Concurrent MET copy number gain and KRAS mutation is a poor prognostic factor in pancreatobiliary subtype ampullary cancers

Hepatocyte growth factor (HGF) and MET are candidates of targeted therapies for cancer patients. Although MET and HGF are commonly expressed in biliary tract cancers, their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas (A-ACs), one of the aggressive periampullary cancers. MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 62 surgically resected, paraffin-embedded tumors, respectively. High MET and HGF protein expressions were detected in 24 (38.7%) and 15 (24.2%) tumors. High MET expression was associated with KRAS mutation. However, there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival. MET SISH positivity was detected in 19 tumors (30.6%), where 84.2% were due to high trisomy or polysomy and only 3 cases (15.8%) were MET gene amplification. The overall MET protein overexpression was well correlated with METSISH positivity. The concurrent MET SISH positivity and KRAS mutation, not each alone, was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs, but not in intestinal subtype.Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs, indicating those markers could be potent candidates for a new therapeutic target in this cancer type. MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers. (C) 2017 Elsevier GmbH. All rights reserved.This research was supported by Hallym University Research Funds (HURF-2015-08) and (HURF-2016-40) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03935447)

Loss of p27(kip1) expression is associated with poor prognosis in patients with taxane-treated breast cancer

Purpose: Decreased expression of p27(kip1) and p57(kip2) is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27(kip1) and p57(kip2) is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27(kip1) and p57(kip2) expression with outcomes in patients with breast cancer.Methods: We investigated 226 cases of breast cancer from Kangbuk SMC between 2000 and 2005. Levels of p27(kip1) and p57(kip2) expression were evaluated using immunohistochemical staining of tumor tissue microarray specimens. The relationships between the expression levels of the markers and patients' outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazard model.Results: Low p57(kip2) expression was only associated with negative progesterone receptor status (p = 0.034), whereas p27(kip1) expression was associated with poor prognosis of patients receiving adjuvant chemotherapy (p = 0.005). More detailed analysis revealed that low p27(kip1) expression affects the overall survival rate of patients receiving adjuvant chemotherapy including taxane (p = 0.026), but not that of patients receiving chemotherapy without taxane.Conclusions: Low p27(kip1) expression may be useful to predict overall survival in patients with breast cancer who are treated with taxane. Evaluation of p27(kip1) expression may provide further prognostic information beyond traditional prognostic biomarkers and an understanding of the mechanisms that impart resistance against chemotherapy.This work was supported by the research fund of Hanyang University (HY-2017)

Middle power 視角에서 본 韓國軍事交易의 實證的硏究

학위논문(석사)--서울大學校 行政大學院 :行政學科 行政學專攻,1996.Maste

Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer

Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by in vitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and in vivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance in vitro and in vivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm(3), vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm(3), P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1- HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (No. 2015R1A2A1A10052578)

Task and Flow-based Manufacturing Execution Language for Rapid Control Programming

MasterNowadays, market demand is becoming more diverse and unpredictable, and the life cycle of products is getting shorter. For these reasons, manufacturing systems consisting of integrated equipment and control software must be flexible and reconfigurable. Programmable Logic Controllers (PLCs) have been widely used in most industries as industrial computers owing to some advantages of PLCs such as flexibility in programming and easy troubleshooting. However, PLC programming is still tricky and ladder programs for high-level controls are sometimes unmanageably long. It is important to note that recent manufacturing systems are getting more complicated, and very often require complex algorithms involving a larger number of contacts and variables. To tackle these issues, this study presents a conceptual framework of Manufacturing Execution Language (MEL) that enables task and flow-based rapid control programming. MEL is a structured information format defined in XML format to delineate the dynamics of manufacturing systems with abstracted factory objects and task flows. Furthermore, a new control programming framework and its implementation environment are proposed using MEL and a virtual workcell in ROS simulation tool, Gazebo. The proposed MEL-based programming method makes it easy for users to develop and verify control logic in a virtual environment. The effectiveness of MEL is examined using a laboratory-scale factory testbed.오늘날 소비자들의 요구는 더욱 다양해지고 예측하기 힘들어졌으며, 제품 수명 주기 또한 점점 짧아지고 있다. 따라서, 다양한 제조 설비와 제어 프로그램으로 구성된 제조시스템은 유연하고 재구성가능 하여야 한다. Programmable Logic Controllers (PLCs)는 프로그래밍의 유연성과 간편한 문제해결과 같은 여러 장점으로 인해 다양한 산업 분야에서 산업용 제어기로 사용되어오고 있다. 하지만, PLC 프로그래밍은 여전히 번거로우며, 복잡하게 구성된 시스템을 제어하기 위한 래더 프로그램은 관리하기 힘들 정도로 복잡하다. 제조 시스템은 점점 더 복잡해지고 있으며, 이에 따른 상당한 수의 접점과 변수를 포함하는 복잡한 제어 알고리즘이 요구된다. 이러한 문제를 해결하기 위하여 이 연구에서는 task와 flow 중심의 신속 제어 프로그래밍을 가능하게 하는 Manufacturing Execution Language(MEL)의 개념적 프레임워크를 제안한다. MEL은 XML 형식으로 정의된 구조화된 정보 형식으로, 추상화된 공장 object와 task flow들을 통해 제조시스템의 동작을 설명한다. 또한, 이 연구에서는 MEL과 가상 제조 워크셀을 활용한 새로운 제어 프로그래밍 방법을 제안한다. 제안한 MEL 기반의 프로그래밍 방법은 사용자가 가상환경에서 제어로직을 쉽게 개발하고 검증할 수 있게 한다. MEL의 효율성에 대해서는 연구실 규모의 테스트베드를 활용하여 설명한다

제조설비 제어 및 운용을 위한 다층 하드웨어 추상화

2

High SLC2A1 expression associated with suppressing CD8 T cells and B cells promoted cancer survival in gastric cancer

High expression of glucose transporter family members, which augment glucose uptake and glycolytic flux, has been shown to play a pivotal role in the proliferation and survival of tumor cells, contributing to the energy supply, biosynthesis and homeostasis of cancer cells. Among the many members, solute carrier family 2 member 1 (SLC2A1) encodes a glucose transporter, GLUT1, that is critical in the metabolism of glucose, which is an energy source for cell growth that contributes to cancer progression and development. The aim of this study was to analyze the survival and genetic changes/immune profiles in patients with gastric cancer with high SLC2A1 expression and to provide treatment for improving prognosis. This study investigated the clinicopathologic parameters, the proportion of immune cells and gene sets affecting SLC2A1 expression in 279 and 415 patients with gastric cancer from the Eulji Hospital cohort and The Cancer Genome Atlas, respectively. We assessed the response to conventional chemotherapy drugs, including fluorouracil, a compound of fluoropyrimidine S-1, oxaliplatin, and all-trans-retinoic acid (ATRA), in gastric cancer cell lines with high SLC2A1 expression. High SLC2A1 expression was associated with poor prognosis, cancer cell proliferation, decreased immune cells, including CD8 T cells and B cells, and a low prognostic nutrition index, representing body nutrition-related status. In pathway network analysis, SLC2A1 was indirectly linked to the retinoic signaling pathway and negatively regulated immune cells/receptors. In the drug response analysis, the drug ATRA inhibited gastric cancer cell lines with high SLC2A1 expression. Treatment involving the use of SLC2A1 could contribute to better clinical management/research for patients with gastric cancer