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( Yoo Jin Na ),( Eun Sang Yu ),( Dae Sik Kim ),( Dae-hee Lee ),( Sang Cheul Oh ),( Chul Won Choi ) 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.0
Background/Aims: Nilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance. Methods: We observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force. Results: Sub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition. Conclusions: This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.
TNF-like ligand 1A is a promising biomarker of disease activity in rheumatoid arthritis
( Yoo Jin Hong ),( Yun Jong Lee ),( Ki Chul Shin ),( Byoong Yong Choi ),( Sung Hae Chang ),( Hae Won Kim ),( In Ah Choi ),( Eun Young Lee ),( Eun Bong Lee ),( Yeong Wook Song ) 대한내과학회 2011 대한내과학회 추계학술대회 Vol.2011 No.1
Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of multiple joints. TN -like ligand 1A (TL1A), a ligand belonging to the TNF superfamily, is expressed by endothelial cells, lymphocytes, monocytes and plasma cells. These are also the key cell lineages participating in the pathogenesis of RA. Moreover, TL1A is up-regulated by proinflammatory cytokines TNF- and IL-1. We thereby examined the serum and synovial fluid levels of TL1A in patients with RA. In addition, we investigated the relationship between serum TL1A concentration and clinical parameters in RA patients. Methods: Serum samples were obtained from 232 patients with RA and 29 with osteoarthritis (OA). Thirty-eight and 27 synovial fluid (SF) samples were collected from respective group of patients. Additional 45 serum samples before and after (14 weeks) anti-TNF- treatment were collected from RA patients. TL1A concentrations were measured by ELISA. Clinical parameters were acquired at the time of sampling. Results: Serum concentrations of TL1A in RA patients were significantly higher than those in OA patients (mean±SD, 1327.4±3858.8 pg/ml vs. 150.3±269.6 pg/ml, p<0.0001). The SF levels of TL1A were elevated in patients with RA compared with those in OA (965.7±1617.2 vs. 271.4±238.9, p=0.013). Levels of TL1A were significantly increased in SF than serum in matched samples (RA; p=0.006, OA; p<0.0001). Serum levels of TL1A decreased substantially with anti-TNF- treatment (p=0.002). Serum levels of TL1A correlated well with DAS28-ESR (r=0.170, p=0.021), DAS28-CRP (r=0.166, p=0.037), SDAI (r=0.201, p=0.016), CDAI (r=0.195, p=0.011) and rheumatoid factor positivity (r=0.876, p=0.044). Conclusion: Serum and SF levels of TL1A were significantly increased in RA patients compared with OA patients, and correlated well with clinical parameters representing disease activity.Our results support that TL1A could be a potential biomarker in assessing disease activity and treatment response in RA patients.
Yoo, Hee-Bong,Oh, Donggeun,Song, Jae Yong,Kawaharasaki, Mamoru,Hwang, Jeeseong,Yang, In Chul,Park, Sang-Ryoul Springer-Verlag 2014 METROLOGIA -BERLIN- Vol.51 No.5
<P>This work demonstrates accurate measurement of the amount of substance concentration of low concentration plasmid DNA by counting individual DNA molecules using a high-sensitivity flow cytometric setup. Plasmid DNA is a widely used form of DNA, and its quantity often needs to be accurately determined. This work establishes a reference analytical method for direct quantification of low concentration plasmid DNA prepared as reference standards for polymerase chain reaction-based DNA quantification. The model plasmid DNA pBR322 (4361?bp) was stained with a fluorescent dye and was detected in a flow stream in a micro-fluidic channel with laser-induced fluorescence detection, for which the DNA flow was electro-hydrodynamically focused at the centre of the channel. 200 to 8000 DNA molecules in a ∼1??L sample volume were counted within 2?min in an ‘exhaustive counting’ manner, which facilitated quantitation without calibration. The sample volume was measured and validated from the close agreement of the results of two independent measurement methods, gravimetric determination of water filling the capillary and graphical estimation of actual cross sectional area of the capillary tubing with the image of calibrated scanning electron microscopy. Within the given concentration range, an excellent measurement linearity (<I>R</I><SUP>2</SUP>?=?0.999) was achieved with appropriate data processing for the correction of the events of double molecules (detection of double molecules opposed to single molecule detection assumed, which occurs due to their coincidental passing of the detection zone). The validity of the proposed method was confirmed from the close agreement with the results of quantitation of enzymatically released nucleotides using capillary electrophoresis.</P>
Yoo, Seung-Ah,Park, Ji-Hwan,Hwang, Seong-Hye,Oh, Sang-Min,Lee, Saseong,Cicatiello, Valeria,Rho, Sangchul,De Falco, Sandro,Hwang, Daehee,Cho, Chul-Soo,Kim, Wan-Uk The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.194 No.6
<P>Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified <I>PlGF-1</I> and <I>PlGF-2</I> as the major <I>PlGF</I> isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for <I>PlGF</I>. Indeed, <I>PlGF</I>-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. <I>PlGF</I> gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of <I>PlGF</I> transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.</P>
Yoo, Min-Hyuk,Woo, Chang-Hoon,You, Hye-Jin,Cho, Sung-Hoon,Kim. Byung-Chul,Choi, Ji-Eun,Chun, Jang-Soo,Jhun, Byung H.,Kim, Tae-Sung,Kim, Jae-Hong 전남대학교 약품개발연구소 2001 약품개발연구지 Vol.10 No.-
Activation of Ras signaling by growth factors has been associated with gene regulation and cell proliferation. Here we characterize the contributory role of cytosolic phospholipase A_2 in the oncogenic Ha-Ras^v12 signaling pathway leading to activation of c-fos serum response element (SER) and transformation in Rat-2 fibroblasts. Using a c-fos SER-luciferase reporter gene, we showed that the transacrtivation of SER by Ha-Ras^v12 is mainly via a Rac-linked cascade, although the Raf-mitogen-activated protein kinase cascade is required for full activation. In addition, Ha-Ras^12-induced DNA synthesis was significantly attenuated by microinjection of recombinant Rac^N17, a dominant negative mutant of Rac1. To identify the mediators downstream of Rac in the Ha-Ras^v12 signaling, we investigated the involvement of cytosolic phospholipase A_2. Oncogenic inhibited by either pretreatrnent with mepacrine, a phospholipase A_2 inhibitor, or cotransfection with the antisense oligonucleotide of cytosolic phospholipase A_2. We slso found cytosolic phospholipase A_2 to be situatied downstream of Ha-Ras ^v12 in a signal pathway leading to transformation. Together, these results are indicative of mediatory roles of Rac and cytosolic phospholipase A-2 in the signaling pathway by which Ha-Ras^v12 transactivaes c-fos SRE and transformation. Our fidings point to cytosolic phospholiase A_2 as a novel potential target for suppressing oncogenic Ha-Ras^v12 signaling in the cell.