed in non-neoplastic urothelium at a proportion of 80% and TCCs were observed at a rate of 23%. A positive rate of CD10 expression was observed in 10% of total cases of a low grade tumor and in 35% of those of a high grade tumor. It was also observed in 15% of pTa tumors, 13% of pT1 tumors, and 48% of pT2 tumors. In addition, CD10 expression showed reciprocal correlation with expression of membranous E-cadherin in tumors. CONCLUSION: CD10 is again expressed at a certain stage during the neoplastic process of TCCs and could play some roles intheir carcinogenesis.

Reciprocal correlation between the expression of cyclooxygenase-2 and E-cadherin in human bladder transitional cell carcinomas.

Carcinoma cells become more motile and invasive via downmodulation of E-cadherin. Cyclooxygenase-2 (COX-2) expression is associated with tumor invasion and metastasis. The aim of this study is to investigate the relationship between the expression of COX-2 and E-cadherin in a bladder cancer cell line and human bladder transitional cell carcinoma (TCCs). Phorbol 12-myristate 13-acetate (PMA) treatment for 5637 bladder cancer cells increased COX-2 expression, slightly induced Slug expression, and decreased E-cadherin expression. Ectopic expression of COX-2 or prostaglandin E(2) (PGE(2)) treatment for 5637 cells reduced E-cadherin expression. This finding was confirmed by the result that knockdown of COX-2 expression or indomethacin administration increased the expression of E-cadherin. When compared with cells' motility in serum-free medium, the treatment of PMA and PGE(2) increased cell motility, and indomethacin treatment slightly decreased cell motility. In the tissues of bladder TCCs, COX-2 expression was inversely correlated with membranous E-cadherin expression and positively correlated with nuclear beta-catenin expression. The expression of COX-2 and nuclear beta-catenin expression was significantly higher in TCCs of high grade and invasive growth than in TCCs of low grade and noninvasive growth. In contrast, membranous E-cadherin expression was more decreased in tumors of high grade and invasive growth. In addition, nuclear beta-catenin expression was significantly related to tumor recurrence. We suggest that COX-2 pathway reduces membranous E-cadherin expression in bladder TCCs and their expression pattern may provide important information in predicting the clinical behavior of bladder TCCs.

The number of Foxp3-positive regulatory T cells is increased in Helicobacter pylori gastritis and gastric cancer.

Helicobacter pylori (H. pylori) colonization induces vigorous innate and specific immune responses; however, the infection is not removed, a state of chronic active gastritis persists for life if untreated. Recent studies have shown that CD4(+) CD25(+) Foxp3-positive regulatory T cells (Tregs) suppress the immune response to H. pylori. Persistent H. pylori-associated gastritis is closely associated with gastric carcinogenesis. We investigated the number of Tregs in the context of H. pylori colonization in chronic gastritis, examined the relationship between it and histopathological findings and compared it with that of gastric dysplasia and adenocarcinoma. This study was based on the analysis of gastric biopsy specimens from 126 cases of H. pylori-associated gastritis, 16 cases of H. pylori-negative gastritis, 17 cases of gastric dysplasia, and 25 cases of gastric adenocarcinoma. The number of Tregs was elevated in H. pylori-associated gastritis, where it was positively correlated with the grade of chronic inflammation and the number of lymphoid follicles. It was significantly elevated in adenocarcinomas compared to chronic gastritis and gastric dysplasia. In summary, the number of Tregs is increased in H. pylori-associated gastritis and gastric cancer.

The breakdown of preformed peritoneal advanced glycation end products by intraperitoneal alagebrium.

It has been demonstrated that inhibitors of advanced glycation end products (AGE), such as aminoguanidine, can suppress peritoneal AGE in rats on peritoneal dialysis (PD). However, it is unknown whether late administration of a putative cross-link breaker, alagebrium, could reverse peritoneal AGE. We therefore compared alagebrium with aminoguanidine in their ability to reverse peritoneal AGE in rats on PD. Male Sprague-Dawley rats were randomly divided into 3 groups: group I dialyzed with 4.25% glucose solution for all exchanges; group II dialyzed with 4.25% glucose solution containing aminoguanidine, and group III dialyzed with 4.25% glucose solution containing alagebrium for last 8 weeks of 12-week dialysis period. Dialysis exchanges were performed 2 times a day for 12 weeks. Immunohistochemistry was performed using a monoclonal anti-AGE antibody. One-hour PET was performed for comparison of transport characteristics. The immunolabelling of AGE in peritoneal membrane was markedly decreased in the alagebrium group. Consistent with this, the alagebrium group exhibited significantly higher D/Do glucose and lower D/P urea, suggesting low peritoneal membrane transport. But there were no significant differences between the control and the aminoguanidine group. These results suggest that the alagebrium may be the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in rats on PD.