위장관 간질성 종양의 Epidermal Growth Factor Receptor 유전자 돌연변이 연구

유남진,이종우,송영화,전해명,남석우,김수영,박원상,이정용,이석형,Yoo Nam Jin,Lee Jong Woo,Soung Young Hwa,Jeon Hae Myung,Nam Suk Woo,Kim Su Young,Park Won Sang,Lee Jung Young,Lee Sug Hyung 대한위암학회 2004 대한위암학회지 Vol.4 No.4

Purpose: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the KIT or the platelet-derived growth factor receptor alpha (PDGFRA) genes, but approximately $10\%$ of the GISTs are wild types for both the KIT and the PDGFRA genes. The purpose of this study was to investigate the possibility that epidermal growth factor receptor (EGFR) gene mutation might be responsible for the pathogenesis of GIST. Materials and Methods: We analyzed the EGFR gene in 60 GISTs for the detection of somatic mutations by using the polymerase chain reaction (PCR), the single strand conformation polymorphism (SSCP), and DNA sequencing in exon 18, 19, and 21 encoding the kinase domain. Results: The SSCP analysis revealed no evidence of EGFR mutations in exon 18, 19, and 21 in GISTs. Conclusion: The data indicate that the EGFR gene may not be mutated in human GIST and suggest that therapies targeting the mutated EGFR gene products might not be useful in the treatment of GISTs.

위암에서의 고사유발성 Bcl-2 Family의 돌연변이에 관한 연구

유남진,이종우,송영화,김홍석,박원상,이정용,이석형,Yoo Nam Jin,Lee Jong Woo,Soung Young Hwa,Kim Hong Sug,Park Won Sang,Lee Jung Young,Lee Sug Hyung 대한위암학회 2003 대한위암학회지 Vol.3 No.2

Purpose: Evidence exists that dysregulation of Bcl-2 family members is involved in the pathogenesis of cancer development. The aim of this study was to explore whether the somatic mutation of proapoptotic Bcl-2 member genes, one of the mechanisms that prolong the survival of cancer cells, is involved in gastric carcinogenesis. Materials and Methods: In the current study, to detect somatic mutations of the DNA sequences encoding the Bcl-2 homology 3 (BH3) domain of the human BAD, BIM, BIK, and Bcl-G genes in 60 advanced gastric adenocarcinomas, we used the polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP), and DNA sequencing. Results: The SSCP analysis revealed no mutations in the coding regions of the BH3 domain in the cancers. Conclusion: The data presented here indicate that proapoptotic Bcl-2 member genes, BAD, BIM, BIK, and Bcl-G, may not be mutated in human gastric carcinomas and suggest that these genes might be altered by mechanisms other mechanisms somatic mutation.

위암의 BAD 단백질의 발현

유남진,이종우,박원상,이정용,이석형,Yoo, Nam-Jin,Lee, Jong-Woo,Park, Won-Sang,Lee, Jung-Young,Lee, Sug-Hyung 대한위암학회 2003 대한위암학회지 Vol.3 No.2

Purpose: Evidence exists that dysregulation of apoptosis is involved in the pathogenesis of cancer development. The Bcl-$x_{L}$/Bcl-2-associated death promoter (BAD), a member of the Bcl-2 family, is a critical regulatory component of the intrinsic cell-death pathway that exerts its pro-apoptotic effect upon heterodimerization with anti-apoptotic proteins Bcl-2 and Bcl-$X_{L}$. Expression of the BAD protein has been reported in several cancer types, but not in stomach cancer. The aim of this study was to explore the expression status of the BAD protein in gastric carcinomas. Materials and Methods: In the current study, we analyzed the expression of the BAD protein in 60 advanced gastric adenocarcinomas by using immunohistochemistry and a tissue microarray approach. Results: Immunopositivity (defined as $\geq\30\%$) was observed for the BAD protein in 57 ($95\%$) of the 60 cancers. Normal gastric mucosal cells showed weaker expressions of the BAD protein than gastric carcinomas. Conclusion: Taken together, these results suggest that stomach cancer cells in vivo may need BAD protein expression for apoptosis. Also, the higher expression of the BAD protein in stomach cancer cells than in normal gastric mucosal cells suggests that apoptosis might be easily triggered in susceptible stomach cancer cells, thereby producing selective pressure to make more apoptosis-resistant cells during tumor development.

제2형 당뇨병 환자에서 Rosiglitazone 병용 투여에 의한 동맥경직도의 개선 효과

송미진 ( Mi Jin Song ),김남호 ( Nam Ho Kim ),최준호 ( Joon Ho Choi ),박은미 ( Eun Mi Park ),김연경 ( Yeon Kyung Kim ),윤경호 ( Kyeong Ho Yun ),유남진 ( Nam Jin Yoo ),이은미 ( Eun Mi Lee ),오석규 ( Seok Kyu Oh ),정진원 ( Jin Won Je 대한내과학회 2007 대한내과학회지 Vol.72 No.4

목적: 당뇨병은 동맥경화의 중요한 위험인자이다. 인슐린 저항성을 개선시키는 새로운 치료제인 PPARγ agonist인 rosiglitazone이 혈당강하효과 외에도 지질대사이상의 개선, PAI-1과 섬유소원의 감소, 혈소판 응집능의 감소 등의 작용이 알려지고 있으며, 최근에는 동맥경화 예방에도 커다란 역할을 할 것으로 예측되고 있다. 그러나 rosiglitazone이 동맥 경직도에 미치는 직접적인 영향에 대한 연구는 아직까지 없다. 본 연구에서는 동맥경직도를 평가할 수 있는 방법 중 하나인 맥파전도속도를 비침습적인 방법으로 측정하여 인슐린 비의존성 당뇨병 환자에서 rosiglitazone 병용에 의한 동맥 경직도에 미치는 영향을 살펴보고자 하였다. 방법: 인슐린 비의존성 당뇨병 환자에서 GLIME군 20명(Glimepiride: 61.5±8.2세, M:F=9:11)과 ROSI군 20명(Rosiglitazone: 65.6±9.5세, M:F=4:16)을 대상으로 치료 시작 전과 치료 12개월째 PP-1000 (Hanbyul Meditech, Jeonju, Korea)을 이용하여 맥파전도속도를 측정하여 비교하였다. 모든 환자는 치료 시작 전과 치료 12개월 후 공복시 혈당, 당화혈색소, 혈중 콜레스테롤 농도, 간기능 수치, HOMAIR 및 hsCRP를 측정하였다. 결과: GLIME군과 ROSI군 간의 임상적인 특징의 차이는 없었다. 기저치 carotid-femoral 맥파전도속도는 양 군 간에 차이가 없었으며(8.30±1.62 vs. 8.38±1.60 m/sec, p=0.879), 12개월 후 맥파전도속도는 GLIME군에서는 변화가 없었으나(8.30±1.62 vs. 8.29±1.25 m/sec, p=0.941), ROSI 군에서는 의의있게 감소하였다(8.38±1.60 vs. 7.26±1.49 m/sec, p=0.002). hsCRP의 변화 정도는 ROSI군에서 의미있게 감소하였다(2.68±4.53 vs. -0.50±0.93 mg/dL, p=0.007). 맥파전도속도의 변화정도와 hsCRP 변화 정도는 양의 상관관계를 나타내었다(r=0.412, p=0.033). 결론: 제2형 당뇨병 환자에서 rosiglitazone의 병용투여에 의해 동맥경직도가 감소하였으며, hsCRP도 감소하였다. 이러한 결과는 rosiglitazone이 최소한 염증의 완화와 관련하여 동맥경직도의 개선과 관련이 있을 것으로 생각된다. Background: Diabetes is a major risk factor for the development of coronary artery disease. Atherosclerosis is thought to arise as a result of a chronic inflammatory process within the arterial wall. Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherosclerosis, either directly or through associated risk factors. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is used in the treatment of type 2 diabetes mellitus, and previous findings suggest that it may have anti-inflammatory effects on atherosclerosis. This study was performed to evaluate whether rosiglitazone can improve arterial stiffness in type 2 diabetic patients. Methods: This study consisted of 40 patients with type 2 diabetes. These subjects were classified into two groups either medicated with glimepiride (GLIME group, 61.5±8.2 years, M:F = 9:11) or with glimepiride and rosiglitazone (ROSI group, 65.6±9.5 years, M:F = 4:16). For each group, plasma a hsCRP, lipid profile, HOMAIR and HbA1c were measured before and after 12 months of medical treatment. At the same time, pulse wave velocity (PWV) using an automatic device (PP 1000, Hanbyul, Jeonju, Korea) was measured. Results: The plasma hsCRP level was significantly decreased in the ROSI group as compared with the GLIME group (4.22±4.65 vs. 1.07±0.80 mg/L, p=0.025). The carotid-femoral PWV of the ROSI group improved significantly as compared with the GLIME group (8.29±1.25 vs. 7.26±1.49 m/sec, p=0.024). The changes of PWV were correlated with the changes of hsCRP (r=0.412, p=0.033). Conclusions: These findings suggest that rosiglitazone can improve the arterial stiffness in type 2 diabetic patients. (Korean J Med 72:376-383, 2007)

성과중심교육과정 개발사례: 가톨릭대학교 의과대학

김선,박주현,유남진,이수정,Kim, Sun,Park, Joo Hyun,Yoo, Nam Jin,Lee, Soo Jung 연세대학교 의과대학 2013 의학교육논단 Vol.15 No.1

The recent medical education paradigm shift from teacher-centered to student-centered education, has led to a concentration on students' performance and competency. This means that a physician should be able to provide adequate health care in any real medical treatment situation. In order to reflect such a paradigm shift, The Catholic University of Korea School of Medicine launched a new curriculum in 2009 that emphasizes students' performance and competency-based education, known as "outcome-based education." In outcome-based education, the educational process is determined by the desired outcome, signifying the detailed competency that a graduating student should have. Thus, in outcome-based education, we should first determine the competency that results from adequate training and education, followed by specific teaching and learning strategies, methods, and assessment. This paper reviews how The Catholic University School of Medicine developed its new curriculum according to the development steps of outcome-based education.

위 선종 및 선암에서 Trefoil Factor Family 1 단백의 발현 양상

박원상,김영실,유남진,박조현,유진영,이연수,이정용,Park Won Sang,Kim Young Sil,Yoo Nam Jin,Park Cho Hyun,Yoo Jin Young,Lee Youn Soo,Lee Jung Young 대한위암학회 2001 대한위암학회지 Vol.1 No.1

Purpose: The trefoil factor family 1 (TFF1) has a protective effect against gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs or ethanol. In addition, a TFF1 knockout mouse model has exhibited circumferential adenomas with high-grade dysplasia, of which $30\%$ progressed into frankly invasive carcinomas. We tried to determine whether the expression pattern of the TFF1 could be involved in the development of sporadic gastric carcinomas. Materials and Methods: We examined TFF1 expression in a series of 43 sporadic gastric carcinomas and 18 gastric adenomas by immunohistochemistry. Results: Strong positive TFF1 staining was identified primarily in the normal gastric mucosa, mainly in the cytoplasm of the superficial and foveolar epithelium. We found TFF1 expression in $55.8\%$ (24 out of 43) of the gastric carcinomas and in $16.7\%$ (3 out of 18) of the gastric adenomas. Statistically, TFF1 immunoreactivity was significantly higher in diffuse-type ($82.4\%$) than in intestinal-type ($38.5\%$) carcinomas(p=0.0058, Fisher's exact test). Conclusion: Our findings provide sufficient evidence that the expression of TFF1 in gastric cancer may simply disclose gastric-type differentiation of neoplastic cells and provide further support for the existence of at least two pathways of malignant transformation of the gastric mucosa: one via intestinal metaplasia and adenomatous dysplasia, leading to glandular carcinomas with intestinal-type differentiation, and the other via hyperplastic changes or de novo changes, leading to diffuse carcinomas and to a subset of glandular carcinomas displaying gastric-type differentiation.

위암의 Phosphorylated Akt 단백질의 발현

이석형,이종우,박원상,이정용,유남진,김수영,Lee Sug Hyung,Lee Jong Woo,Park Won Sang,Lee Jung Young,Yoo Nam Jin,Kim Su Young 대한위암학회 2003 대한위암학회지 Vol.3 No.2

Purpose: Mounting evidence suggests that alterations of Akt/protein kinase B (PKB) play an important role in tumorigenesis. Phosphorylated Akt regulates many of the key effector molecules involved in apoptosis, angiogenesis, and cell-cycle progression during tumorigenesis. The expression of phosphorylated Akt has been described in some human malignancies, but not in primary human gastric cancer. The purpose of this study was to explore the expression status of phosphorylated Akt protein in gastric carcinomas. Materials and Methods: In the current study, we analyzed the expression of phosphorylated Akt protein in 60 advanced gastric adenocarcinomas by using immunohistochemistry and a tissue microarray approach. Results: Immunopositivity (defined as $\geq\30\%$) was observed for the phosphorylated Akt in 42 ($70\%$) of the 60 cancers. Normal gastric mucosal cells showed no or weak expression of phosphorylated Akt protein. Conclusion: Taken together, these results indicate that Akt is frequently activated in gastric adenocarcinoma cells and suggest that phosphorylayed Akt may play a role in the development of human gastric adenocarcinomas.

위암의 Fas-associated Death Domain Protein 단백질의 발현

이석형,이종우,박원상,이정용,유남진,Lee, Sug-Hyung,Lee, Jong-Woo,Park, Won-Sang,Lee, Jung-Young,Yoo, Nam-Jin 대한위암학회 2003 대한위암학회지 Vol.3 No.2

Purpose: Evidence exists that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Fasassociated death domain (FADD) protein, an adaptor protein of death receptors, is a critical regulatory component of the extrinsic cell- death pathway that exerts its pro-apoptotic effect upon binding with death receptors. Expression of the FADD protein has not been reported in stomach cancer. The aim of this study was to explore the expression status of the FADD protein in stomach cancers. Materials and Methods: In the current study, we analyzed the expression of the FADD protein in 60 advanced stomach cancer by using immunohistochemistry and a tissue microarray approach. Results: Immunopositivity (defined as $\geq\30\%$) was observed for the FADD protein in 23 ($38\%$) of the 60 cancers. Normal gastric mucosal cells showed expression of the FADD protein. Conclusion: Taken together, these results indicate that decreased expression of the FADD protein is a frequent event in stomach cancers and suggest that to avoid apoptosis, stomach cancer cells in vivo may need loss of FADD expression, which might contribute to tumor development.

Interleukin-1$\beta$ 및 Interleukin-1 Receptor Antagonist의 유전적 다형성과 한국인 위암과의 연관 관계

박직영,조용구,김창재,박용규,김영실,박조현,이석형,유남진,이정용,박원상,Park Jik Young,Cho Young Gu,Kim Chang Jae,Park Yong Kyu,Kim Young Sil,Park Cho Hyun,Lee Sug Hyung,Yoo Nam Jin,Lee Jung Young,Park Won Sang 대한위암학회 2002 대한위암학회지 Vol.2 No.3

Purpose: Interleukin 1$\beta$ (IL-1$\beta$) polymorphisms are associated with hypochlorhydria, atrophic gastritis, and increased risk of gastric cancer in Caucasians. We tried to determine whether the IL-1.. and IL-1 receptor antagonist (IL-1 RN) genetic polymorphisms contribute to the development of gastric cancer and the specific type of gastritis in Korean. Materials and Methods: The study population was comprised of 128 gastric cancer patients with histologically proven carcinoma and 63 normal healthy individuals. Sixty-eight carcinomas were of intestinal-type and sixty tumors were of diffuse-type. No patient had a familial gastric cancer history. The 511 bp and 31 bp polymorphisms in the IL-1.. were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism. The polymorphism of the IL-1 RN was analyzed with variable number tandem repeat after PCR. Results: The genotype of 511C/-31T of IL-1$\beta$ and allele 1 of IL-1 RN was dominant in the present subjects. The allelic frequencies of the C allele IL-1$\beta$, which is a high risk genotype for gastric cancer, were 0.551 and 0.429 in gastric cancer and normal controls, respectively. Statistically, significant difference in allelic frequencies of three polymorphic sites between gastric cancer patients and normal controls, and between intestinal-type and diffuse-type was not observed. Conclusions: These results suggest that the polymorphisms of IL-1$\beta$ and IL-1 RN may not contribute to the development of Korean gastric caner and that other endogenous or exogenous factors will be important for gastric carcinogenesis.

한국인 위암에서 KLF6 단백 발현 양상

조용구,김창재,박조현,김수영,남석우,이석형,유남진,이정용,박원상,Cho Young Gu,Kim Chang Jae,Park Cho Hyun,Kim Su Young,Nam Suk Woo,Lee Sug Hyung,Yoo Nam Jin,Lee Jung Young,Park Won Sang 대한위암학회 2005 대한위암학회지 Vol.5 No.1

목적: KLF6는 모든 조직에서 발현되고 있는 zinc finger를 가진 종양억제유전자로 인체 여러 암에서 불활성화되어 있다. 연구자들은 KLF6 단백의 발현 변화가 위암의 발생에 관여하는 지를 알아보고자 하였다. 대상 및 방법: 85예의 파라핀 포매된 위암조직에서 암세포들으 각각 3군데에서 펀치하여 새로운 파라핀 블록으로 옮겨 위암의 tissue microarray를 제작하였다. Tissue microarray 절편에서 KLF6 단백에 대한 항체로 면역화학염색을 실시한 후 발현 양상을 병리 지표들인 조직학적 소견, 침습 정도, 림프절 전이 및 복막파종 등과의 연관성을 조사하였다. 결과: KLF6 단백은 위점막의 표면과 소와 상피세포에서 주로 발현되고 있었고 85예 중 28예($28.9\%$)에서 발현 소실이 관찰되었다. 흥미롭게도 KLF6 단백의 발현 소실은 림프절 전이와 통계적으로 연관성이 있었으나 조직학적 소견, 침습 정도와 복막파종과는 연관성이 없었다. 결론: 이러한 소견들은 KLF6 단백의 발현 소실이 위장관 상피세포의 비정상적인 성장과 분화를 유도하고 위암의 발생 및 진행에 관여한다는 것을 의미한다. Purpose: KLF6, a member of the KLF family, is a ubiquitous zinc finger tumor suppressor protein that is mutated in several human cancers. Our aim was to determine whether the expression pattern of KLF6 might be associated with gastric cancer development and, if so, to determine to which pathologic parameter it is linked. Materials and Methods: For the construction of the gastric cancer tissue microarray, 85 paraffin-embedded tissues containing gastric cancer areas were cored 3 times and transferred to the recipient master block. The expression pattern of KLF6 was examined on tissue microarray slides by using immunohistochemistry and was compared with pathologic parameters, including histologic type, depth of invasion, lymph node metastasis, and peritoneal dissemination. Results: The KLF6 protein was expressed on superficial and foveolar epithelial cells in the gastric mucosa. We found loss of KLF6 expression in 28 ($32.9\%$) of the 85 gastric cancer tissues. There was a significant correlation between loss of KLF6 expression and lymph-node metastasis. However, other pathologic parameters, such as histologic type, depth of invasion, and peritoneal dissemination, were not statistically associated with loss of KLF6 expression. Conclusion: Our findings suggest that loss of KLF6 expression may contribute to abnormal regulation of gastrointestinal epithelial cell growth and differentiation and to the development and/or progression of Korean gastric cancer.