• Journal of the Korea Society of Computer and Information
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• v.21 no.11
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• pp.17-21
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• 2016

Heterogeneity assessment of tumor in oncology is important for diagnosis of cancer and therapy. The aim of this study was performed assess heterogeneity tumor region in PET image using texture analysis. For assessment of heterogeneity tumor in PET image, we inserted sphere phantom in torso phantom. Cu-64 labeled radioisotope was administrated by 156.84 MBq in torso phantom. PET/CT image was acquired by PET/CT scanner (Discovery 710, GE Healthcare, Milwaukee, WI). The texture analysis of PET images was calculated using occurrence probability of gray level co-occurrence matrix. Energy and entropy is one of results of texture analysis. We performed the texture analysis in tumor, liver, and background. Assessment textural features of region-of-interest (ROI) in torso phantom used in-house software. We calculated the textural features of torso phantom in PET image using texture analysis. Calculated entropy in tumor, liver, and background were 5.322, 7.639, and 7.818. The further study will perform assessment of heterogeneity using clinical tumor PET image.

• Biomolecules & Therapeutics
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• v.27 no.1
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• pp.63-70
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• 2019

Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate $NF-{\kappa}B$ signaling. Moreover, expression of PD-L1 and CD80 on $PD-1^+$ MDSCs was higher than on $PD-1^-$ MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in $PD-1^+$ MDSCs than in $PD-1^-$ MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that $PD-1^+$ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

• The Korean Journal of Applied Statistics
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• v.32 no.3
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• pp.331-348
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• 2019

Understanding the tumor heterogeneity due to differences in the growth pattern of metastatic tumors and rate of change is important for understanding the sensitivity of tumor cells to drugs and finding appropriate therapies. It is often possible to test for differences in population means using t-test or ANOVA when the group of N samples is distinct. However, these statistical methods can not be used unless the groups are distinguished as the data covered in this paper. Statistical methods have been studied to test heterogeneity between samples. The minimum combination t-test method is one of them. In this paper, we propose a maximum combinatorial t-test method that takes into account combinations that bisect data at different ratios. Also we propose a method based on the idea that examining the heterogeneity of a sample is equivalent to testing whether the number of optimal clusters is one in the cluster analysis. We verified that the proposed methods, maximum combination t-test method and gap statistic, have better type-I error and power than the previously proposed method based on simulation study and obtained the results through real data analysis.

• Genomics & Informatics
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• v.17 no.1
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• pp.3.1-3.4
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• 2019

Intratumor heterogeneity within a single tumor mass is one of the hallmarks of malignancy and has been reported in various tumor types. The molecular characterization of intratumor heterogeneity in breast cancer is a significant challenge for effective treatment. Using single-cell RNA sequencing (RNA-seq) data from a public resource, an ERBB pathway activated triple-negative cell population was identified. The differential expression of three subtyping marker genes (ERBB2, ESR1, and PGR) was not changed in the bulk RNA-seq data, but the single-cell transcriptomes showed intratumor heterogeneity. This result shows that ERBB signaling is activated using an indirect route and that the molecular subtype is changed on a single-cell level. Our data propose a different view on breast cancer subtypes, clarifying much confusion in this field and contributing to precision medicine.

• Genomics & Informatics
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• v.13 no.4
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• pp.132-136
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• 2015

Studies of cancer heterogeneity have received considerable attention recently, because the presence or absence of resistant sub-clones may determine whether or not certain therapeutic treatments are effective. Previously, we have reported G64, a co-regulated gene module composed of 64 different genes, can differentiate tumor intra- or inter-subpopulations in lung adenocarcinomas (LADCs). Here, we investigated whether the G64 module genes were also expressed distinctively in different subpopulations of other cancers. RNA sequencing-based transcriptome data derived from 22 cancers, except LADC, were downloaded from The Cancer Genome Atlas (TCGA). Interestingly, the 22 cancers also expressed the G64 genes in a correlated manner, as observed previously in an LADC study. Considering that gene expression levels were continuous among different tumor samples, tumor subpopulations were investigated using extreme expressional ranges of G64-i.e., tumor subpopulation with the lowest 15% of G64 expression, tumor subpopulation with the highest 15% of G64 expression, and tumor subpopulation with intermediate expression. In each of the 22 cancers, we examined whether patient survival was different among the three different subgroups and found that G64 could differentiate tumor subpopulations in six other cancers, including sarcoma, kidney, brain, liver, and esophageal cancers.

• BMB Reports
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• v.28 no.1
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• pp.46-50
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• 1995

Three kinds of mouse tumor necrosis factor (TNF), which have molecular weights of 35 kDa, 45 kDa, and 18 kDa on SDS-PAGE, were partially purified from serum-free culture supernatants of mouse peritoneal macrophages induced with lipopolysaccharide. Analysis of the native molecular weights by gel filtration indicated that the 18 kDa and 45 kDa TNFs aggregate into 50 kDa and 100 kDa molecules, respectively, while the 35 kDa TNF is contained in high molecular weight aggregates of approximately 200 kDa. The three kinds of cytotoxic factors all elicited tumor reducing responses.

• BMB Reports
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• v.56 no.1
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• pp.24-31
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• 2023

Urological cancers such as kidney, bladder, prostate, and testicular cancers are the most common types of cancers worldwide with high mortality and morbidity. To date, traditional cell lines and animal models have been broadly used to study pre-clinical applications and underlying molecular mechanisms of urological cancers. However, they cannot reflect biological phenotypes of real tissues and clinical diversities of urological cancers in vitro system. In vitro models cannot be utilized to reflect the tumor microenvironment or heterogeneity. Cancer organoids in three-dimensional culture have emerged as a promising platform for simulating tumor microenvironment and revealing heterogeneity. In this review, we summarize recent advances in prostate and kidney cancer organoids regarding culture conditions, advantages, and applications of these cancer organoids.

• BMB Reports
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• v.56 no.4
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• pp.225-233
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• 2023

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases.

• Biomolecules & Therapeutics
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• v.26 no.1
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• pp.10-18
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• 2018

Tumors are dynamic metabolic systems which highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenecity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells.

• BMB Reports
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• v.55 no.2
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• pp.81-86
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• 2022

Macrophages are a major cellular component of innate immunity and are mainly known to have phagocytic activity. In the tumor microenvironment (TME), they can be differentiated into tumor-associated macrophages (TAMs). As the most abundant immune cells in the TME, TAMs promote tumor progression by enhancing angiogenesis, suppressing T cells and increasing immunosuppressive cytokine production. N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene, whose expression is down-regulated in various cancers. However, the effect of NDRG2 on the differentiation of macrophages into TAMs in breast cancer remains elusive. In this study, we investigated the effect of NDRG2 expression in breast cancer cells on the differentiation of macrophages into TAMs. Compared to tumor cell-conditioned medium (TCCM) from 4T1-mock cells, TCCM from NDRG2-over-expressing 4T1 mouse breast cancer cells did not significantly change the morphology of RAW 264.7 cells. However, TCCM from 4T1-NDRG2 cells reduced the mRNA levels of TAM-related genes, including MR1, IL-10, ARG1 and iNOS, in RAW 264.7 cells. In addition, TCCM from 4T1-NDRG2 cells reduced the expression of TAM-related surface markers, such as CD206, in peritoneal macrophages (PEM). The mRNA expression of TAM-related genes, including IL-10, YM1, FIZZ1, MR1, ARG1 and iNOS, was also downregulated by TCCM from 4T1-NDRG2 cells. Remarkably, TCCM from 4T1-NDRG2 cells reduced the expression of PD-L1 and Fra-1 as well as the production of GM-CSF, IL-10 and ROS, leading to the attenuation of T cell-inhibitory activity of PEM. These data showed that compared with TCCM from 4T1-mock cells, TCCM from 4T1-NDRG2 cells suppressed the TAM differentiation and activation. Collectively, these results suggest that NDRG2 expression in breast cancer may reduce the differentiation of macrophages into TAMs in the TME.