Cell Surface Modification by Activated Polyethylene Glycol Prevents Allosensitization after Islet Transplantation

Wee, Yu-Mee,Lim, Dong-Gyun,Kim, Yang-Hee,Kim, Jin-Hee,Kim, Song-Cheol,Yu, Eunsil,Park, Myung-Ok,Choi, Monica Young,Park, Youn-Hee,Jang, Hyuk-Jai,Cho, Eun-Young,Cho, Myung-Hwan,Han, Duck-Jong SAGE Publications 2008 CELL TRANSPLANTATION Vol.17 No.10

<P>The necessity to transplant islet tissue without the need for immunosuppressant therapy has led to the development of materials for immune modulation. Pegylation makes islets antigenically silent, protecting them from the adsorption of foreign protein and thus avoiding immune injury. The aim of this study is to determine whether pegylation of islets prolongs islet survival and function both during tissue culture and posttransplantation. We used cyanuric chloride-activated methoxy-polyethylene glycol for cell surface modification. To detect the pegylation effect on splenocytes, we measured antibody binding inhibition and abrogation of lymphocyte proliferation. To detect the pegylation effect on islet grafts, we performed rodent islet transplantation. Islet viability and function were maintained after pegylation. Pegylated islets showed a 90% decrease in antibody binding and decreased lymphocyte proliferation in a mixed lymphocyte culture. However, when pegylated islets were transplanted, no prolongation of graft survival was observed. When a subtherapeutic dose of immunosuppressant was given at the time of transplantation of pegylated islets, islet graft survival was significantly prolonged. In addition, when rats were sensitized with donor splenocytes, graft survival was prolonged by pegylation. We observed that pegylation of islets, combined with a subtherapeutic dose of immunosuppressant, protects the graft from rejection. Prolonged graft survival in sensitized recipients showed that pegylation of islets shifted the pattern of rejection from an acute humoral response to a less aggressive cellular alloresponse.</P>

위 점막연관림프조직 림프종에서 헬리코박터 치료 후 발견된 림프구 위염 -2 증례 보고-

송동은 ( Dong Eun Song ),김정선 ( Jung-Sun Kim ),허주령 ( Joo Ryung Huh ),최진 ( Jene Choi ),장세진 ( Se Jin Jang ),유은실 ( Eunsil Yu ) 대한소화기학회 2005 대한소화기학회지 Vol.45 No.5

Both lymphocytic gastritis and gastric mucosa associated lymphoid tissue (MALT) lymphoma are associated with Helicobacter pylori (H. pylori) infection. However, this association has not been fully elucidated. We report two cases of lymphocytic gastritis i

Pancreatic serous cystic neoplasms accompanying other pancreatic tumors

Kim, So-Woon,Song, In Hye,An, Soyeon,Kim, So Yeon,Kim, Hyoung Jung,Song, Ki-Byung,Hwang, Dae Wook,Lee, Sang Soo,Byun, Jae Ho,Seo, Dong-Wan,Kim, Song Cheol,Yu, Eunsil,Hong, Seung-Mo Elsevier 2017 Human pathology Vol.60 No.-

<P>Serous cystic neoplasms (SCNs) are benign cystic neoplasms that predominantly occur in the tail of the pancreas in elderly women. It is well known that patients with von Hippel - Lindau syndrome can develop SCNs and neuroendocrine tumors in the pancreas. However, our understanding on SCNs accompanying other pancreatic tumors (SCNAOPTs) is limited. We compared the clinicopathological features of 15 surgically resected SCNAOPTs with 259 conventional SCNs. The prevalence of SCNAOPT was 5%. The SCNAOPTs were significantly smaller than conventional solitary SCNs, and they were more commonly observed in the head of the pancreas, whereas conventional solitary SCNs were more frequently noted in the body and tail. However, no differences were found in terms of sex, patient age, or the gross patterns of the SCNs. Accompanying neoplasms included 7 intraductal papillary mucinous neoplasms, 1 colloid carcinoma arising from intraductal papillary mucinous neoplasm, 6 neuroendocrine tumors, and 1 solid pseudo papillary neoplasm. Four neuroendocrine tumors associated with von Hippel Lindau syndrome occurred as multiples, whereas 2 neuroendocrine tumors without von Hippel Lindau syndrome were solitary. In summary, SCNAOPTs comprise 5% of all SCNs and tend to be smaller and located in the head of the pancreas. Common accompanying tumors include intraductal papillary mucinous neoplasms, neuroendocrine tumors, and other neoplasms such as colloid carcinoma and solid pseudopapillary neoplasm. (C) 2016 Elsevier Inc. All rights reserved.</P>

The estrogen receptor alpha pathway induces oncogenic Wip1 phosphatase gene expression.

Han, Hye-Sook,Yu, Eunsil,Song, Ji-Young,Park, Ji-Young,Jang, Se Jin,Choi, Jene American Association for Cancer Research 2009 Molecular Cancer Research Vol.7 No.5

<P>Wild-type p53-induced phosphatase (Wip1) is a serine/threonine phosphatase induced by DNA-damaging agents. This enzyme dephosphorylates several cell cycle regulating proteins, including p53, p38 mitogen-activated protein kinase, Chk1, and Chk2, resulting in negative feedback regulation of p38-p53 signaling after damage repair. Moreover, the Wip1 gene may be amplified or overexpressed, especially in hormone-regulated organs, and Wip1 gene amplification has been correlated with poor prognosis in hormone-related malignancies, including ovarian cancers. We therefore investigated the link between estrogen signaling and Wip1 expression. We identified seven putative estrogen response elements within 3 kb of the Wip1 promoter. We also found that estradiol (E(2)) treatment produced a 3-fold increase in endogenous Wip1 mRNA and protein expression in MCF7 cells. Direct binding of estrogen receptor (ER)alpha to the Wip1 promoter after E(2) treatment was confirmed by a chromatin immunoprecipitation assay using ERalpha antibody and an electrophoretic mobility shift assay. Wip1 overexpression induced by adenovirus and E(2) facilitated the proliferation of serum-starved ZR-75-1 cells, with cell proliferation induced by overexpressed Wip1 approximately 25% higher than that induced by E(2). Wip1 phosphatase activity was essential for cell cycle progression. Wip1 stimulated the transcriptional activity of its own promoter through E(2)-ERalpha signaling. In addition, Wip1 overexpression induced Rb phosphorylation during cancer cell proliferation. These results indicate that Wip1 up-regulation is important in the pathogenesis of p53(+) and ER(+) breast cancer through the inactivation of p53 by dephosphorylation and the amplification of subsequent estrogenic effects through the E(2)-ERalpha-Wip1 pathway.</P>

비인강암에서 방사선치료의 예측인자로써 Ku70 발현의 의의

송시열(Si Yeol Song),이상욱(Sang-wook Lee),유은실(Eunsil Yu),조경자(Kyung-Ja Cho),박진홍(Jin-hong Park),김상윤(Sang Yoon Kim),남순열(Soon Yuhl Nam),이봉재(Bong-Jae Lee),김성배(Sung Bae Kim),최승호(Seung-Ho Choi),안승도(Seung Do Ahn) 대한방사선종양학회 2005 Radiation Oncology Journal Vol.23 No.1

목 적: 방사선치료를 시행 받은 비인강암 환자에서 Ku70과 DNA-PKcs의 발현 정도가 국소제어율과 치료 실패 양 상에 미치는 영향을 알아보고자 하였다. 대상 및 방법: 1995년 6월부터 2001년 12월까지 서울아산병원에서 방사선치료 단독 또는 동시항암화학-방사선치료를 시행 받은 66명의 원격전이가 없는 비인강암 환자를 후향적으로 분석하였다. 진단 시 얻은 조직검사 표본에서 Ku70과 DNA-PKcs의 면역활성도를 분류하였는데, 그 기준은 면역활성도가 50% 이상 Ku (+)과, 50% 미만 Ku(-) 이었다. Ku70과 DNA-PKcs의 면역활성도와 방사선치료에 대한 종양의 반응 정도와 재발양상과의 상관관계를 알아보았으며, 비인강암의 국소제어율에 영향을 미치는 예후인자를 알아보기 위하여 단변량분석을 시행하였다. 결 과: Ku (-) 환자에서 Ku (+) 환자보다 높은 5년 국소제어율(85% vs. 42%, p=0.042)을 보였으나, 원격전이율은 두 집단간에 차이를 보이지 않았다(78% vs. 82%, p=0.8672). 단변량분석결과 Ku70의 과발현이 기존에 알려진 비인 강암의 예후인자보다 우위에 있음을 알 수 있었다. 국소재발을 보였던 22명의 환자 중 18명의 환자에서 Ku70 (+) 으로 관찰되었다. DNA-PKcs의 발현 정도는 방사선치료 결과에 영향을 미치지 않는 것으로 나타났다. 결 론: Ku70은 원격전이가 없는 비인강암 환자에서 방사선치료 단독 또는 동시항암화학-방사선치료 시행 이후 종양의 반응과 국소제어율을 예측할 수 있는 분자생물학적인 예측인자로 사용될 수 있을 것으로 생각한다. Purpose: The objective of this study was to determine whether the expressions of the two components of DNA-dependent protein kinase, Ku70 and DNA-PKcs, influence the response to radiotherapy (RT) and outcome of treatment of non-disseminated nasopharyngeal carcinoma (NPC) in patients who received definitive RT. Materials and Methods: Sixty-six patients with NPC who were treated with radiotherapy alone or with concurrent chemotherapy between June 1995 and December 2001 were divided into groups based on the levels of immunoreactivity for Ku70 and DNA-PKcs in pretreatment biopsy specimens. The over-expression of Ku70 or DNA-PKcs groups included patients whose biopsy specimens showed at least 50% immunopositive tumor cells; patients in which less than 50% of the tumor cells in the biopsy tissues were immunopositive were placed in the low Ku70 and DNA-PKcs groups. The immunoreactivities for Ku70 and DNA-PKcs were retrospectively compared with the sensitivity of the tumor to radiation and the patterns of therapy failure. Univariate analyses were performed to determine the prognostic factors that influenced locoregional control of NPC. Results: The five-year locoregional control rate was significantly higher in the low Ku70 group (Ku(-)) (85%) than in the high Ku70 group (Ku(+)) (42%) (p=0.0042). However, there were no differences in the metastases- free survival rates between the two groups (Ku70 (+), 82%; Ku70 (-), 78%; p=0.8672). Univariate analysis indicated that the over-expression of Ku70 surpassed other well-known predictive clinocopathologic parameters as an independent prognostic factor for locoregional control. Eighteen of 22 patients who had locoregional recurrences of the tumor displayed an over-expression of Ku70. No significant association was found between the level of DNA-PKcs expression and the clinical outcome. Conclusion: Our data suggest that the level of Ku70 expression can be used as a molecular marker to predict the response to RT and the locoregional control after RT and concurrent chemotherapy in patients with non-disseminated NPC.

Clinical and prognostic significances of nuclear and cytoplasmic KIT expressions in extrahepatic bile duct carcinomas

Hong, Seung-Mo,Hwang, Ilseon,Song, Dong Eun,Choi, Jene,Yu, Eunsil Springer Science and Business Media LLC 2007 Modern pathology Vol.20 No.5

Clinicopathologic and Prognostic Significance of Multiple Hormone Expression in Pancreatic Neuroendocrine Tumors

Kim, Joo Young,Kim, Min-Sun,Kim, Ki-Suk,Song, Ki-Byung,Lee, Seung Hun,Hwang, Dae Wook,Kim, Kyu-pyo,Kim, Hyoung Jung,Yu, Eunsil,Kim, Song Cheol,Jang, Hyeung-Jin,Hong, Seung-Mo Wolters Kluwer Health, Inc. All rights reserved. 2015 The American journal of surgical pathology Vol.39 No.5

Pancreatic neuroendocrine tumors (PanNETs) produce variable peptide hormones. The expression status of some hormones has been linked to the biological and clinical behaviors of PanNETs. A total of 226 surgically resected PanNETs were selected. Immunolabeling for peptide hormones was compared with various clinicopathologic factors, including patient survival. Expression of insulin, glucagon-like peptide 1, glucagon, gastrin, somatostatin, and serotonin were observed in 56 (24.8%), 41 (18.1%), 25 (11.1%), 5 (2.2%), 5 (2.2%), and 4 (1.8%) cases, respectively. Expression of 1, 2, and 3 hormones was noted in 70 (31.0%), 28 (12.4%), and 3 (1.3%) cases, respectively; 125 cases (55.3%) were negative for all hormones. PanNETs with insulin and glucagon-like peptide 1 expression were associated with a lower grade, smaller size, lower pT and pN classifications, absence of lymphovascular invasion, and lymph node metastasis and had better survival by univariate analysis, whereas PanNETs with gastrin expression were associated with a higher grade, larger size, higher pT and pN classifications, presence of lymphovascular invasion, and lymph node metastasis and had worse survival. Gastrin expression, increased age, and tumor grade were negative prognostic factors in multivariate analysis. As the number of hormones expressed increased, the survival rate of PanNET patients increased. In summary, PanNET patients showing insulin or glucagon-like peptide 1 expression and increased numbers of expressed hormones had a better survival outcome by univariate analysis, whereas gastrin expression was a negative prognostic indicator in surgically resected PanNET patients.

Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival

Kim, Joo Young,Brosnan-Cashman, Jacqueline A.,An, Soyeon,Kim, Sung Joo,Song, Ki-Byung,Kim, Min-Sun,Kim, Mi-Ju,Hwang, Dae Wook,Meeker, Alan K.,Yu, Eunsil,Kim, Song Cheol,Hruban, Ralph H.,Heaphy, Christ American Association for Cancer Research 2017 Clinical Cancer Research Vol.23 No.6

<P><B>Purpose:</B> Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET).</P><P><B>Experimental Design:</B> In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors.</P><P><B>Results:</B> In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, <I>P</I> < 0.001). ALT also strongly correlated with lymphovascular (<I>P</I> < 0.001) and perineural invasion (<I>P</I> = 0.001) and the presence of lymph node (<I>P</I> < 0.001) and distant metastases (<I>P</I> = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83–6.27; <I>P</I> < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08–0.68; <I>P</I> = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (<I>P</I> < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (<I>P</I> < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (<I>P</I> = 0.003).</P><P><B>Conclusions:</B> Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. <I>Clin Cancer Res; 23(6); 1598–606. ©2016 AACR</I>.</P>

Histological Expression of Methionine Adenosyltransferase (MAT) I and MAT II as Post-surgical Prognostic Surrogates in Patients with Hepatitis B Virus-related Hepatocellular Carcinoma

( Mi-jung Jun ),( Ju Hyun Shim ),( Joo Ho Lee ),( Gi-won Song ),( Yangsoon Park ),( Eunsil Yu ),( Sung-gyu Lee ),( Jihyun An ),( Danbi Lee ),( Kang Mo Kim ),( Young-suk Lim ),( Han Chu Lee ),( Young-h 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: It has been found that methionine adenosyltransferase 1A (MAT1A) gene, encoding isoenzymes MAT I/III, is dysregulated in hepatocellular carcinoma (HCC), and reduced MAT1A expression correlates with worse HCC prognosis. The X protein of hepatitis B virus (HBV) inhibits apoptosis in HCC cells through enhancing the expression of MAT2A gene, encoding MAT II. MA1A/MAT2A switch has been severally demonstrated to be involved in hepatocarcinogenesis. We aimed to investigate prognostic implication of MAT I and MAT II protein expression in HBV-infected patients undergoing hepatic resection for HCC. Methods: In this study, we used a tissue microarray constructed from archival surgical specimens of 166 patients with HBV-related HCC who underwent curative hepatectomy at Asan Medical Center. The tumor tissue microarray was immunohistochemically stained with primary antibodies against MAT I and MAT II. We examined pre- and post-surgical clinical factors related to MAT 1 and MAT II, using logistic regression analysis, and predictive effect of the two proteins on post-surgical recurrence and survival, using Cox proportional hazards model. Results: Of the 166 patients, 74.1% were male with a mean age of 52.8 ± 8.7 years, 94% were Child-Pugh class A disease, and 55.4% had liver cirrhosis. In terms of histological factors, most patients had solitary tumor (93.4%) and tumors of 5cm or less (74.7%). Microvascular invasion and Edmondson grade III/IV tumors were observed in 30.7% and 66.9%, respectively of the patients. During a median follow-up of 39 months (range 5-81 months), 12 deaths and 63 recurrences had been found, where 52 recurrences occurred early within 2 years after resection. MAT I and MAT II were positively expressed in 83.7% and 87.3%, respectively of the 166 tumor tissues. MAT I expression was independently associated with male and tumors of 5 cm or less (adjusted P<0.05 for both). Expression of MAT II had a significant relationship with only serum AFP >200 ng/mL (adjusted P<0.05). Multivariate Cox regression analyses showed that MAT II expression was significantly correlated with shorter times to overall and early recurrences (hazard ratios 9.97 and 8.26, respectively; adjusted P<0.05 for both), as was not positive MAT I (hazard ratio 1.13; P=0.730). Immunopositivity for two proteins did not influence overall survival (P>0.05 for both). MAT I : MAT II activity ratio below 1.0 was observed in 12.7% of the patients, and not significantly associated with post-surgical recurrence and survival outcomes. Conclusions: Immunohistological expression of MAT II in tumor may be helpful in predicting and monitoring tumor recurrence, especially in the early phase after hepatic resection, in patients with HBV-related HCC.

The Effects of Immune Checkpoint Modulators on the Clinical Course of Patients with Resectable Hepatocellular Carcinoma

( Jihyun An ),( Hyo Jeong Kang ),( Ju Hyun Shim ),( Gi-won Song ),( Gwang Hyun Choi ),( Han Chu Lee ),( Bora Oh ),( Naomi Park ),( Jihyun ),( Song Eunsil Yu ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Immune checkpoint proteins regulating T-cell mediated anti-tumor immunity have been reported to affect clinical outcomes in multiple malignancies. This study aimed to investigate the prognostic effect of histological expression of immune checkpoint proteins in patients with resected hepatocellular carcinoma (HCC). Methods: A total of 221 patients with HCC who underwent curative resection were included. Expression of Programmed-cell death ligand- 1 in tumor cells (tPD-L1) and tumor infiltrating mononuclear cells (TIMCs) (iPD-L1), Programmed-cell death-1 in TIMCs (iPD-1), and cytotoxic T lymphocyte antigen-4 in TIMCs (iCTLA-4) were measured immunohistochemically. Results: Among the 221 patients, histo-positivity for iCTLA-4, iPD-1, iPD-L1, and tPD-L1 was 32.1% (n=71), 42.5% (n=94), 35.3% (n=78), and 14.9% (n=33), respectively. Multivariate logistic analyses revealed that male sex and tumor >5cm were variables related to iCTLA-4 positivity (odds ratios [ORs] 0.46 and 1.94 respectively; Ps<0.05). Poor differentiation was related to PD-L1 expression in both tumor cells and TIMCs (ORs 2.88 and 3.46, respectively; Ps<0.05). Microvascular invasion was significantly associated only with iPD-L1, whereas tPD-L1 was positively correlated with baseline elevation of serum alpha-fetoprotein (≥200 ng/ml) (ORs 2.24 and 2.45; Ps<0.05). In time-dependent outcome analyses, expression of immune checkpoint proteins in TIMCs (i.e., iCTLA-4, iPD-1, and iPD-L1) was significantly related to longer overall survival and non-cancer-related survival (all Ps< 0.05), but not to time-to-recurrence or cancer-specific deaths (all Ps >0.05). Concurrent activation of the PD-1:PD-L1 and CTLA-4 pathways predicted improved outcomes in terms of overall survival and non-cancer related survival (P=0.06 and P=0.03, respectively). Conclusions: Immune checkpoint proteins upregulated in TIMCs in HCC tissues have individual and additive effects in prolonging the survival of patients, specifically in terms of survival not related to cancer recurrence.