Han-Seong Kim

Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner

BACKGROUND AIMS Graft-versus-host disease (GvHD) remains a major complication after allogeneic hematopoietic cell transplantation (HCT). Recent literature demonstrates a potential benefit of human mesenchymal stromal cells (MSC) for the treatment of refractory GvHD; however, the optimal dose remains uncertain. We set out to develop an animal model that can be used to study the effect of MSC on GvHD. METHODS A GvHD mouse model was established by transplanting C3H/he donor bone marrow (BM) cells and spleen cells into lethally irradiated BALB/c recipient mice. MSC were obtained from C3H/he mice and the C3H/10T1/2 murine MSC line. RESULTS The mRNA expression of Foxp3 in regional lymph nodes (LN) localized with T cells was markedly increased by the addition of C3H10T1/2 cells in a real-time polymerase chain reaction (PCR). Using a mixed lymphocyte reaction, we determined the optimal splenocyte proliferation inhibition dose (MSC:splenocyte ratios 1:2 and 1:1). Three different C3H10T1/2 cell doses (low, 0.5 x 10(6), intermediate, 1 x 10(6), and high, 2 x 10(6)) with a consistent splenocyte dose (1 x 10(6)) were evaluated for their therapeutic potential in an in vivo GvHD model. The clinical and histologic GvHD score and Kaplan-Meier survival rate were improved after MSC transplantation, and these results demonstrated a dose-dependent inhibition. CONCLUSIONS We conclude that MSC inhibit GvHD in a dose-dependent manner in this mouse model and this model can be used to study the effects of MSC on GvHD.

Loss of p16 and p27 is associated with progression of human gastric cancer

We performed the immunohistochemical staining for six G1 check point cell cycle proteins to study their expression patterns and roles in the gastric carcinogenesis. We studied 76 cases of paraffin blocks that included the sections of 18 tubular adenomas (TA), 38 early gastric carcinomas (EGC) (20 cases of mucosal type, nine cases of submucosal type with no nodal metastasis, nine cases of submucosal type with nodal metastasis), 20 advanced gastric carcinomas (AGC) (ten cases with no nodal metastasis, ten cases with nodal metastasis). We found that abnormal expression of p16 and p27 increased with the progression of tubular adenomas to advanced gastric cancers. Inverse relationship between pRb and p16 proteins was found in a small portion of the gastric tumors. Expressions of pRb and cdk4 were consistently high in benign and malignant gastric tumors. Expression of cyclin D1 and cyclin E rather decreased with the tumor progression. In conclusion, losses of p16 and p27 seem to play a significant role during the gastric carcinogenesis, and the G1 checkpoint cell cycle proteins such as pRb, cdk4, cyclin D1, and cyclin E variably participate in the gastric carcinogenesis and metastasis by the mechanisms which are yet unknown; thus, further studies need to be performed to elucidate the mechanisms.

Down regulation of Bc12 expression in invasive ductal carcinomas is both estrogen- and progesterone-receptor dependent and associated with poor prognostic factors

In normal breast, Bcl2 is expressed in the non-pregnant and non-involuting mammary epithelium. The exact mechanism and the effect of the down regulation of the Bcl2 expression on breast cancer cells are not clearly defined. We compared down regulation as well as the persistent expression of Bcl2 with ER, PR, p53, and c-erb-B2 overexpression and clinicopathologic variables, and tumor stage in 11 cases of ductal carcinomas in situ (DCIS) and 44 cases of invasive ductal carcinomas (IDC) of Korean women by immunohistochemical studies. Bcl2 down regulation was found in 39% of IDC and in 18% of DCIS cases. In IDC, while persistent Bcl2 expression was displayed in 95% and 78.9% of ER and PR immunoreactive ones and 71.9 % of c-erb-B2 immnonegative ones. Seventeen cases of Bcl2 down regulated IDC had a significant correlation with ER negativity (94.1%), PR negativity, (76.5%), and high nuclear (61.1% is grade III) and histological grade (76% is grade III). However, in DCIS, no significant correlation between the Bcl2 expression and various parameters were obtained, probably due to small sample size. In conclusion, the Bcl2 expression was both ER and PR dependent and down regulation of Bcl2 in IDC was significantly correlated with poor prognostic factors.

Overexpression of cyclin D1 and cdk4 in tumorigenesis of sporadic hepatoblastomas

Abnormality of the cyclin D1/cdk4/p16INK4a/pRb pathway during tumorigenesis has recently been reported. Hepatoblastoma is a rare malignant liver tumor of childhood, but underlying abnormalities of cell-cycle regulating protein remain to be elucidated. The expression of cyclin D1, cdk4, p16 and retinoblastoma gene product (pRb) was studied by immunohistochemistry in 17 paraffin-embedded tissues consisting of both tumor and corresponding non-neoplastic tissues. Tumor tissues showed overexpression of cyclin D1 (13/17, 76%) and cdk4 (15/17, 88%). Eleven cases showed co-overexpression of both cyclin D1 and cdk4. No abnormal p16 or pRb expression was noted. In the group with a high score (+4) for cyclin D1 expression, a positive correlation with tumor recurrence was noted (P = 0.043). These data suggest that overexpressed cyclin D1 and cdk4 protein might play an important role in the tumorigenesis of hepatoblastoma and that in the group with high cyclin D1 expression, tumor recurrence may be more frequent.

Primary gastrointestinal clear cell sarcoma: report of 2 cases, one case associated with IgG4-related sclerosing disease, and review of literature

Clear cell sarcoma (CCS) is a distinctive soft tissue sarcoma that shows melanocytic differentiation. Primary gastrointestinal (GI) CCSs have been rarely reported, but to our knowledge, no association between GI CCSs and immunoglobulin G4 (IgG4)-related sclerosing disease has been described in the literature. We experienced 2 cases of CCS that arose in the small intestine and metastasized to the liver. Histologic features and immunophenotype were typical of CCS. One of them showed a unique peritumoral sclerosing inflammatory reaction, which was highly reminiscent of IgG4-related sclerosing inflammatory disease. Dense lymphoplasmacytic infiltration with extensive sclerosis and obliterative phlebitis was observed in the immediate vicinity of the primary and metastatic tumors, but not in the distant areas from the tumor. The average number of IgG4-positive plasma cells was more than 50 per high-power field. We report 2 cases of primary GI CCS with one case showing a unique peritumoral IgG4-related lymphoplasmacytic sclerosing inflammation.

Helicobacter heilmannii-associated Gastritis: Clinicopathologic Findings and Comparison with Helicobacter pylori-associated Gastritis

The aims of this study were to evaluate the clinicopathologic features of Helicobacter heilmannii-associated gastritis and to compare H. heilmannii-associated gastritis with H. pylori-associated gastritis. We reviewed 5,985 consecutive gastric biopsy specimens. All cases of chronic gastritis with Helicobacter infection were evaluated with the Updated Sydney System, and the grades of all gastritis variables were compared between H. heilmannii-associated gastritis and H. pylori-associated gastritis groups. There were 10 cases of H. heilmannii-associated gastritis (0.17%) and 3,285 cases of H. pylori-associated gastritis (54.9%). The organisms were superficially located within the mucous layer without adhesion to epithelial cells. Interestingly, in one case many intracytoplasmic H. heilmannii organisms were observed in parietal cells with cell damage. A case of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma concomitant with H. heilmannii infection was detected. Compared to H. pylori-associated gastritis, H. heilmannii-associated gastritis showed less severe neutrophilic activity (p<0.0001), mononuclear cell infiltration (p=0.0029), and endoscopic findings of chronic gastritis devoid of erosion or ulcer (p=0.0309). In conclusion, we present the detailed clinicopathologic findings of H. heilmannii-associated gastritis compared to H. pylori-associated gastritis. H. heilmannii-associated gastritis is uncommon and milder than H. pylori-associated gastritis, however it may be noteworthy with respect to the development of MALT lymphoma.

IgG4-related sclerosing esophagitis: a case report

decided to initially use an OVESCO (over-the-scope clip) with an 11-mm diameter that partially occluded the fistula and worked as an anchor point for the posterior placement of a self-expandable covered metal stent (20-mm diameter and 8-cm length) (Figs. 2-4). At the end of the procedure, there was a good flow of contrast to the stomach, with no evidence of the fistulous tract (Figs. 5 and 6). At the 48-hour evaluation, there was proper positioning of the clip and stent and no evidence Figure 5. Stent and endoclip in situ.

Cell cycle protein profile of the hepatic stellate cells(HSCs)in dimethylnitrosamine-induced rat hepatic fibrosis.

Cell cycle regulating proteins are known to have close relation with the proliferation of the mammalian cells. In injured liver, the number of HSCs is increased from proliferation. However, the expression of cell cycle proteins of HSCs during proliferation remains unevaluated. Therefore, cell cycle protein profiles of HSCs were studied in dimethyl-nitrosamine (DMN)-induced rat liver fibrosis model. Sprague-Dawley rats were intraperitoneally injected of DMN and the animals were sacrificed every week up to 4 weeks. HSCs were separated and the number of the cells in S phase was counted to evaluate the cell proliferation by flow cytometry. The expression of cyclin A, cyclin B, cyclin D1, cdk2, cdk4, cdc2, proliferating cell nuclear antigen (PCNA), p21Cip/WAF1, and p27 was examined with immunoblotting analysis. Portion of S-phase cells peaked 7days after DMN injection. At that time, cyclin A, and PCNA showed significant increase in HSCs compared to untreated HSCs (114% and 116%, respectively, P<0.001). p21Cip/WAF1 was decreased significantly in DMN-treated HSCs compared to control cells (88%, P<0.001). The increase of cyclin A, and PCNA and the decrease of p21Cip/WAF1 seem to play important roles in the proliferation of HSCs during the early period of DMN treatment.

Expression of Ep-CAM in intestinal metaplasia, gastric epithelial dysplasia and gastric adenocarcinoma

Background:  The epithelial cell adhesion molecule (Ep‐CAM) is widely associated with human carcinomas. However, the expression and distribution of Ep‐CAM in gastric premalignant and malignant lesions are not well known.

Ultrastructural Studies of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract (GIT). Although interstitial cells of Cajal has been suggested as origin of this tumor, the cytological and ultrastructural features of GISTs are heterogeneous and unclear. A total 10 cases of normal gastrointestinal tissue (control), 13 GISTs of the stomach (8), small intestine (3), mesocolon (1) and liver (1), and 2 gastrointestinal autonomic nervous tumor (GANT) of small intestine were ultrastructurally studied. Normal interstitial cells of Cajal (ICC) were abundantly present around the myenteric plexuses or individually scattered through the wall of GIT. ICC was characterized by slender cytoplasmic processes, well-developed endoplasmic reticulum (ER), mitochondria, Golgi apparatus, caveolae and intermediate filaments. The GISTs and GANTs had overlapping ultrastructures. The most common and important ultrastructural features of GISTs were rich villous cytoplasmic processes, dispersed intermediate filaments and abundant SER, and those of GANTs were neurosecretory granules and skenoid fibers. Compared with ICC, the GISTs and GANTs had remarkably reduced caveolae and gap junctions. Our study suggested that ultrastructural analysis gives much information to investigate lineage differentiation of neoplastic cells and make a differential diagnosis of these tumors from other mesenchymal tumors and between GISTs and GANTs.