Genetic alterations of TGF-beta signaling pathway drives immune evasion in a genetic models of gastric cancer

Hyeok-Won An,Sang-Hyuk SeoK,Jong-Wan Kwon,Yu-Jin Lee,Jun-Won Park 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Tumor development is a Darwinian evolutionary process of cancer subclones harboring driver gene mutations which dictate the cancer immune microenvironment. However, in gastric cancer, the driver gene mutations leading to immune evasion and tumor development have not been investigated yet. Thus, we performed in vivo CRISPR-Cas9-based knockout screening of candidate driver genes for gastric cancer development in immunocompetent mice. We used a genetic model of mouse gastric organoid lacking p53 (encoded by Trp53) and/or E-cadherin (encoded by Cdh1). We functionally screened 20 candidate genes using the mouse gastric organoids by transplanting pooled knockout organoids into subcutaneous tissues of mice to study clonal advantages in the context of a complex process of tumor development. As a result, Smad4, Tgfbr1, Fbxw7, and Bap1 were identified as strong candidate genes that drive tumor development in immunodeficient mice. Interestingly, Smad4 and Tgfbr1 knockout gastric organoids retain the ability to form tumors in immunocompetent wild-type C56BL/6 mice. Here, we uncovered changes both in tumor cells and host immune cells induced by these mutations. We identify that tumor immune suppression induced by Smad4 and Tgfbr1 KO might be attributed to exhausted T cells. In addition, immune checkpoint blockade such as anti-Pd-L1 antibody effectively blocks Smad4 knockout gastric cancer growth in immunocompetent mice. Overall, we demonstrate that the genetic alterations of TGF-beta signaling pathway dictates the cancer immune environment in gastric cancer.

Emergence of adefovir-resistant mutants after reversion to YMDD wild-type in lamivudine-resistant patients receiving adefovir monotherapy

Kwon, Hyeok Choon,Cheong, Jae Youn,Cho, Sung Won,Choi, Jae Myoung,Hong, Sun Pyo,Kim, Soo-Ok,Yoo, Wang Don Blackwell Publishing Asia 2009 Journal of gastroenterology and hepatology Vol.24 No.1

<P>Abstract</P><P>Background: </P><P>To evaluate the effect of reversion to YMDD wild-type on emergence of adefovir (ADV)-resistant mutation and antiviral activity of ADV in lamivudine (LAM)- resistant patients.</P><P>Methods: </P><P>We determined YMDD mutations and ADV-resistant mutations before and every 3 months during ADV monotherapy in 33 LAM-resistant patients using the restriction fragment mass polymorphism (RFMP) method.</P><P>Results: </P><P>Reversion to pure YMDD wild-type hepatitis B virus (HBV) occurred in 6% (2/33), 9% (3/33), 20% (4/20) and 35% (6/17) of patients after 12, 24, 36 and 48 weeks, respectively. Five (29%) patients were found to have pure YMDD mutants at 48 weeks of therapy. Among 33 patients, 4 (12%) patients developed ADV-resistant mutations at 48 weeks of therapy. Adefovir-resistant mutants emerged in all patients after reversion to YMDD wild-type HBV. The mean serum HBV reductions, evaluated at 24 weeks of therapy, were not different between patients with and without reversion to YMDD wild-type HBV (−3.1 log<SUB>10</SUB> copies/mL <I>vs</I>−3.4 log<SUB>10</SUB> copies/mL, <I>P</I> > 0.05).</P><P>Conclusions: </P><P>ADV-resistant mutations emerged after reversion to YMDD wild-type in LAM-resistant patients who received ADV monotherapy. Thus, ADV add-on therapy may be necessary to reduce the incidence of developing ADV resistance in patients with LAM resistance.</P>

Suppression of pine wilt disease by an antibacterial agent, oxolinic acid

Kwon, Hyeok Ran,Choi, Gyung Ja,Choi, Yong Ho,Jang, Kyoung Soo,Sung, Nack-Do,Kang, Mun Seong,Moon, Yilseong,Lee, Seung Kyu,Kim, Jin-Cheol John Wiley Sons, Ltd. 2010 PEST MANAGEMENT SCIENCE Vol.66 No.6

<P>BACKGROUND: Pine wilt disease (PWD) is very complex and has been reported to be caused by pine wood nematode, Bursaphelenchus xylophilus (Steiner & Buhrer) Nickle, and its accompanying bacteria. However, there is no report on the control of PWD by antibacterial agent. The present study was performed to investigate disease control efficacy of antibacterial agents against PWD.</P><P>RESULTS: Among six antibacterial antibiotics tested, oxolinic acid (OA) showed the strongest antibacterial activity against five bacteria isolated from three strains of pine wood nematode. In in vivo assay, it effectively suppressed the development of PWD in three-year-old seedlings of Pinus densiflora Sieb. & Zucc.; it showed 71% control when injected at 3 mg per seedling. A mixture of OA and the nematicidal agent abamectin (Ab) showed higher disease control efficacy against PWD than either OA or Ab alone. In addition, OA alone and a mixture of OA and Ab also controlled PWD in approximately 20-year-old pine trees under field conditions.</P><P>CONCLUSION: This is the first report on the suppression of PWD by OA. The result strongly indicates that PWD could be controlled by antibacterial antibiotic alone and a combination of antibacterial and nematicidal agents. Copyright © 2010 Society of Chemical Industry</P>

Dependence of the RFQ Output Beam Current on the Proton Injector Operation Parameters

Hyeok-Jung Kwon,Han-Sung Kim,Dae-Il Kim,Ji-Ho Jang,Yong-Sub Cho 한국물리학회 2009 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.54 No.5

A 20-MeV proton accelerator has been developed by the Proton Engineering Frontier Project (PEFP). It consists of a 50-keV proton injector, a 3-MeV radio-frequency quadrupole (RFQ) and a 20-MeV drift tube linac (DTL). An ion source and a low-energy beam transport (LEBT) system constitute the proton injector. The main roles of the proton injector are to generate the proton beams and to transport and match the beam from the ion source into the RFQ. The output beam current and the transmission of the RFQ are directly influenced by the operation parameters of the proton injector, especially the two solenoid magnets. The output beam current of the RFQ was measured for various values of the solenoid magnet current and the results were compared with that of the simulation.

Beam Emittance Measurement and Simulation of the PEFP Front End Accelerator

Hyeok-Jung Kwon,Han-Sung Kim,Dae-Il Kim,Ji-Ho Jang,조용섭 한국물리학회 2010 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.56 No.61

A 20-MeV proton accelerator has been developed and tested at the Korea Atomic Energy Institute (KAERI) by the Proton Engineering Frontier Project (PEFP). It consists of a 50-keV proton injector, a 3-MeV radio frequency quadrupole (RFQ), and a 20-MeV drift tube linac (DTL). The beam emttance was measured at the middle point between two solenoids of the proton injector. Based on the measured data, the beam properties through the proton injector were simulated using the T-step code for various operating conditions. Also, the transmission ratio through the RFQ was calculated using the output data obtained from the T-step code. In this paper, the emittance measurement results are presented, and the simulation results based on the measurement data are discussed.

Error Analysis of the PEFP RFQ

Hyeok-Jung Kwon,Han-Sung Kim,Kyung-Tae Seol,Yong-Sub Cho 한국물리학회 2006 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.48 No.4

A 3-MeV radio frequency quadrupole (RFQ) has been developed as a front-end component of the Proton Engineering Frontier Project (PEFP) 100-MeV proton linear accelerator. Because the frequency and the field profile are very sensitive to the mechanical error of the RFQ vane, vane alignment is required before brazing. When the initial alignment was performed, it was noticed that the measured resonant frequency of each section was 3 4 MHz higher than the designed frequency of 349.336 MHz and that the field profiles deviated from the designed value. To understand the differences between the measured RF parameters and the designed values, we proposed an error analysis method. The proposed error analysis method included several types of mechanical errors in the RFQ structures and their effects. The study showed that all the vane tips of PEFP RFQ section 3 and section 4 had dimensional errors of .0.1 mm and that two major vanes were consistently shifted from their designed positions by ±0.05 . 0.10 mm. Those errors could be compensated for by using slug tuners.p눊릲?릹

Basic, HCC basic : PO-21 ; Increased apolipoprotein E in hepatocellular carcinoma

( Hyeok Choon Kwon ),( Seung Woo Nam ),( Jae Youn Cheong ),( Soon Sun Kim ),( Marie Yeo ),( Dong Kyu Kim ),( Sung Won Cho ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide. The goal of our study was to identify new biomarkers for HCC for early detection and for gaining an improved understanding of hepatocarcinogenesis by performing a comparative proteomic analysis of HCC and adjacent non-tumor tissue. Methods: Pairs of tumor and adjacent non-tumor tissue were obtained from 167 HCC patients after surgical resection at Ajou University Hospital, Korea. We assessed the histopathological features and additional clinical data. Proteomic analysis of tumor and non-tumor tissue revealing differential expression using 2D electrophoresis and MALDI-TOF MS analysis reveals some xenobiotic enzymes and apo E was selected. The associations between the expression of apoE and the clinical and pathological parameters were analyzed using SPSS. Results: One of the xenobiotic enzymes, apoE was significantly increased in tumor tissue compared with surrounding nontumor tissue. Paired T-test showed significant high level of apoE in tumor compared with non-tumor (209.91 vs 87.59, p < .01). Oneway ANOVA revealed that levels of apoE were elevated independently among different Child classes, etiologies, sex and consumption of alcohol. Conclusions: We compared the protein profiles between tumor and non-tumor tissue in HCC patients. This study revealed that apoE was significantly higher in HCC than in non-tumor tissue. The multivariate analysis confirmed apoE was higher in regardless of Child class, etiology, sex and alcohol consumption. ApoE has long been known as plasma lipoproteins responsible for cholesterol transport and metabolism. Plasma apoE is produced mainly in the liver but also in the brain, adrenal glands, kidney, and macrophage and not increased in gene expression and serum level in patients with HCC. Some proteomic studies reports a strong relationship between other cancers and apoE. We suppose that this report add a clue to understand hepatocarcinogenesis from hepatic steatosis to consequently hepatic carcinoma.

Identification of anti-HIV and anti-Reverse Transcriptase activity from Tetracera scandens

( Hyeok Sang Kwon ),( Jung Ae Park ),( Joo Hwan Kim ),( Ji Chang You ) 생화학분자생물학회 (구 한국생화학분자생물학회) 2012 BMB Reports Vol.45 No.3

We report here that an ethanol extract of Tetracera scandens, a Vietnamese medicinal plant, has anti-HIV activity and possesses strong inhibitory activity against HIV-1 reverse transcriptase (RTase). Using a MT-4 cell-based assay, we found that the T. scandens extract inhibited effectively HIV virus replication with an IC50 value in the range of 2.0-2.5 μg/ml while the cellular toxicity value (CC50) was more than 40-50 μg/ml concentration, thus yielding a minimum specificity index of 20-fold. Moreover, the anti-HIV efficacy of the T. scandens extract was determined to be due, in part, to its potent inhibitory activity against HIV-1 RTase activity in vitro. The inhibitory activity against the RTase was further confirmed by probing viral cDNA production, an intermediate of viral reverse transcription, in virus-infected cells using quantitative DNA-PCR analysis. Thus, these results suggest that T. scandens can be a useful source for the isolation and development of new anti- HIV-1 inhibitor(s). [BMB reports 2012; 45(3): 165-170]

Double primary lung adenocarcinoma diagnosed by epidermal growth factor receptor mutation status

Kwon, Oh Jung,Lee, Min Hyeok,Kang, Sung Ju,Kim, Seul Gi,Jeong, In Beom,Jeong, Ji Yun,Cha, Eun Jung,Cho, Do Yeun,Kim, Young Jin,Son, Ji Woong Yeungnam University College of Medicine 2017 Yeungnam University Journal of Medicine Vol.34 No.2

A nodular density was detected on a chest radiograph taken from a 57-year-old Korean woman who was visiting a hospital for a routine check. Chest computed tomography revealed a 4.8 cm lobulated mass in the right lung and another focal nodular lesion in the left lung; biopsies of both lungs revealed adenocarcinoma. We conducted DNA sequencing and peptide nucleic acid clamping to investigate the potential double primary lung cancer. The results verified that the mass in the right lung had a mutation in the epidermal growth factor receptor, whereas the nodule in the left lung had a wild-type sequence, showing that these two were genetically different cancers from one another. Thus, we demonstrate that genetic testing is useful in determining double primary lung cancer, and we herein report on this case.

The Analysis of Vorticity and Kinetic Energy Budget of Typhoon with the Use of TCM-90 Data

Hyeok-Joe Kwon(권혁조),Kyung-Sup Shin(신경섭),Sang-Ok Han(한상옥) 한국기상학회 1997 Asia-Pacific Journal of Atmospheric Sciences Vol.33 No.2