765 results on '"Woo-Ho Kim"'
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2. Aberrant Methylation of Somatostatin Receptor 2 Gene Is Initiated in Aged Gastric Mucosa Infected with Helicobacter pylori and Consequential Gene Silencing Is Associated with Establishment of Inflammatory Microenvironment In Vitro Study
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Hee-Jin Kim, Jong-Lyul Park, Byoung-Ha Yoon, Keeok Haam, Haejeong Heo, Jong-Hwan Kim, Seon-Young Kim, Mirang Kim, Woo-Ho Kim, Sang-Il Lee, Kyu-Sang Song, Kwang-Sung Ahn, and Yong Sung Kim
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SSTR2 ,gastric cancer ,WGBS ,hypermethylation ,inflammation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The loss-of-function variants are thought to be associated with inflammation in the stomach. We here aimed to evaluate the extent and role of methylation at the SSTR2 promoter in inflammation and gastric tumor formation. A whole-genome bisulfite sequencing analysis revealed that the SSTR2 promoter was significantly hypermethylated in gastric tumors, dysplasia, and intestinal metaplasia compared to non-tumor tissues from patients with gastric cancer. Using public data, we confirmed SSTR2 promoter methylation in primary gastric tumors and intestinal metaplasia, and even aged gastric mucosae infected with Helicobacter pylori, suggesting that aberrant methylation is initiated in normal gastric mucosa. The loss-of-function of SSTR2 in SNU638 cell-induced cell proliferation in vitro, while stable transfection of SSTR2 in AGS and MKN74 cells inhibited cell proliferation and tumorigenesis in vitro and in vivo. As revealed by a comparison of target genes differentially expressed in these cells with hallmark molecular signatures, inflammation-related pathways were distinctly induced in SSTR2-KO SNU638 cell. By contrast, inflammation-related pathways were inhibited in AGS and MKN74 cells ectopically expressing SSTR2. Collectively, we propose that SSTR2 silencing upon promoter methylation is initiated in aged gastric mucosae infected with H. pylori and promotes the establishment of an inflammatory microenvironment via the intrinsic pathway. These findings provide novel insights into the initiation of gastric carcinogenesis.
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- 2022
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3. Gold thread implantation promotes hair growth in human and mice
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Jong-Hwan Kim, Eun-Young Cho, Euna Kwon, Woo-Ho Kim, Jin-Sung Park, Yong-Soon Lee, Jun-Won Yun, and Byeong-Cheol Kang
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Gold thread ,hair loss ,hair growth ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Thread-embedding therapy has been widely applied for cosmetic purposes such as wrinkle reduction and skin tightening. Particularly, gold thread was reported to support connective tissue regeneration, but, its role in hair biology remains largely unknown due to lack of investigation. When we implanted gold thread and Happy Lift™ in human patient for facial lifting, we unexpectedly found an increase of hair regrowth in spite of no use of hair growth medications. When embedded into the depilated dorsal skin of mice, gold thread or polyglycolic acid (PGA) thread, similarly to 5% minoxidil, significantly increased the number of hair follicles on day 14 after implantation. And, hair re-growth promotion in the gold threadimplanted mice were significantly higher than that in PGA thread group on day 11 after depilation. In particular, the skin tissue of gold thread-implanted mice showed stronger PCNA staining and higher collagen density compared with control mice. These results indicate that gold thread implantation can be an effective way to promote hair re-growth although further confirmatory study is needed for more information on therapeutic mechanisms and long-term safety.
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- 2018
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4. Supplementary Figure Legend from RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib
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Yung-Jue Bang, Woo-Ho Kim, Mark J. O'Connor, Tae-You Kim, Do-Youn Oh, Sae-Won Han, Kyung-Hun Lee, Hwang-Phill Kim, Hyung-Seok Hur, Hyun-Jin Nam, Sang-Hyun Song, Young-Kwang Yoon, Seock-Ah Im, and Ahrum Min
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PDF file - 176K
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- 2023
5. Data from RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib
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Yung-Jue Bang, Woo-Ho Kim, Mark J. O'Connor, Tae-You Kim, Do-Youn Oh, Sae-Won Han, Kyung-Hun Lee, Hwang-Phill Kim, Hyung-Seok Hur, Hyun-Jin Nam, Sang-Hyun Song, Young-Kwang Yoon, Seock-Ah Im, and Ahrum Min
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A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G2–M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib. Mol Cancer Ther; 12(6); 865–77. ©2013 AACR.
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- 2023
6. Supplementary Figures 1 - 9, Tables 1 - 2 from RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib
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Yung-Jue Bang, Woo-Ho Kim, Mark J. O'Connor, Tae-You Kim, Do-Youn Oh, Sae-Won Han, Kyung-Hun Lee, Hwang-Phill Kim, Hyung-Seok Hur, Hyun-Jin Nam, Sang-Hyun Song, Young-Kwang Yoon, Seock-Ah Im, and Ahrum Min
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PDF file - 3250K, Figure S1 Olaparib has variable levels of anti-tumor activity in human cancer cell lines. Figure S2 Olaparib sensitive cell lines have different patterns of gene expression compared to insensitive cell lines. Figure S3 PTEN expression does not affect olaparib sensitivity. Figure S4 RAD51C expression affects olaparib sensitivity in human cancer cell lines. Figure S5 RAD51C over-expression decreases sensitivity to olaparib in the BT-549 cell line. Figure S6 Olaparib induces G2/M cell cycle arrest and apoptosis in sensitive cell lines. Figure S7 RAD51C depletion increases the accumulation of DNA damage. Figure S8 RAD51C expression decreases in tumor tissues. Figure S9 RAD51C expression is down-regulated in gastric tumor tissues via DNA methylation. Table S1. Sequences of the primers for PCR and real-time PCR analyses. Table S2. BRCA1 and BRCA2 mutations in the gastric cancer cell lines.
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- 2023
7. Supplementary Tables 1-2 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Tables 1-2. Table S1. HER2/CEP17 ratio and HER2 gene copy number by HER2 IHC; Table S2: Univariateand multivariate Cox analysis of overall survival
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- 2023
8. Supplementary Figure 2 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 2. Representative images of HER2 IHC and HER2 FISH
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- 2023
9. Supplementary Figure 1 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 1. CONSORT diagram
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- 2023
10. Supplementary Figure 3 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 3. Receiver operating characteristic curves of HER2 gene copy number according to HER2 IHC status.
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- 2023
11. Supplementary Figure 4 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 4. Overall survival and objective response rate according to HER2 gene copy number.
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- 2023
12. Supplementary Figure Legends from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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legends for supplementary figures
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- 2023
13. Data from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
- Abstract
Purpose: Chemotherapy plus trastuzumab is standard of care for HER2-positive advanced gastric cancer (AGC). However, not all patients with HER2-positive AGC seem to benefit from trastuzumab. We evaluated the association between treatment outcomes with trastuzumab and HER2 status in patients with HER2-positive AGC.Experimental Design: We enrolled 126 patients with HER2-positive AGC treated with trastuzumab plus chemotherapy in a training cohort. HER2 IHC (N = 126), HER2/CEP17 ratio (N = 66), and HER2 gene copy number (GCN; N = 59) were analyzed, and the optimal values for discriminating overall survival (OS) were determined using receiver operating characteristic (ROC) curve analysis. We validated the findings from the training cohort using an independent validation cohort (N = 72).Results: Patients with HER2 IHC 3+ showed significantly longer OS (29 vs. 15.3 months; P = 0.025) than patients with IHC ≤ 2+. An HER2/CEP17 ratio of 4.48 was the optimal cutoff for predicting longer OS (26.9 vs. 14.7 months; P = 0.027). In subgroup analysis, treatment outcomes of patients with IHC 3+ were not influenced by the level of HER2 gene amplification. However, in patients with IHC ≤ 2+, an HER2/CEP17 ratio more than 3.69 and HER2 GCN more than 7.75 were positive predictive factors for better outcomes with trastuzumab-based chemotherapy. These findings were confirmed in both the validation cohort and the combined cohort.Conclusions: HER2 IHC status, HER2/CEP17 ratio, and HER2 GCN were correlated with clinical outcomes of trastuzumab-based treatment in HER2-positive AGC. Clinical outcomes of patients with IHC ≤ 2+ were strongly dependent on the HER2/CEP17 ratio and HER2 GCN. Clin Cancer Res; 21(11); 2520–9. ©2015 AACR.
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- 2023
14. Supplementary Figure 5 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 5. Survival analysis according to HER2 gene copy number in validation cohort
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- 2023
15. Supplementary Figures S1-S13 and Table S1 from KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78
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Seong-Jin Kim, Woo Ho Kim, Han-Kwang Yang, Shin Tae Kim, Jinah Park, Junil Kim, Bona Lee, Hyojung Kim, Staci Jakyong Kim, Sujin Park, and Jin Muk Kang
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Supplementary Figures S1-S13 and Table S1. Confirmation of KIAA1324 mRNA expression in primary tissues from gastric cancer (GC) patients and GC cell lines (S1). Analysis of correlation between copy number variation (CNV) and KIAA1324 mRNA expression in gastric cancer cell lines (S2). KIAA1324 enhanced cisplatin- and etoposide-induced apoptosis of gastric cancer cells (S3). KIAA1324 knockdown reduced staurosporine-induced apoptosis (S4). KIAA1324 did not have a considerable effect on cell cycle (S5). KIAA1324 did not affect autophagy of gastric cancer cells (S6). KIAA1324 â–³C caused growth inhibition and apoptosis in gastric cancer cells (S7). KIAA1324 â–³N did not induce apoptosis of gastric cancer cells (S8). 1-303 a.a. of KIAA1324 was required for KIAA1324-mediated apoptosis (S9). Subcellular localization of KIAA1324 (S10). 1-303 a.a. of KIAA1324 bound to GRP78. (A) A schematic model of KIAA1324 fragments (S11). GRP78 knockdown induced apoptosis of MKN28 cells (S12). A schematic model of the anti-tumorigenic ability of KIAA1324 through regulation of GRP78 activity (S13). Semi-quantitative and quantitative RT-PCR primers (Table S1).
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- 2023
16. Data from KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78
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Seong-Jin Kim, Woo Ho Kim, Han-Kwang Yang, Shin Tae Kim, Jinah Park, Junil Kim, Bona Lee, Hyojung Kim, Staci Jakyong Kim, Sujin Park, and Jin Muk Kang
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Recent advances in genome and transcriptome analysis have contributed to the identification of many potential cancer-related genes. Furthermore, biological and clinical investigations of the candidate genes provide us with a better understanding of carcinogenesis and development of cancer treatment. Here, we report a novel role of KIAA1324 as a tumor suppressor in gastric cancer. We observed that KIAA1324 was downregulated in most gastric cancers from transcriptome sequencing data and found that histone deacetylase was involved in the suppression of KIAA1324. Low KIAA1324 levels were associated with poor prognosis in gastric cancer patients. In the xenograft model, KIAA1324 significantly reduced tumor formation of gastric cancer cells and decreased development of preformed tumors. KIAA1324 also suppressed proliferation, invasion, and drug resistance and induced apoptosis in gastric cancer cells. Through protein interaction analysis, we identified GRP78 (glucose-regulated protein 78 kDa) as a KIAA1324-binding partner. KIAA1324 blocked oncogenic activities of GRP78 by inhibiting GRP78–caspase-7 interaction and suppressing GRP78-mediated AKT activation, thereby inducing apoptosis. In conclusion, our study reveals a tumor suppressive role of KIAA1324 via inhibition of GRP78 oncoprotein activities and provides new insight into the diagnosis and treatment of gastric cancer. Cancer Res; 75(15); 3087–97. ©2015 AACR.
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- 2023
17. Supplementary Figure 3 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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Young Il Yeom, Jong Young Choi, Hyang Sook Yoo, Kyung Chan Park, Soo Jung Kim, Goo Taeg Oh, Mi-Ni Lee, Dong Min Kim, Eun Young Song, Jae Wha Kim, Jong Seok Lim, Hee Gu Lee, Hyun Ahm Sohn, Bo Hwa Sohn, In Young Park, Dong Joon Kim, Ye Jin Jang, Woo Ho Kim, Yun Kyung Kang, and Dong Chul Lee
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Supplementary Figure 3 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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- 2023
18. Supplementary Figures 1-2 from Enzastaurin, a Protein Kinase Cβ Inhibitor, Suppresses Signaling through the Ribosomal S6 Kinase and Bad Pathways and Induces Apoptosis in Human Gastric Cancer Cells
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Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Byeong-Cheol Kang, Jung-Hyun Park, Hyung-Jun Choi, Jiran You, Euna Kwon, Hwang-Phill Kim, Sang Gyun Kim, and Keun-Wook Lee
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Supplementary Figures 1-2 from Enzastaurin, a Protein Kinase Cβ Inhibitor, Suppresses Signaling through the Ribosomal S6 Kinase and Bad Pathways and Induces Apoptosis in Human Gastric Cancer Cells
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- 2023
19. Supplementary Figure 1 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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Young Il Yeom, Jong Young Choi, Hyang Sook Yoo, Kyung Chan Park, Soo Jung Kim, Goo Taeg Oh, Mi-Ni Lee, Dong Min Kim, Eun Young Song, Jae Wha Kim, Jong Seok Lim, Hee Gu Lee, Hyun Ahm Sohn, Bo Hwa Sohn, In Young Park, Dong Joon Kim, Ye Jin Jang, Woo Ho Kim, Yun Kyung Kang, and Dong Chul Lee
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Supplementary Figure 1 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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- 2023
20. Data from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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Young Il Yeom, Jong Young Choi, Hyang Sook Yoo, Kyung Chan Park, Soo Jung Kim, Goo Taeg Oh, Mi-Ni Lee, Dong Min Kim, Eun Young Song, Jae Wha Kim, Jong Seok Lim, Hee Gu Lee, Hyun Ahm Sohn, Bo Hwa Sohn, In Young Park, Dong Joon Kim, Ye Jin Jang, Woo Ho Kim, Yun Kyung Kang, and Dong Chul Lee
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We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA–mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor β1–mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix–based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC. [Cancer Res 2008;68(11):4210–20]
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- 2023
21. Supplementary Methods and Materials, Tables 1-4, Figure Legends 1-3 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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Young Il Yeom, Jong Young Choi, Hyang Sook Yoo, Kyung Chan Park, Soo Jung Kim, Goo Taeg Oh, Mi-Ni Lee, Dong Min Kim, Eun Young Song, Jae Wha Kim, Jong Seok Lim, Hee Gu Lee, Hyun Ahm Sohn, Bo Hwa Sohn, In Young Park, Dong Joon Kim, Ye Jin Jang, Woo Ho Kim, Yun Kyung Kang, and Dong Chul Lee
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Supplementary Methods and Materials, Tables 1-4, Figure Legends 1-3 from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
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- 2023
22. Supplementary Materials and Methods from KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78
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Seong-Jin Kim, Woo Ho Kim, Han-Kwang Yang, Shin Tae Kim, Jinah Park, Junil Kim, Bona Lee, Hyojung Kim, Staci Jakyong Kim, Sujin Park, and Jin Muk Kang
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Supplementary Materials and Methods
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- 2023
23. Data from Enzastaurin, a Protein Kinase Cβ Inhibitor, Suppresses Signaling through the Ribosomal S6 Kinase and Bad Pathways and Induces Apoptosis in Human Gastric Cancer Cells
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Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Byeong-Cheol Kang, Jung-Hyun Park, Hyung-Jun Choi, Jiran You, Euna Kwon, Hwang-Phill Kim, Sang Gyun Kim, and Keun-Wook Lee
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Activation of protein kinase C (PKC) has been implicated in gastric carcinogenesis. Enzastaurin is an oral ATP-competitive inhibitor of the PKCβ isozyme. Although enzastaurin was initially advanced to the clinic based on its antiangiogenic activity, it is also known to have a direct effect on a variety of human cancer cells, inducing apoptosis by inhibiting the Akt signal pathway. However, data on enzastaurin for gastric cancer are limited. Therefore, this study was performed to assess the antitumor activity of enzastaurin on gastric cancer cells and to investigate the underlying antitumor mechanisms. Enzastaurin suppressed the proliferation of cultured gastric cancer cells and the growth of gastric carcinoma xenografts. Enzastaurin did not have an effect on gastric cancer cell cycle progression; however, it had a direct apoptosis-inducing effect through the caspase-mediated mitochondrial pathway. Glycogen synthase kinase 3β phosphorylation, a reliable pharmacodynamic marker of enzastaurin activity, and Akt phosphorylation were both decreased after treatment with enzastaurin. Although the p90 ribosomal S6 kinase (Rsk) was also dephosphorylated, Erk phosphorylation was not affected in the enzastaurin-treated gastric cancer cells. Enzastaurin activated Bad, one of the Bcl-2 proapoptotic proteins, through dephosphorylation at Ser112, and depletion of Bad activity resulted in resistance to enzastaurin-induced apoptosis and cytotoxicity in gastric cancer cells. These data suggest that enzastaurin induces apoptosis through Rsk-mediated and Bad-mediated pathways, besides inhibiting the Akt signal cascade. Furthermore, enzastaurin had synergistic or additive effects when combined with 5-fluorouracil, cisplatin, paclitaxel, or irinotecan. These results warrant further clinical investigation of enzastaurin for gastric cancer treatment. [Cancer Res 2008;68(6):1916–26]
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- 2023
24. Comparison of East‐Asia and West‐Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness
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Carolina Wälbhy, Hyuk-Joon Lee, Seong-Ho Kong, Diana Martins, Fátima Carneiro, Carolina Lemos, Ana André, Gabriela M. Almeida, Carla Pereira, Irene Gullo, Raquel Almeida, D. Almeida, Dina Leitão, Leslie Solorzano, Woo Ho Kim, Ji-Hyeon Park, Gilza Gonçalves, Sofia Campelos, Han-Kwang Yang, Carla Oliveira, and C. Borges
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Metastasis ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Lymph node ,Survival analysis ,Aged ,Neoplasm Staging ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Tissue microarray ,business.industry ,Cancer ,Middle Aged ,Cadherins ,medicine.disease ,3. Good health ,Early Gastric Cancer ,Hyaluronan Receptors ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cohort ,Lymph Node Excision ,Female ,Lymphadenectomy ,business - Abstract
Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin_abnormal and CD44v6_very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin_abnormal/CD44v6_very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy.
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- 2021
25. Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate -Induced Gastritis
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Sang Jun Ha, Woo Ho Kim, Su Hyung Lee, Sang Ho Woo, Seunghyun Lee, Dae Yong Kim, Kibyeong Kim, Jong Hwan Park, Jaehoon Choi, Kyu Seong Park, Kyeongdae Kim, and Du Min Go
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0301 basic medicine ,Hepatology ,biology ,T cell ,Gastroenterology ,Dendritic cell ,Helicobacter pylori ,biology.organism_classification ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Immunology ,Helicobacter felis ,Gastric mucosa ,medicine ,030211 gastroenterology & hepatology ,Helicobacter ,Gastritis ,medicine.symptom - Abstract
Background & Aims Helicobacter pylori has been reported to modulate local immune responses to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of H pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated. Methods The blockades of PD-L1 with antibody or PD-L1–deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or H pylori–infected dendritic cell (DC)-deficient mouse models including Flt3–/–, Zbtb46–diphtheria toxin receptor, and BDCA2–diphtheria toxin receptor mice were analyzed for pathologic changes and colonization levels. Finally, the location of PD-L1–expressing DCs and the correlation with H pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry. Results Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and human beings. H felis– or H pylori–infected Flt3–/– or classical DC-depleted mice showed aggravated gastritis with severe T-cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1–expressing DCs were co-localized with T cells and showed a positive correlation with H pylori infection in human subjects. Conclusions The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.
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- 2021
26. Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate Helicobacter-Induced GastritisSummary
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Du-Min Go, Seung Hyun Lee, Su-Hyung Lee, Sang-Ho Woo, Kibyeong Kim, Kyeongdae Kim, Kyu Seong Park, Jong-Hwan Park, Sang-Jun Ha, Woo Ho Kim, Jae-Hoon Choi, and Dae-Yong Kim
- Subjects
Immune Regulation ,T Cell ,Mucosal Metaplasia ,Gastric Inflammation ,RC799-869 ,Diseases of the digestive system. Gastroenterology - Abstract
Background & Aims: Helicobacter pylori has been reported to modulate local immune responses to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of H pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated. Methods: The blockades of PD-L1 with antibody or PD-L1–deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or H pylori–infected dendritic cell (DC)-deficient mouse models including Flt3–/–, Zbtb46–diphtheria toxin receptor, and BDCA2–diphtheria toxin receptor mice were analyzed for pathologic changes and colonization levels. Finally, the location of PD-L1–expressing DCs and the correlation with H pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry. Results: Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and human beings. H felis– or H pylori–infected Flt3–/– or classical DC-depleted mice showed aggravated gastritis with severe T-cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1–expressing DCs were co-localized with T cells and showed a positive correlation with H pylori infection in human subjects. Conclusions: The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.
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- 2021
27. RUNX3 methylation drives hypoxia-induced cell proliferation and antiapoptosis in early tumorigenesis
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Minh Phuong Nguyen, Ju Won Jang, Do Young Hyeon, Sojin An, Sun Hee Lee, Suk Chul Bae, Ji Hak Jeong, Woo Ho Kim, Saeng Myung Han, Xin Zi Chi, Soo Hyun Yoon, Hee Jung Jung, Ji-Joon Song, Kyung Gi Hyun, Daehee Hwang, and You Mie Lee
- Subjects
Male ,Cancer microenvironment ,Methyltransferase ,Carcinogenesis ,Mice, Nude ,Apoptosis ,medicine.disease_cause ,Article ,Mice ,Transactivation ,Cell Line, Tumor ,Histocompatibility Antigens ,medicine ,Animals ,Humans ,Tumour-suppressor proteins ,Molecular Biology ,Transcription factor ,Cell Proliferation ,Mice, Inbred BALB C ,Chemistry ,Cell growth ,Acetylation ,Histone-Lysine N-Methyltransferase ,Cell Biology ,Methylation ,DNA Methylation ,Cell cycle ,Xenograft Model Antitumor Assays ,Cell Hypoxia ,digestive system diseases ,Cell biology ,Gene Expression Regulation, Neoplastic ,Core Binding Factor Alpha 3 Subunit - Abstract
Inactivation of tumor suppressor Runt-related transcription factor 3 (RUNX3) plays an important role during early tumorigenesis. However, posttranslational modifications (PTM)-based mechanism for the inactivation of RUNX3 under hypoxia is still not fully understood. Here, we demonstrate a mechanism that G9a, lysine-specific methyltransferase (KMT), modulates RUNX3 through PTM under hypoxia. Hypoxia significantly increased G9a protein level and G9a interacted with RUNX3 Runt domain, which led to increased methylation of RUNX3 at K129 and K171. This methylation inactivated transactivation activity of RUNX3 by reducing interactions with CBFβ and p300 cofactors, as well as reducing acetylation of RUNX3 by p300, which is involved in nucleocytoplasmic transport by importin-α1. G9a-mediated methylation of RUNX3 under hypoxia promotes cancer cell proliferation by increasing cell cycle or cell division, while suppresses immune response and apoptosis, thereby promoting tumor growth during early tumorigenesis. Our results demonstrate the molecular mechanism of RUNX3 inactivation by G9a-mediated methylation for cell proliferation and antiapoptosis under hypoxia, which can be a therapeutic or preventive target to control tumor growth during early tumorigenesis.
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- 2020
28. Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas
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Ju Seog Lee, Hyuk-Joon Lee, Charles Lee, Jimin Min, Giyong Jang, Ji Eun Lee, Joshy George, Yun-Suhk Suh, Eui Hyun Kim, Han-Kwang Yang, Deukchae Na, Jeesoo Chae, Seong-Ho Kong, Seong-Jin Kim, Chan Young Ock, Chengsheng Zhang, Jong Il Kim, and Woo Ho Kim
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Proteomics ,Oncology ,medicine.medical_specialty ,Esophageal Neoplasms ,Adenocarcinoma ,Lapatinib ,Gastroesophageal Junction ,Transcriptome ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Stomach Neoplasms ,Internal medicine ,Covariate ,medicine ,Humans ,business.industry ,Alternative splicing ,Bayes Theorem ,medicine.disease ,030220 oncology & carcinogenesis ,Cohort ,030211 gastroenterology & hepatology ,Surgery ,Esophagogastric Junction ,business ,medicine.drug - Abstract
Objective To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. Summary of background data Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. Methods The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. Results AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015). Conclusions AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.
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- 2020
29. Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer
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Yujun Park, Hyunjin Park, Jiwon Koh, Hye Seung Lee, Hye Jung Hwang, Woo Ho Kim, Hee Young Na, Yoonjin Kwak, and Soo Kyung Nam
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Mutation ,Histology ,medicine.diagnostic_test ,business.industry ,Surrogate endpoint ,Cancer ,medicine.disease_cause ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Biopsy ,Medicine ,Missense mutation ,Immunohistochemistry ,Stage (cooking) ,business ,Survival analysis - Abstract
BACKGROUND Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC. METHODS Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated. RESULTS Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p
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- 2020
30. Helicobacter pylori Eradication Can Reverse the Methylation-Associated Regulation of miR-200a/b in Gastric Carcinogenesis
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Ji Min Choi, Hyun Chae Jung, Joo Sung Kim, Hyo Joon Yang, Joo Hyun Lim, Woo Ho Kim, Nam Yun Cho, and Sang Gyun Kim
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Stomach neoplasm ,Hepatology ,biology ,business.industry ,Gastroenterology ,Cancer ,Methylation ,Helicobacter pylori ,medicine.disease ,biology.organism_classification ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,microRNA ,Cancer research ,Gastric mucosa ,Medicine ,030211 gastroenterology & hepatology ,Helicobacter ,Epigenetics ,business - Abstract
Background/Aims: Epigenetic change is one of the mechanisms that regulates the expression of microRNAs (miRNAs) and is known to play a role in Helicobacter pylori-associated gastric carcinogenesis. We aimed to evaluate the epigenetic changes of miR-200a/b in H. pylori-associated gastric carcinogenesis and restoration after eradication. Methods: The expression and methylation levels of miR-200a/b were evaluated in gastric cancer (GC) cell lines, human gastric mucosa of H. pylori-negative and -positive controls, and H. pyloripositive GC patients. Next, the changes in the expression and methylation levels of miR-200a/b were compared between H. pylori -eradication and H. pylori -persistence groups at 6 months. Real-time reverse transcription-polymerase chain reaction was conducted to investigate the miRNA expression levels, and MethyLight was performed to assess the methylation levels. Results: In the GC cell lines, the level of miR- 200a/b methylation decreased and the level of expression increased after demethylation. In the human gastric mucosa, the miR-200a/b methylation levels increased in the following group order: H. pylori-negative control group, H. pylori-positive control group, and H. pylori-positive GC group. Conversely, the miR-200a/b expression levels decreased in the same order. In the H. pylori -persistence group, no significant changes were observed in the methylation and expression levels of miR-200a/b after 6 months, whereas the level of methylation decreased and the level of expression of miR-200a/b increased significantly 6 months in the H. pylori-eradication group. Conclusions: Epigenetic alterations of miR-200a/b may be implicated in H. pylori -induced gastric carcinogenesis. This field defect for cancerization is suggested to be improved by H. pylori eradication. (Gut Liver 2020;14:571- 580)
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- 2020
31. Immunoscore is a strong predictor of survival in the prognosis of stage II/III gastric cancer patients following 5-FU-based adjuvant chemotherapy
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Sang Hoon Ahn, Jiwon Koh, Soo Kyung Nam, Joong Do Park, Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Hyung Ho Kim, and Sumi Yun
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Cancer Research ,Chemotherapy ,Univariate analysis ,medicine.medical_specialty ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Cancer ,Microsatellite instability ,Subgroup analysis ,medicine.disease ,Gastroenterology ,Confidence interval ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Internal medicine ,medicine ,Immunology and Allergy ,business ,030215 immunology - Abstract
The prognostic impact of Immunoscore (IS) in gastric cancer (GC) patients treated with adjuvant chemotherapy remains unelucidated. We evaluated the CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in tumor centers and invasive margin regions of 389 patients with surgically resected stage II/III GC who received 5-FU-based adjuvant chemotherapy and investigated the impact of IS on survival. In univariate analysis, high CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in the invasive margin were correlated with better prognosis (all P
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- 2020
32. Evaluation of molecular subtypes and clonal selection during establishment of patient-derived tumor xenografts from gastric adenocarcinoma
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Vincent Vuaroqueaux, Isabella H. Wulur, Swee-Seong Wong, Manuel Landesfeind, Greg Donoho, Kerstin Klingner, Steven M. Bray, Han-Kwang Yang, Peter Bronsert, Anne-Lise Peille, Amit Aggarwal, Seong-Ho Kong, Woo Ho Kim, Bruno Zeitouni, Jason C. Ting, Christoph Reinhard, Nina Zanella, Heinz-Herbert Fiebig, and Hyuk-Joon Lee
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0301 basic medicine ,endocrine system ,endocrine system diseases ,Medicine (miscellaneous) ,Translational research ,Biology ,digestive system ,Article ,General Biochemistry, Genetics and Molecular Biology ,Immune compromised ,Efficacy ,03 medical and health sciences ,Gastric adenocarcinoma ,0302 clinical medicine ,Text mining ,Cancer models ,Cancer genetics ,lcsh:QH301-705.5 ,Tumor biology ,business.industry ,nutritional and metabolic diseases ,Histology ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Cancer research ,Gastric cancer ,General Agricultural and Biological Sciences ,business ,hormones, hormone substitutes, and hormone antagonists ,Clonal selection - Abstract
Patient-derived xenografts (PDX) have emerged as an important translational research tool for understanding tumor biology and enabling drug efficacy testing. They are established by transfer of patient tumor into immune compromised mice with the intent of using them as Avatars; operating under the assumption that they closely resemble patient tumors. In this study, we established 27 PDX from 100 resected gastric cancers and studied their fidelity in histological and molecular subtypes. We show that the established PDX preserved histology and molecular subtypes of parental tumors. However, in depth investigation of the entire cohort revealed that not all histological and molecular subtypes are established. Also, for the established PDX models, genetic changes are selected at early passages and rare subclones can emerge in PDX. This study highlights the importance of considering the molecular and evolutionary characteristics of PDX for a proper use of such models, particularly for Avatar trials., Peille et al. establish patient-derived xenografts (PDX) from gastric adenocarcinoma, expanding our knowledge on what subtypes can be developed into PDX models. Their extensive molecular characterization also reveals that PDX are subject to clonal selection in early passages, which is an important consideration for clinical studies.
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- 2020
33. Trop2 is upregulated in the transition to dysplasia in the metaplastic gastric mucosa
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Qing Yang, Woo Ho Kim, William T. Fesmire, Sophie Camilleri-Broët, Joseph T. Roland, Lorenzo E. Ferri, Bogun Jang, Katherine M. Riera, Jimin Min, Eun-Young Choi, and James R. Goldenring
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Stomach Neoplasms ,Metaplasia ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Gastric mucosa ,Animals ,Humans ,Cells, Cultured ,Tissue microarray ,Stomach ,Microfilament Proteins ,Intestinal metaplasia ,medicine.disease ,digestive system diseases ,Up-Regulation ,Organoids ,Disease Models, Animal ,Cell Transformation, Neoplastic ,Genes, ras ,030104 developmental biology ,medicine.anatomical_structure ,Gastric Mucosa ,Dysplasia ,030220 oncology & carcinogenesis ,KRAS ,medicine.symptom ,Cell Adhesion Molecules ,Precancerous Conditions ,Immunostaining ,Signal Transduction - Abstract
Intestinal-type gastric adenocarcinoma arises in a field of pre-existing metaplasia. While biomarkers of cancer and metaplasia have been identified, the definition of dysplastic transition as a critical point in the evolution of cancer has remained obscure. We have evaluated Trop2 as a putative marker of the transition from metaplasia to dysplasia in the stomach in multiple mouse models of metaplasia induction and progression. In addition, TROP2 expression was evaluated in human samples by immunostaining tissue microarrays for metaplasia, dysplasia, and gastric cancer. Dysplastic mouse organoids were evaluated in vitro following shRNA knockdown of Trop2 expression. In mouse models, no Trop2 was observed in the normal corpus and Trop2 was not induced in acute models of metaplasia induction with either L635 or DMP-777. In Mist1-Kras mice, Trop2 expression was not observed in metaplasia at 1 month after Kras induction, but was observed in dysplastic glands at 3-4 months after Kras induction. In human tissues, no Trop2 was observed in normal corpus mucosa or SPEM, but Trop2 expression was observed in incomplete intestinal metaplasia, with significantly less expression in complete intestinal metaplasia. Trop2 expression was observed in all dysplastic and 84% of gastric cancer lesions, although expression levels were variable. Dysplastic mouse organoids from Mist1-Kras mice expressed Trop2 strongly. Knockdown of Trop2 with shRNA markedly reduced organoid growth and budding behavior, and induced the upregulation of apical villin expression. We conclude that Trop2 is upregulated in the transition to dysplasia in the stomach and promotes dysplastic cell behaviors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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- 2020
34. Differential prognostic impact of CD8+ T cells based on human leucocyte antigen I and PD-L1 expression in microsatellite-unstable gastric cancer
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Yoonjin Kwak, Yujun Park, Sang Hoon Ahn, Hyung Ho Kim, Woo Ho Kim, Kyoung Un Park, Jiwon Koh, Yun Ji Hong, Hye Seung Lee, and Do Joong Park
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0303 health sciences ,Cancer Research ,business.industry ,Microsatellite instability ,Human leukocyte antigen ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Genotype ,Cancer research ,medicine ,Immunohistochemistry ,Cytotoxic T cell ,Allele ,business ,CD8 ,Survival analysis ,030304 developmental biology - Abstract
Background The aim of the study was to determine the human leucocyte antigen class-I (HLA-I), programmed death-ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) of microsatellite instability-high gastric cancer. Methods The HLA-I expression type was determined by immunohistochemistry of HLA-A, HLA-B, HLA-C and β2-microglobulin in the centre of the tumour (CT) and in the invasive margin (IM) of samples from 293 patients (total loss vs. preserved type). PD-L1 expression and TIL density was examined immunohistochemically. HLA-I genotyping was also performed. Results The expression loss of the HLA-I molecules was significantly associated with low TIL density. According to survival analyses, the HLA-I expression type and PD-L1 positivity were not independent prognostic factors. The TIL density had no prognostic implication when survival analysis was performed for the whole patient group; however, high CD8+ TIL infiltration was significantly associated with good prognosis in only HLA-I-preserved-type/PD-L1-positive group (p = 0.034). The homozygosity of the HLA-I allele was more frequently observed in the total loss type group. Conclusions We confirmed differential prognostic implication of CD8+ TILs according to the HLA-I and PD-L1 expression. Determination of the HLA-I expression could be helpful to select patients who would benefit from anti-PD-1/PD-L1 therapy.
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- 2020
35. Downregulation of SMOC2 expression in papillary thyroid carcinoma and its prognostic significance
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Jae Kyung Myung, Jae Young Lee, Woo Ho Kim, Bo Gun Jang, Jae Hyuck Choi, Hye Sung Kim, and JiHoon Kang
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Male ,Proto-Oncogene Proteins B-raf ,endocrine system diseases ,Down-Regulation ,lcsh:Medicine ,Biology ,Article ,Epigenesis, Genetic ,Thyroid carcinoma ,Tumour biomarkers ,Cell Line, Tumor ,medicine ,Humans ,Thyroid Neoplasms ,lcsh:Science ,Thyroid cancer ,Neoplasm Staging ,Regulation of gene expression ,Sex Characteristics ,Multidisciplinary ,Thyroid ,Calcium-Binding Proteins ,lcsh:R ,Cancer ,Cell cycle ,DNA Methylation ,medicine.disease ,Prognosis ,Survival Analysis ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Thyroid diseases ,medicine.anatomical_structure ,Amino Acid Substitution ,Thyroid Cancer, Papillary ,Case-Control Studies ,DNA methylation ,Cancer research ,Female ,lcsh:Q ,V600E - Abstract
Secreted Protein Acidic and Rich in Cysteine (SPARC)-related modular calcium-binding protein-2 (SMOC2), a secreted matricellular protein, is reported to be involved in various processes related to cancer progression such as regulating the cell cycle, angiogenesis, and invasion. However, its expression and prognostic significance in papillary thyroid carcinomas (PTCs) remains unknown. Using immunohistochemistry, we evaluated the expression profile of SMOC2 and its prognostic value in a large cohort of PTCs. Real time-PCR analysis with fresh-frozen tissues showed that SMOC2 mRNA expression in PTCs was substantially lower than the expression in matched non-cancerous thyroid tissues, consistent with the results from thyroid cancer cell lines. Immunohistochemical analysis demonstrated that SMOC2 was normally present in thyroid follicular epithelial cells and the expression level was maintained in nodular hyperplasia. However, SMOC2 expression was significantly lower in lymphocytic thyroiditis and follicular tumors including follicular adenomas and carcinomas. In particular, 38% of PTCs exhibited a complete loss of SMOC2 expression, which was associated with the presence of BRAF (V600E) mutation. Moreover, SMOC2 further declined during lymph node metastasis in PTCs. DNA methylation chip analysis revealed one hypermethylated CpG site in the promoter region of SMOC2 gene, suggesting an epigenetic regulation of SMOC2 in PTCs. Remarkably SMOC2 positivity was associated with improved recurrence-free survival along with female sex, tumor size, and the N stage. However, SMOC2 was not identified as an independent prognostic marker in multivariate analyses. Taken together, SMOC2 expression is significantly down-regulated in PTCs and SMOC2 positivity is closely associated with better clinical outcomes, suggesting that SMOC2 can be a prognostic marker in PTC patients.
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- 2020
36. Establishment of a [18F]-FDG-PET/MRI Imaging Protocol for Gastric Cancer PDX as a Preclinical Research Tool
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Kyoung Yun Jeong, Hyuk Joon Lee, Seong Ho Kong, Han-Kwang Yang, Woo Ho Kim, Felix Berlth, Seong Woo Bae, June-Key Chung, and Yun Suhk Suh
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Cancer Research ,Pathology ,medicine.medical_specialty ,Standardized uptake value ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Avidity ,medicine.diagnostic_test ,biology ,business.industry ,Xenograft ,Gastroenterology ,Glucose transporter ,Cancer ,Magnetic resonance imaging ,PET scan ,medicine.disease ,carbohydrates (lipids) ,Oncology ,Positron emission tomography ,030220 oncology & carcinogenesis ,biology.protein ,Immunohistochemistry ,030211 gastroenterology & hepatology ,GLUT1 ,Original Article ,business ,Gastric cancer ,Glycolysis - Abstract
Purpose The utility of 18-fluordesoxyglucose positron emission tomography ([18F]-FDG-PET) combined with computer tomography or magnetic resonance imaging (MRI) in gastric cancer remains controversial and a rationale for patient selection is desired. This study aims to establish a preclinical patient-derived xenograft (PDX) based [18F]-FDG-PET/MRI protocol for gastric cancer and compare different PDX models regarding tumor growth and FDG uptake. Materials and methods Female BALB/c nu/nu mice were implanted orthotopically and subcutaneously with gastric cancer PDX. [18F]-FDG-PET/MRI scanning protocol evaluation included different tumor sizes, FDG doses, scanning intervals, and organ-specific uptake. FDG avidity of similar PDX cases were compared between ortho- and heterotopic tumor implantation methods. Microscopic and immunohistochemical investigations were performed to confirm tumor growth and correlate the glycolysis markers glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) with FDG uptake. Results Organ-specific uptake analysis showed specific FDG avidity of the tumor tissue. Standard scanning protocol was determined to include 150 μCi FDG injection dose and scanning after one hour. Comparison of heterotopic and orthotopic implanted mice revealed a long growth interval for orthotopic models with a high uptake in similar PDX tissues. The H-score of GLUT1 and HK2 expression in tumor cells correlated with the measured maximal standardized uptake value values (GLUT1: Pearson r=0.743, P=0.009; HK2: Pearson r=0.605, P=0.049). Conclusions This preclinical gastric cancer PDX based [18F]-FDG-PET/MRI protocol reveals tumor specific FDG uptake and shows correlation to glucose metabolic proteins. Our findings provide a PET/MRI PDX model that can be applicable for translational gastric cancer research.
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- 2020
37. Identification of a molecular signature of prognostic subtypes in diffuse-type gastric cancer
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Sang-Il Lee, Yong Sung Kim, Hee-Jin Kim, Woo-Ho Kim, Kyu-Sang Song, Seon-Kyu Kim, Jong-Lyul Park, Haejeong Heo, and Seon-Young Kim
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Immune checkpoint inhibitor ,Cohort Studies ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Stomach Neoplasms ,Surgical oncology ,Antineoplastic Combined Chemotherapy Protocols ,Intestinal Neoplasms ,Gene expression ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Chemotherapy ,Humans ,Diffuse type ,Medicine ,Insulin-Like Growth Factor I ,Cell Proliferation ,Diffuse-type GC ,Proportional hazards model ,business.industry ,Gene Expression Profiling ,Gastroenterology ,General Medicine ,Immunotherapy ,Middle Aged ,Prognosis ,Predictive value ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Original Article ,Female ,Gastric cancer ,business ,Follow-Up Studies - Abstract
Background Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim to identify a prognostic and predictive signature of diffuse-type GC heterogeneity. Methods We analyzed RNA-seq-based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse-type GCs. The predictive value of the signature was verified using other diffuse-type GC samples in three independent cohorts (n = 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes. Results Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53–2.77, P = 1.76 × 10–6). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity. Conclusions We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.
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- 2019
38. Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa
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Jimin Min, Changqing Zhang, R. Jarrett Bliton, Brianna Caldwell, Leah Caplan, Kimberly S. Presentation, Do-Joong Park, Seong-Ho Kong, Hye Seung Lee, M. Kay Washington, Woo-Ho Kim, Ken S. Lau, Scott T. Magness, Hyuk-Joon Lee, Han-Kwang Yang, James R. Goldenring, and Eunyoung Choi
- Subjects
Hyperplasia ,Hepatology ,Casein Kinase I ,Stem Cells ,Cell Plasticity ,Gastroenterology ,Ligands ,Article ,Proto-Oncogene Proteins p21(ras) ,Mice ,Cell Transformation, Neoplastic ,Gastric Mucosa ,Stomach Neoplasms ,Tumor Microenvironment ,Animals ,Humans ,Precancerous Conditions ,beta Catenin - Abstract
BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development, however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified two putative dysplastic stem cell (DSC) populations, CD44v6(neg)/CD133(+)/CD166(+) (DP) and CD44v6(+)/CD133(+)/CD166(+) (TP), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of non-cancerous Trop2(+)/CD133(+)/CD166(+) DSCs initially developed in the transition from pre-cancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were utilized for transcriptome analysis, in vitro differentiation and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of CK1α regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve towards multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Lastly, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.
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- 2021
39. Predictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts
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Seong Ho Kong, Jinjoo Kang, Jong Il Kim, Hansoo Park, Ahra Lee, Sung Yup Cho, Seock-Ah Im, Woochan Lee, Tae Yong Kim, Wonyoung Kang, Deukchae Na, Min Jung Kim, Jeesoo Chae, Seoyeon Min, Woo Ho Kim, Ahrum Min, Kyung Hun Lee, Dongjin Shin, Han-Kwang Yang, Charles Lee, Yu Jin Kim, Yun Suhk Suh, Hyuk Joon Lee, and Jaeyong Choi
- Subjects
Oncology ,medicine.medical_specialty ,Science ,medicine.medical_treatment ,General Physics and Astronomy ,Mice, SCID ,Adenocarcinoma ,Article ,General Biochemistry, Genetics and Molecular Biology ,Tumour biomarkers ,Mice, Inbred NOD ,Stomach Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Cancer genomics ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Survival analysis ,Mice, Knockout ,Chemotherapy ,Tumor microenvironment ,Multidisciplinary ,business.industry ,Gene Expression Profiling ,Cancer ,General Chemistry ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,digestive system diseases ,Colon cancer ,Tumor Burden ,Oxaliplatin ,Gene Expression Regulation, Neoplastic ,Fluorouracil ,Cancer cell ,Female ,business ,medicine.drug - Abstract
Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies., Gastric cancer is commonly treated by chemotherapy using 5-fluorouracil derivatives and platinum combination, but predictive biomarker remains lacking. Here, the authors develop a 30-gene prediction model to determine the responsiveness to 5-fluorouracil and oxaliplatin-based chemotherapy through the integrative profiling of patient-derived xenografts
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- 2021
40. Mapping of the perigastric lymphatic network using indocyanine green fluorescence imaging and tissue marking dye in clinically advanced gastric cancer
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Yun Suhk Suh, Hyuk Joon Lee, Yoonjin Kwak, Jong Ho Choi, Do Joong Park, Sen Wang, Woo Ho Kim, Shin Hoo Park, Seong Ho Kong, Chao Jie Wang, Ji Hyeon Park, Felix Berlth, and Han-Kwang Yang
- Subjects
Indocyanine Green ,Male ,genetic structures ,medicine.medical_treatment ,Adenocarcinoma ,Lymphatic System ,chemistry.chemical_compound ,Gastrectomy ,Stomach Neoplasms ,medicine ,Humans ,Coloring Agents ,Aged ,Aged, 80 and over ,Intraoperative Care ,integumentary system ,business.industry ,Stomach ,Optical Imaging ,General Medicine ,Perigastric ,Middle Aged ,eye diseases ,body regions ,Dissection ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,chemistry ,Lymphatic Metastasis ,Subserosa ,Lymph Node Excision ,Surgery ,Female ,Lymph ,Lymph Nodes ,Nuclear medicine ,business ,Indocyanine green - Abstract
Background Using indocyanine green (ICG) fluorescence imaging and tissue marking dyes (TMDs), perigastric lymphatic mapping and their pathological correlation were examined to see whether ICG staining covers all metastatic lymph nodes (LNs) in advanced gastric cancer (AGC). Methods Patients with AGC who underwent open distal or total gastrectomy were enrolled. ICG was serially injected intraoperatively into the subserosa along the greater and lesser curvatures. Stomach specimens were examined under a near-infrared camera. ICG-stained LNs were named, excised, and tattooed with different colored TMDs to retrace the exact location after pathological examinations. Results A total of 687 LNs and 69 LN stations were examined from 11 patients. The map of the perigastric lymphatic network showing the topography of ICG-stained and ICG-unstained LNs, including metastatic information, was successfully reconstructed. The average number of ICG-stained and ICG-unstained LNs were 23.6 ± 12.3 (37.8%) and 38.8 ± 17.1 (62.2%), respectively. LN metastases were present in 28 LN stations of 8 patients. Of 8 cases with LN metastases, 40% (11.1–75% per case) of metastatic LNs were stained by ICG. Of 28 metastatic LN stations, 21 (75.0%) were covered by ICG, and actual metastatic LNs were stained in 16 LN stations (57.1%). In 4/8 cases (50%), all metastatic LN stations showed ICG signals. Conclusions ICG fluorescence imaging and TMD are useful tools for visualizing the perigastric lymphatic network and retracing the exact location of ICG-stained LNs in AGC. However, ICG imaging is still not recommended for selective LN dissection in AGC because of the limited staining of perigastric LNs.
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- 2021
41. Assessment of copy number in protooncogenes are predictive of poor survival in advanced gastric cancer
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Tae Shin Kim, Meihui Li, Jeong Mo Bae, Nam Yun Cho, Woo Ho Kim, Young Hoon Kim, and Gyeong Hoon Kang
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Poor prognosis ,DNA Copy Number Variations ,Science ,Gastric carcinoma ,Article ,Tumour biomarkers ,03 medical and health sciences ,Gastrointestinal cancer ,0302 clinical medicine ,Text mining ,Gastrectomy ,Stomach Neoplasms ,Internal medicine ,Proto-Oncogenes ,medicine ,Cancer genomics ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,Gene ,Aged ,Aged, 80 and over ,Multidisciplinary ,GATA6 ,business.industry ,Methylation ,Advanced gastric cancer ,Middle Aged ,medicine.disease ,Prognosis ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Medicine ,Female ,business ,Follow-Up Studies - Abstract
The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.
- Published
- 2021
42. Clinicopathologic significance of human leukocyte antigen class I expression in patients with stage II and III gastric cancer
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Hyung Ho Kim, Yujun Park, Sang Hoon Ahn, Woo Ho Kim, Jiwon Koh, Hye Seung Lee, Yoonjin Kwak, and Do Joong Park
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Adult ,Male ,Cancer Research ,medicine.medical_treatment ,Immunology ,Human leukocyte antigen ,B7-H1 Antigen ,Young Adult ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Antigen ,HLA Antigens ,Stomach Neoplasms ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Aged ,Neoplasm Staging ,Aged, 80 and over ,business.industry ,Beta-2 microglobulin ,Microsatellite instability ,Immunotherapy ,Middle Aged ,medicine.disease ,HLA-A ,Oncology ,Cancer research ,Female ,Microsatellite Instability ,beta 2-Microglobulin ,business ,CD8 ,Follow-Up Studies ,030215 immunology - Abstract
Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLA genes, and beta-2-microglobulin (β2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, β2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array method. Additionally, Epstein–Barr virus (EBV) infection and microsatellite instability (MSI) status were investigated. Negative expression of HLA A/B/C and β2M was observed in 258 (65.3%) and 235 (59.5%) of 395 stage II and III GCs, respectively. Negative HLA I expression was significantly associated with aggressive clinicopathologic features. Furthermore, negative expression of HLA A/B/C and β2M was inversely correlated with CD8-positive cytotoxic T cell infiltration, EBV-positivity, and PD-L1 expression (all p
- Published
- 2019
43. Microsatellite Instability and Programmed Cell Death-Ligand 1 Expression in Stage II/III Gastric Cancer
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Young-Kyu Park, Jongwon Kim, Sung Hoon Noh, Myeong Cherl Kook, Hyung Ho Kim, Young-Woo Kim, Hyunki Kim, Kyung Hee Lee, Ha Yan Kim, Yoon Young Choi, Su Jin Shin, Han-Kwang Yang, Soon Won Hong, Woo Jin Hyung, Mi Jin Gu, Jinae Lee, Hye Seung Lee, Seung Ho Choi, Jae Ho Cheong, and Woo Ho Kim
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Programmed cell death ,business.industry ,medicine.medical_treatment ,Microsatellite instability ,Cancer ,medicine.disease ,digestive system diseases ,03 medical and health sciences ,0302 clinical medicine ,Apoptosis ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Biomarker (medicine) ,Immunohistochemistry ,030211 gastroenterology & hepatology ,Surgery ,Gastrectomy ,business - Abstract
Objective:We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III gastric cancer.Background:The clinical implications of MSI status and PD-L1 expression in gastric canc
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- 2019
44. Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications
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Jin Won Kim, Jiwon Koh, Keun Wook Lee, Hye Seung Lee, Hyung Ho Kim, Ji Won Kim, Soo Kyung Nam, Woo Ho Kim, An Na Seo, and Do Joong Park
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,law ,Internal medicine ,Gastrointestinal Cancer ,medicine ,Humans ,Stage (cooking) ,Polymerase chain reaction ,Aged ,Aged, 80 and over ,business.industry ,Microsatellite instability ,Cancer ,Genomic signature ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Gastrectomy ,business ,Algorithms - Abstract
Background Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)- and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. Materials and Methods A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. Results We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV−, MSI−, non-epithelial-mesenchymal transition [non-EMT]-like, p53−), group 3 (EBV+), group 4 (EBV−, MSI−, non-EMT-like, p53+), and group 5 (EBV−, MSI−, EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. Conclusion We developed and validated a modified IHC- and PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. Implications for Practice Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry- and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.
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- 2019
45. High-Throughput Multiplex Immunohistochemical Imaging of the Tumor and Its Microenvironment
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Yoonjin Kwak, Jiwon Koh, Jin Kim, and Woo Ho Kim
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Formalin fixed paraffin embedded ,H&E stain ,03 medical and health sciences ,Cytokeratin ,0302 clinical medicine ,Neoplasms ,Immunochemistry ,Biomarkers, Tumor ,Image Processing, Computer-Assisted ,Medicine ,Humans ,Multiplex ,Tumor microenvironment ,Tissue microarray ,business.industry ,Tissue microarray analysis ,Computational Biology ,Reproducibility of Results ,Immunohistochemistry ,Computer-assisted image processing ,Molecular Imaging ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,business ,Software ,Microsatellite Repeats - Abstract
Purpose The aim of this study was to develop a formalin-fixed paraffin-embedded (FFPE) tissue based multiplex immunochemistry (mIHC) method for high-throughput comprehensive tissue imaging and demonstrate its feasibility, validity, and usefulness. Materials and methods The mIHC protocol was developed and tested on tissue microarray slides made from archived gastric cancer (GC) tissue samples. On a single FFPE slide, cyclic immunochemistry for multiple markers of immune cells and cytokeratin for tumor cells was performed; hematoxylin staining was used for demarcation of nuclei. Whole slides were digitally scanned after each cycle. For interpretation of mIHC results, we performed computer-assisted image analysis using publicly available software. Results Using mIHC, we were able to characterize the tumor microenvironment (TME) of GCs with accurate visualization of various immune cells harboring complex immunophenotypes. Spatial information regarding intratumoral and peritumoral TME could be demonstrated by digital segmentation of image guided by cytokeratin staining results. We further extended the application of mIHC by showing that subcellular localization of molecules can be achieved by image analysis of mIHC results. Conclusion We developed a robust method for high-throughput multiplex imaging of FFPE tissue slides. The feasibility and adaptability of mIHC suggest that it is an efficient method for in situ single-cell characterization and analysis.
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- 2019
46. Clinical significance of BRCA1 and BRCA2 mRNA and protein expression in patients with sporadic gastric cancer
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Woo Ho Kim, Hee Sung Kim, Hyeyoung Min, In Gyu Hwang, and Yung‑Jue Bang
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,In situ hybridization ,in-situ hybridization ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Gene expression ,medicine ,Clinical significance ,skin and connective tissue diseases ,Survival rate ,neoplasms ,Survival analysis ,business.industry ,gastric cancer ,Cancer ,Articles ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,immunohistochemistry ,breast cancer type 1 and 2 susceptibility protein ,Immunohistochemistry ,business - Abstract
The purpose of the present study was to investigate the clinical significance of BRCA1/BRCA2 DNA repair associated (BRCA1/BRCA2) gene expression in patients with sporadic gastric cancer (GC) who had received postoperative adjuvant chemotherapy. Breast cancer type 1 and 2 susceptibility protein (BRCA1 and BRCA2) expression and BRCA1/BRCA2 mRNA expression were evaluated using immunohistochemistry (IHC) and in-situ hybridization (ISH) on tissue GC microarray tissues, in addition to reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results were analyzed for clinicopathological associations. A total of 367 cases of sporadic GC (stages II and III) were subjected to BRCA1 and BRCA2 expression analysis, and for BRCA1 and BRCA2 IHC, 360 cases were informative. A total of 61 cases (16.9%) displayed a loss of BRCA1 and 63 (17.5%) displayed a loss of BRCA2. BRCA1 and BRCA2 ISH results were obtained in 364 cases, of which 98 (26.9%) presented with low expression of BRCA1 mRNA and 148 (40.7%) with low expression of BRCA2 mRNA. In 72 of the 367 cases, BRCA1 and BRCA2 mRNA expression levels were assessed using RT-qPCR, of which 50 (69.4%) and 56 (77.8%) displayed low expression of BRCA1 and BRCA2, respectively. Positive IHC expression of BRCA2 was associated with advanced tumor stage; however, BRCA1 expression was not associated with any clinicopathological parameters. Associations between the RT-qPCR and ISH methods were not significant for either BRCA1 or BRCA2. The results of Kaplan-Meier survival analysis with stage subgrouping revealed no significant differences with regard to survival rate. Of the multivariate analyses, neither BRCA1 nor BRCA2 IHC results were independent prognostic factors. In summary, the present study indicated that BRCA1 and BRCA2, as assessed by IHC, may be used as clinicopathological biomarkers to evaluate the prognosis of sporadic GC.
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- 2019
47. A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors
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Dong Hyuck Bae, Woo Ho Kim, Keisuke Okuno, Yoshinobu Eishi, Hiroshi Kawachi, Toshiro Tanioka, Sun-Ju Byeon, Hye Seung Lee, Taketo Nishikawaji, Kazuyuki Kojima, Takashi Tokino, Shinji Tanaka, Seon-Kyu Kim, Masatoshi Nakagawa, Shu Shimada, Yoshimitsu Akiyama, Yasushi Sasaki, Mikito Inokuchi, Yasuhito Yuasa, Hiroshi Fukamachi, Jiwon Koh, Kentaro Yamashita, Yong Sung Kim, and Kiichiro Tsuchiya
- Subjects
0301 basic medicine ,PD-L1 ,Cancer Research ,endocrine system ,Temsirolimus ,mTOR inhibitor ,Microsatellite unstable ,Immune checkpoint inhibitor ,lcsh:RC254-282 ,Diffuse-type gastric cancer ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Stomach Neoplasms ,Patient-derived xenograft ,health services administration ,Gene expression ,medicine ,polycyclic compounds ,Animals ,Humans ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Primary culture ,Everolimus ,biology ,TOR Serine-Threonine Kinases ,Research ,Microsatellite instability ,PIK3CA ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Microsatellite Instability ,sense organs ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Background Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs. Methods We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles. Results mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells. Conclusion mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs. Electronic supplementary material The online version of this article (10.1186/s13046-019-1121-3) contains supplementary material, which is available to authorized users.
- Published
- 2019
48. Pylorus-preserving gastrectomy for early cancer involving the upper third: can we go higher?
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Han-Kwang Yang, Chun Chao Zhu, Hyuk Joon Lee, Hwi Nyeong Choe, Hui Cao, Yun Suhk Suh, Shin Hoo Park, Seong Ho Kong, Felix Berlth, Jia Xu, and Woo Ho Kim
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Gastroenterology ,Metastasis ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Gastrectomy ,Stomach Neoplasms ,Surgical oncology ,Internal medicine ,Gastric Stump ,medicine ,Humans ,Prospective Studies ,Pylorus ,Aged ,business.industry ,Stomach ,Incidence (epidemiology) ,General Medicine ,Prognosis ,medicine.disease ,Early Gastric Cancer ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,sense organs ,business ,Organ Sparing Treatments ,Body mass index ,Follow-Up Studies ,Abdominal surgery - Abstract
Pylorus-preserving gastrectomy (PPG) is commonly performed for early gastric cancer (EGC) located in middle third of the stomach. We investigated the surgical, oncological, and functional outcomes of PPG involving the upper third of stomach. We included all patients of the period 2013–2016 who underwent PPG, distal subtotal gastrectomy (DSG), and total gastrectomy (TG) for EGC involving the upper third by carefully defining the localization. Surgical, oncological, and functional outcome analyses included postoperative morbidity, lymph-node metastasis, tumor recurrence, postoperative body weight, body mass index, hemoglobin, total protein, albumin, quantification of intraabdominal fat, and gallstone development. Overall, 288 cases were analyzed: 145 PPG, 61 DSG, and 82 TG. In the study period, patients potentially underwent PPG for EGC involving the upper third, if enough proximal remnant stomach was found whilst achieving a sufficient proximal margin. PPG resulted in less operation time (p
- Published
- 2019
49. Expression of DNA Damage Response Markers in Early-Onset or Familial Gastric Cancers
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Hye Seung Lee, In Gyu Hwang, Jongwon Kim, Hee Sung Kim, and Woo Ho Kim
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0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,DNA damage ,Early-onset gastric cancer ,Biology ,DNA damage response ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Gastrectomy ,Stomach Neoplasms ,medicine ,Overall survival ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Early Detection of Cancer ,Early onset ,BRCA2 Protein ,MRE11 Homologue Protein ,Tissue microarray ,BRCA1 Protein ,Cancer ,Negativity effect ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Immunohistochemistry ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,DNA Repair Enzymes ,030220 oncology & carcinogenesis ,RAD51C ,Female ,Research Article ,DNA Damage ,Follow-Up Studies - Abstract
Background: Early-onset or familial gastric cancer (GC) is known to have clinicopathologic profiles different from those of sporadic GC. We aimed to compare DNA damage response marker expression between early-onset or familial GC and sporadic GC. Methods: GC samples were obtained from patients who underwent gastrectomy for GC at Seoul National University Hospital. Immunohistochemical analyses of various DNA damage response markers, including BRCA1, BRCA2, MRE11, RAD51C, and γH2AX, were performed using 54 early-onset GC, 59 familial GC, and 337 sporadic GC tissue microarray samples. Correlations between marker expression and clinicopathologic features were evaluated by univariate and multivariate analyses, and overall survival was analyzed. Results: The rate of γH2AX positivity was significantly higher (p < 0.001) in early-onset or familial GC than in sporadic GC. In contrast, the rates of MRE11 negativity and RAD51C negativity were significantly higher in sporadic GC than in early-onset or familial GC. BRCA1 negativity was associated with decreased overall survival in sporadic GC (p = 0.002), and MRE11 negativity was associated with decreased overall survival in sporadic GC (p = 0.012). Conclusion: Our results show significant differences in DNA damage response marker expression between early-onset or familial GC and sporadic GC.
- Published
- 2019
50. 344: TROP2+CD133+CD166+ DYSPLASTIC STEM CELLS ARE DE NOVO STEM CELLS DRIVING DYSPLASIA TRANSITION TO GASTRIC CANCER
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Jimin Min, Changqing Zhang, Jarrett Bliton, Brianna M. Caldwell, Leah R. Caplan, Kimberly S. Presentation, Do-Joong Park, Seong-Ho Kong, Mary K. Washington, Woo Ho Kim, Ken S. Lau, Scott Magness, Hyuk-Joon Lee, Han-Kwang Yang, James R. Goldenring, and Eunyoung Choi
- Subjects
Hepatology ,Gastroenterology - Published
- 2022
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