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Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

  • Lee, Ji Eun;Woo, Min Gyu;Jung, Kyung Hee;Kang, Yeo Wool;Shin, Seung-Min;Son, Mi Kwon;Fang, Zhenghuan;Yan, Hong Hua;Park, Jung Hee;Yoon, Young-Chan;Kim, Yong-Sung;Hong, Soon-Sun
    • Biomolecules & Therapeutics
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    • v.30 no.3
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    • pp.274-283
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    • 2022
  • KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

A Comparative Study on the Intake, Digestibility, Nitrogen and Energy Utilization of Some Hay by Dairy Goats (Saanen) (유 산양에 의한 몇 가지 건초의 섭취량, 소화율과 질소 및 에너지이용성 비교 연구)

  • Lee, In-Duk;Lee, Hyung-Suk
    • Journal of The Korean Society of Grassland and Forage Science
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    • v.30 no.1
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    • pp.43-48
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    • 2010
  • This study was conducted to compare the chemical composition, dry matter digestibility (DMD), dry matter intake, and utilization of nitrogen and energy of dairy goats (Saanen), when fed on imported timothy hay (IT), mixture grass hay (MG) and native grass hay (NG), respectively. The experimental trials were conducted from April, 2008 to December, 2008 at the environmental controlled barn of Chungnam National University. Twelve dairy goats (Saanen) were selected which had nearly the same body weight (24.2kg, male). The content of crude protein (CP) of MG hay was higher than that of other diets (p<0.05), but the contents of NDF, ADF, cellulose and lignin of IT and NG diet were higher than those of MG diet (p<0.05). The voluntary DM intake of dairy goats fed with herbage from MG diet (30.7/$BW_{kg}$/day) was higher than that of other diets, but no significant difference was observed between that of IT diet and NG diet (p>0.05). The DMD of MG diet (69.8%) was higher than that of NG diet (62.2%) and IT diet (60.8%) (p<0.05), but no significant difference was observed between that of IT diet and NG diet (p>0.05). In nitrogen utilization, the apparently digested N %, retained % and biological value of dairy goats fed with herbage from MG diet were higher and TG diet was lower (p<0.05). In energy utilization, digestible energy and the energy of apparently digested minus urinary losses of MG diet were higher than those of IT diet and NG diet (p<0.05), but no significant difference was found between IT diet and NG diet (p>0.05). Based on the results, the dry matter intake, DMD and utilization of nitrogen and energy of dairy goats of MG were higher than those of IT diet and NG diet (p<0.05), the DMD and biological value (%) of NG diet was higher than that of IT diet (p<0.05).

HEARING OF RAINBOW TROUT TO COMMERCIAL SIZE IN A INDOOR AQUARIUM (실내수조를 이용한 무지개송어의 사육실험)

  • KIM In-Bae;JO Jae-Yoon
    • Korean Journal of Fisheries and Aquatic Sciences
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    • v.11 no.4
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    • pp.233-238
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    • 1978
  • Rainbow trout were reared in a stainless steel aquarium from Nov. 11, 1977 to June 12, 1978, and the following results were obtained : 1. The volume of water was about $400\iota$ in a aquarium measuring $1m\;(Length)\times1m\;(Width)\times67cm(Height)$ and water depth 40 cm. Water was supplied for about 16 hours daily at a rate $3\iota/min$ and was drained through the conical settling part in the middle of the aquarium bottom. Filter tank was about $23cm(W)\times23cm(L)\times40cm(D)$ and contained pebbles 30 cm in depth. Water recirculation rate was at)out $1,030\iota/hr$, or 2.6 turn-over per hour. 2. During the first period (77 days), the trout grew from 88.3g to 229g in average, the total weight attaining 30.7kg. The food coefficient was 1.249, average daily increment 243.3g, average daily growth rate 1.245%, and the mortality was 2 smallest fish weighing 53 g, owing to unknown reason. During the second period (135 days), the trout grew from 239g to 555g in average, the total weight attaining 57.2 kg. The food coefficient was 1.447, average daily increment 279.8g, average daily growth rate $0.65\%$ and the mortality was 31 fish weighing 11,255 g, owing partly to miss-handling and partly to disease. 3. The feed consisting of fully domestic materials was prepared in this laboratory, and the feed conversion was not inferior to high protein commercial feed available in foreign countries. 4. The result of whole period for 212 days was 56.5 kg in gross increment, and based on this result, when $1\iota/min$ full day inflowing water available, the net production will become 28.25 kg. So, if a 5000kg production is planned, $180\iota/min$ or about $10.8m^3/hr$ be reauired, and the production in value frill become 15million won at local price at the expense of about 5.3 million won. From the result of this experiment, rainbow trout is feasible for commercial production in Korea with relatively small amount of well water and simplified water recirculation system.

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Effects of Mixed Application of Chemical Fertilizer with Liquid Swine Manure on Agronomic Characteristics, Yield and Feed Value of Sorghum × Sorghum Hybrid for Silage in Paddy Field Cultivation (논 토양에서 사일리지용 수수 × 수수 교잡종 재배시 화학비료와 발효 돈분 액비 혼용 시용이 생육특성 및 영양성분에 미치는 영향)

  • Hwan, Hwang Joo;Lee, Sang Moo
    • Journal of The Korean Society of Grassland and Forage Science
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    • v.35 no.4
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    • pp.290-296
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    • 2015
  • This study was conducted to investigate the influence of the mixed application of chemical fertilizer (CF) with liquid swine manure (LSM) on the agronomic characteristics, dry matter yield, minerals, and free sugar in cultivating Sorghum ${\times}$ Sorghum Hybrid (SSH) on paddy soil. The field experiment was designed in a randomized block design with three replications and consisted of CF 100% (C), CF 70% + LSM 30% (T1), CF 50% + LSM 50% (T2), CF 30% + LSM 70% (T3), and LSM 100% treatment (T4). The application of LSM was based only on the nitrogen (150 kg/ha). Plant length, leaf length, leaf width and stem diameter were significantly the lower in T4 (p<0.05). Stem hardness increased significantly (p<0.05) as the LSM application rate decreased. Fresh yield was the highest in T2, whereas the lowest in T3 (p<0.05). However, dry matter yields and TDN yield did not show significant difference among treatments. Crude protein was the highest in T1 (p<0.05). Crude fat content did not significant differences between the T1, T2, T3 and T4, but C showed a significantly different (p<0.05). NDF and crude fiber were the highest in T3 and C, respectively (p<0.05). However, ADF did not show significant difference among treatments. Total mineral contents were higher in the order of T1> T2> T4> T3> C (p<0.05). Free sugar contents were significantly higher at T1 and C as compared to other treatments. The analysis of all the above results suggests that the application of liquid swine manure is very effective, considering the yield performance and the content of mineral and free sugar. In addition, liquid swine manure may be possible to grow SSH without chemical fertilizer.

The Effect of Percutaneous Multiple Puncture BCG Vaccination on PPD 1TU, 2TU and 5TU Tuberculin Skin Test (경피용 BCG 백신의 PPD 1TU, 2TU 및 5TU 결핵 피부반응 검사에 대한 영향)

  • Kim, Bo Sun;Hwang, Min Ho;Kim, Chang Hwi;Park, Jae Ok;Shin, Sang Man
    • Pediatric Infection and Vaccine
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    • v.8 no.2
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    • pp.175-180
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    • 2001
  • Purpose : Recently in Korea since 1998, 2TU has been used instead of 5TU, which caused a confusion in interpreting tuberculin skin tests. We compared the tuberculin skin reaction to PPD(purified protein derivatives) 1TU, 2TU and 5TU. Methods : We studied tuberculin skin reaction to PPD 1TU, 2TU and 5TU on 92 infants who were vaccinated with percutaneous multiple puncture BCG vaccine(Tokyo 172 strain, Japan BCG Laboratory Co.) in neonatal period. Diameters of indurations were measured in millimeters 48~72 hours after the intradermal injection of PPD 1TU, 2TU and 5TU. Results : Among 92 infants(male : 56, female : 36), 1TU was used on 31 infants, 2TU on 31 infants and 5TU on 30 infants for tuberculin skin test. The mean diameter of induration for PPD 1TU, 2TU and 5TU were $5.7{\pm}4.2mm$, $7.1{\pm}3.7mm$, and $9.2{\pm}4.2mm$, respectively. There was no statistical difference in mean diameter of induration between 1TU and 2TU. However, when tested with 5TU, the diameter of induration was significantly larger than those of PPD 1TU and 2TU(P<0.05). Six subjects(19.4%) tested with 1TU, 9 subjects(29%) tested with 2TU and 16 subjects(53.3%) tested with 5TU had diameter of 10 mm or more. There was no statistical difference between 1TU and 2TU but for 5TU, number of subjects with diameter of 10 mm or more was significantly higher than PPD 1TU and 2TU(P<0.05). Number of subjects with induration diameter of 5 mm or more for 1TU, 2TU and 5TU was 19(61.3%), 22(71.0%) and 26(86.7%), respectively. However, there was no statistical difference. Conclusion : A new standard criteria for interpreting the tuberculin skin test with PPD 2TU should be established for clinical diagnosis of tuberculosis.

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Establishment of an Optimal Washing Condition of a High Temperature Steaming System for the Production of High Quality Pork (고품질 돈육 생산을 위한 고온증기세척수의 최적 조건)

  • Yang, H.S.;Jeong, J.Y.;Moon, S.H.;Park, G.B.;Joo, Seon-Tea
    • Journal of Animal Science and Technology
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    • v.49 no.1
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    • pp.121-128
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    • 2007
  • The objective of this study was to determine the efficacy of different water temperatures and time of spray-washing on the removal of bacteria contamination from surface of pork carcass and to obtain better meat quality with high temperature stream between 60 to 90℃ for the time ranged from 10 to 60 sec. Results showed that total plate counts were significantly decreased with increasing steam temperature(P<0.05). Similar results were found with the spray time(P<0.05). The lightness(CIE L*) value was significantly increased in both loin and ham cuts over 80℃(P<0.05). Ultimate pH of muscle and water-holding capacity were decreased with increasing steam temperature(P<0.05). There was a significant difference in solubility of sarcoplasmic protein between 70℃ and 80℃ of the steam treatments with higher value at 70℃(P<0.05). Again, longer than 30 sec spray at 70℃ steam, the lightness value of pork was significantly increased(P<0.05), while pH and water-holding capacity of muscle were significantly decreased(P<0.05). Therefore, a desirable pork quality would be achieved with spray-steam washing at 70℃ for 20 sec on pork carcass.

Evaluation of the Cell-Mediated Immunity in Treatment Failure Pulmonary Tuberculosis (치료실패 폐결핵 환자의 세포성면역반응에 관한 연구)

  • Park, Jeong-Kyu;Park, Jang-Seo;Kim, Hwa-Jung;Jo, Eun-Gyeong;Min, Dul-Lel;Lim, Jae-Hyun;Suhr, Ji-Won;Paik, Tae-Hyun
    • Tuberculosis and Respiratory Diseases
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    • v.47 no.1
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    • pp.13-25
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    • 1999
  • Background: Ineffective cell-mediated immune response in human tuberculosis is associated with a depressed Thl cytokine response and reduced production of IFN-$\gamma$. Most persons infected with Mycobacterium tuberculosis are healthy tuberculin reactors with protective immunity, but a minority with ineffective immunity develop extensive pulmonary tuberculosis. The cell-mediated immune response is an important aspect of host resistance to mycobacterial infection and is believed to be tightly regulated by a balance between Th1 cytokines including IFN-$\gamma$, IL-12, IL-18, regulated on activation, normal T cell expressed and secreted (RANTES) and Th2 counterparts such as IL-4, monocyte chemoattractant protein-l (MCP-l). Methods: Proliferation and mRNA expression of IFN-$\gamma$, RANTES and MCP-l by RT-PCR in peripheral blood mononuclear cells (PBMCs) in response to in vitro stimulation with mycobacterial antigens were compared in pulmonary tuberculosis patients with cured and treatment failure and in tuberculin-positive and tuberculin-negative healthy subjects. Results: Defective proliferative responsiveness to aqueous TSP antigen was involved with treatment failure tuberculosis patients. Aqueous TSP antigen-induced IFN-$\gamma$ and RANTES mRNA expression was decreased in treatment failure tuberculosis patients compared with healthy tuberculin reactors and cured tuberculosis patients (23.1 % versus 90.0% for IFN-$\gamma$ and 46.2% versus 70.0% versus 46.2% for RANTES). The frequency of MCP-l mRNA expression to aqueous TSP antigen in treatment failure tuberculosis patients was greater than in healthy tuberculin reactors and cured tuberculosis patients (76.9% versus 40.0%). Conclusion: The increasing expression of MCP-1 mRNA in response to aqueous TSP antigen might be predicted to favor Th1 responses and restricted Th1 responses in treatment failure of pulmonary tuberculosis.

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Effects of Korean Zingiber mioga R. (Flower Buds and Rhizome) Extract on Memory (한국산 양하(꽃봉오리와 지하경)의 인지 기능 개선 효과)

  • Cho, Kyo-Hee;Oh, Myung-Sook;Kim, Hyo-Geun;Lee, Sun-Hee;Chung, Kun-Sub;Kim, Ae-Jung
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.43 no.10
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    • pp.1519-1526
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    • 2014
  • This study investigated the biological activities and effects of Korean Zingiber mioga R. (flower buds and rhizome) on memory. The general composition, minerals, anti-oxidative activities, and AChE inhibitory effects were analyzed, and NORT (Novel object recognition test) and Y-Maze test in vivo were performed. The general contents (moisture, crude fat, crude protein, and crude ash; wet basis) of ZB (flower buds) were 91.96%, 0.15%, 1.99%, and 11.90%, respectively. The general contents (moisture, crude fat, crude protein, and crude ash; wet basis) of ZR (rhizome) were 75.21%, 0.53%, 2.20%, and 9.50%, respectively. The macro mineral contents (Ca, P, Na, and K) of ZB were 31.70 mg%, 15.20 mg%, 8.20 mg%, and 258.60 mg%, respectively. Inhibitory effects (IC50 value) of DPPH and ABTS radicals were higher with ZBD (flower buds water extract) than with ZBE (flower buds EtOH extract), ZRD (rhizome water extract) or ZRE (rhizome EtOH extract). AChE inhibitory effect of ZBD was higher and that of ZRD. NORT and Y-Maze test were performed with scopolamine-induced mice treated with ZBD and ZBE. In NORT, effects of ZBD and ZBE were similar to that of donepezil. In the Y-maze test, performances of ZBD and ZBE-treated mice were similar to that of the normal group. These results suggest that Korean Zingiber mioga R. has potential to be developed into a new functional food for cognition enhancement in the global food market.

Diagnostic Utility of MAGE Expression in Exudative Pleural Effusion (삼출성 흉수에서 악성 감별을 위한 MAGE 유전자 검출의 의의)

  • Kim, Kyung Chan;Seo, Chang Gyun;Park, Sun Hyo;Choi, Won-Il;Han, Seung Beom;Jeon, Young June;Park, Jong-Wook;Jeon, Chang-Ho
    • Tuberculosis and Respiratory Diseases
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    • v.56 no.2
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    • pp.159-168
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    • 2004
  • Background : In recent years, numerous human tumor specific antigens such as melanoma antigen gene(MAGE) that is recognized by autologous cytotoxic T lymphocytes have been identified. MAGE is expressed in many human malignancies in various organs, such as lung, breast, stomach, esophagus and leukemia. Therefore MAGE has been studied widely for tumor diagnosis and immunotherapy. But, so far there were no clinical studies evaluating the role of MAGE in pleural effusion. We investigated the expression of MAGE in the patients with exudative pleural effusion for it's diagnostic utility and the results were compared with those of cytologic examinations. Methods : Diagnostic thoracentesis was performed in 44 consecutive patients with exudative pleural effusion during 6 months. We examined the expression of MAGE and cytology with the obtained pleural effusion. Expression of MAGE was interpreted by means of a commercial kit using RT-PCR method. Enrolled patients were divided into two groups such as malignant and benign and we analyzed its' sensitivity and specificity. Results : There were no significant differences between two groups in age, sex, white blood cell counts in pleural fluid, pleural fluid/serum protein ratio and pleural fluid/serum LDH ratio. The sensitivity and specificity of MAGE were 72.2% and 96.2% respectively and the positive predictive value and negative predictive value of MAGE were also 92.9% and 83.3% respectively. The sensitivity and negative predictive value of cytologic examinations were 66.7% and 81.3% respectively. There were no significant differences between sensitivities of MAGE and cytologic examinations but false positive result of MAGE was found in 1 case of tuberculous pleurisy. Conclusion : MAGE is a sensitive and specific marker for the differential diagnosis between benign and malignant effusion in patients with exudative pleural effusion. And MAGE would provide the equal sensitivity compared with that of cytologic examination in patients with malignant pleural effusion if 5mL of the pleural fluid is examined.

A Correlation between Pulmonary Involvement of Acute Febrile Illness with High Incidence during the Fall and C-reactive Protein (가을철 유행하는 급성열성질환의 폐침범과 CRP와의 연관관계)

  • Kim, Go Woon;Lee, Woo Jin;Hong, Won Ki;Lee, Sung Hoa;Lee, Chang Youl;Lee, Myung Goo;Hyun, In Gyu;Jung, Ki Suck
    • Tuberculosis and Respiratory Diseases
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    • v.66 no.2
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    • pp.116-121
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    • 2009
  • Background: Tsutsugamushi, leptospirosis and hemorrhagic fever with renal syndrome (HFRS) are the prevalent diseases among the acute febrile illnesses in Korea. Pulmonary involvement in the patients with these diseases remains poorly recognized in endemic regions, and this is despite reports of recent outbreaks and epidemic episodes. Pulmonary involvement and a higher CRP level as clinical manifestations show a more severe form of infection. The aim of this study is to analyze the correlation of pulmonary involvement and the CRP level in patients with acute febrile illnesses. Methods: We retrospectively reviewed the clinical records of 105 patients who were diagnosed with tsutsugamushi, HFRS and leptospirosis from January 2002 to May 2008 in Chuncheon Sacred Heart Hospital. The radiographic images were retrospectively analyzed by two radiologists. We analyzed the pulmonary complications of the patients with these febrile diseases and we checked the CRP level at admission. Results: The study included 105 patients who were diagnosed with febrile diseases. Of these patients, 32 patients had hantaan, 10 patients had leptospirosis and 63 patients had tsutsugamushi disease. 42 (40%) patients had pulmonary complications, 20 patients had pulmonary edema, 20 patients had pleural effusion and 2 patients had interstitial pneumonitis. The patients with pulmonary involvement showed a more severe form of infection and a higher CRP level than that of those patients without pulmonary involvement (p=0.0073). Conclusion: Pulmonary involvement in patients with acute febrile diseases might be correlated with a higher CRP level. Identification of this factor on admission might provide useful selection criteria for the patients who need early intensive care.