Publications by authors named "Young Chul Park"

63 Publications

Catalytic Decomposition of Energetic Liquid Solution Over Various Types of Hexaaluminate Catalysts.

J Nanosci Nanotechnol 2020 Nov;20(11):7114-7118

Department of Chemical Engineering, Kongju National University, Cheonan, Chungcheongnam-do 31080, South Korea.

A hexaaluminate support was prepared by a co-precipitation method, and a metal (Cu, Pt, or Ir) was impregnated on the support to prepare a powdered catalyst. After that, organic and inorganic binders were added to the powdery catalyst and then pellets were formed. The so-formed catalysts were heat-treated at 1200°C, and their physicochemical properties were analyzed by N₂-adsorption, X-ray diffraction (XRD), X-ray fluorenscence (XRF), and scanning electron microscopy (SEM). The decomposition activity of the catalysts on an ammonium dinitramide (ADN)-based liquid propellant was evaluated repeatedly, and the effects of catalyst composition and morphology on low temperature decomposition activity and durability were investigated. It was confirmed that the Cu-hexa-pellet, Pt-hexa-pellet, and Ir-hexa-pellet catalysts could be recovered and reused as a catalyst for decomposition of an ADN-based liquid monopropellant. The initial activity and the thermal stability of the Cu-hexa-pellet catalyst for the decomposition of ADN-based liquid monopropellants were better than for the other catalysts. The better activity of the Cu-hexa-pellet catalyst seems to be because the dispersion of the copper was higher than the metal dispersion in the other two catalysts.
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http://dx.doi.org/10.1166/jnn.2020.18842DOI Listing
November 2020

Decomposition of Ionic Liquid Solution Over CuIr-Hexaaluminate Catalysts.

J Nanosci Nanotechnol 2020 Jul;20(7):4466-4469

Department of Chemical Engineering, Kongju National University, 1223-24 Cheonan-daero, Seobuk-gu, Cheonan, 31080, Korea.

The objective of this study is to elucidate the catalytic performance of hexaaluminate catalysts incorporating Cu and Ir simultaneously during the decomposition of an ammonium dinitramide (ADN)-based liquid propellant. Pellet-type catalysts were prepared and their chemico-physical properties were characterized by N₂ adsorption, XRD, and XRF. It was confirmed that Cu and Ir atoms are well incorporated inside the hexaaluminate matrix of the Cu(x)Ir(10-x)-hexaaluminate catalysts and the content of Ir incorporated into hexaaluminte matrix was in the range of 2.5-8.2 wt%. The Cu(7)Ir(3)-hexaaluminate catalyst showed excellent activity in decomposition of ADN-based liquid monopropellant. The activity of the Cu(7)Ir(3)-hexaaluminate catalyst was much higher than that of the Cu(7)Ir(3)/hexaaluminate-imp catalyst prepared by impregnation of Cu and Ir onto the hexaaluminate pellet surface. This is attributed to the Cu and Ir being well incorporated in the hexaaluminate matrix and the dispersion of the Cu and Ir being greater in the Cu(7)Ir(3)-hexaaluminate than in the Cu(7)Ir(3)/hexaaluminate-imp.
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http://dx.doi.org/10.1166/jnn.2020.17599DOI Listing
July 2020

A phase 1/2a, dose-escalation, safety and preliminary efficacy study of oral therapeutic vaccine in subjects with cervical intraepithelial neoplasia 3.

J Gynecol Oncol 2019 Nov;30(6):e88

Department of Obstetrics and Gynecology, Korea University Guro Hospital, College of Medicine, Korea University, Seoul, Korea.

Objective: Persistent infection of HPV increases the chance of carcinoma in situ of cervix through stages of cervical intraepithelial neoplasia (CIN) 1, 2, and 3, and finally progresses into cervical cancer. We aimed to explore the safety and efficacy of BLS-M07 which is orally administered agent expressing human papillomavirus (HPV) 16 E7 antigen on the surface of in patients with CIN 3.

Methods: Patients with CIN 3 were recruited in our clinical trial. Reid Colposcopic Index (RCI) grading and serum HPV16 E7 specific antibody production were used to evaluate efficacy of BLS-M07. In phase 1, BLS-M07 was administered orally, 5 times a week, on weeks 1, 2, 4, and 8 with dosages of 500 mg, 1,000 mg, and 1,500 mg. In phase 2a, patients were treated with 1,000 mg. The primary endpoints were the safety and the pathologic regression on colposcopic biopsy.

Results: Nineteen patients were enrolled in the CIN 3 cohort. In phase 1, no patients experienced dose limiting toxicity. No grade 3 or 4 treatment-related adverse events or deaths were observed. At 16 weeks after treatment, RCI grading was improved and serum HPV16 E7 specific antibody production increased (p<0.05). Six of 8 (75%) patients with CIN 3 were cured in phase 2a.

Conclusions: Oral immunization with BLS-M07 increases production of serum HPV16 E7 specific antibody which induces protective humoral immunity. The safety of this oral vaccine was proved and could be a competitive non-surgical therapeutic agent of CIN 3.

Trial Registration: ClinicalTrials.gov Identifier: NCT02195089.
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http://dx.doi.org/10.3802/jgo.2019.30.e88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779607PMC
November 2019

Short-term clinical and immunologic effects of poly-gamma-glutamic acid (γ-PGA) in women with cervical intraepithelial neoplasia 1 (CIN 1): A multicenter, randomized, double blind, phase II trial.

PLoS One 2019 20;14(6):e0217745. Epub 2019 Jun 20.

Department of Obstetrics and Gynecology, Guro Hospital, College of Medicine, Korea University, Seoul, Korea.

Objective: The aim of this study was to investigate the short-term efficacy and safety of Poly-gamma-glutamic acid (γ-PGA) and the immunologic changes in patients with CIN 1.

Methods: Participants were randomly assigned to one of two groups and orally treated with placebo or 1,500 mg of γ-PGA for 4 weeks. The primary endpoint of the study was histologic regression rate of CIN 1 at 12 weeks between γ-PGA and control groups. The secondary endpoints were HPV clearance and change in immune responses.

Result: From April 2013 to December 2015, 195 patients participated in the study. In the intention-to-treat analysis, 42 (42.4%) of the women who received γ-PGA experienced histologic remission versus 26 (27.1%) in the control group, with a statistically significant difference (p = 0.018). In the γ-PGA group, HPV clearance was found in 37 (43.5%) of 85 patients infected with high-risk HPV, showing a significant difference compared to the control group, in which 20 (26.7%) of 75 patients exhibited HPV clearance (p = 0.026). However, there was no significant difference between the two groups in the change of NK cell activity, major histocompatibility complex (MHC) class II CD8 count, and CD56 count.

Conclusion: γ-PGA showed a short-term therapeutic effect on CIN 1 and high-risk HPV infection. It is a non-invasive, promising oral medication for women with these conditions.

Trial Registration: Clinical Trials NCT01826045.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586279PMC
February 2020

Cyclosporin A inhibits differentiation and activation of monocytic cells induced by 27-hydroxycholesterol.

Int Immunopharmacol 2019 Apr 15;69:358-367. Epub 2019 Feb 15.

Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea. Electronic address:

27-Hydroxycholesterol (27OHChol) is a bioactive molecule that induces monocytic cell activation and differentiation and thereby participates in immune responses under hypercholesterolemic condition. However, it is unknown whether cyclosporin A (CsA), an immunosuppressant, affects biological effects of 27OHChol. In this study, we investigated whether CsA alters 27OHChol-induced cellular and molecular responses using the human monocyte/macrophage THP-1 cells. Treatment of the cells with CsA resulted in decreased expression of the mDC-specific markers (CD80, CD83 and CD88) induced by 27OHChol. Reduced endocytic activity recovered in the presence of CsA. The drug also inhibited the expressions of MHC class I and II molecules and CD197, a homing molecule of mDCs. We further investigated the outcomes of CsA treatment on the expression of M1 polarization markers and CD14, a component of the innate immune system. The drug decreased transcript levels of genes associated with the M1 polarization of monocytic cells, including CCL2, as well as expression of CD14 and MMP-9 which is involved in soluble CD14 shedding. Taken together, these results indicate that CsA inhibits the 27OHChol-induced differentiation and activation of monocytic cells into a mature dendritic cell (mDC) type and an immuno-stimulatory M1 subset, respectively, thereby modifying immune responses in a milieu rich in cholesterol and oxidized cholesterol molecules.
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http://dx.doi.org/10.1016/j.intimp.2019.01.045DOI Listing
April 2019

Inhibition of protein kinase CK2 facilitates cellular senescence by inhibiting the expression of HO-1 in articular chondrocytes.

Int J Mol Med 2019 Feb 4;43(2):1033-1040. Epub 2018 Dec 4.

Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea.

Protein kinase casein kinase 2 (CK2) is important in the regulation of cell proliferation and death, even under pathological conditions. Previously, we reported that CK2 regulates the expression of heme oxygenase‑1 (HO‑1) in stress‑induced chondrocytes. In the present study, it was shown that CK2 is involved in the dedifferentiation and cellular senescence of chondrocytes. Treatment of primary articular chondrocytes with CK2 inhibitors, 4,5,6,7‑terabromo‑2‑azabenzimidazole (TBB) or 5,6‑dichlorobenzimidazole 1‑β‑D‑ribofuranoside (DRB), induced an increase in senescence‑associated β‑galactosidase (SA‑β‑gal) staining. In addition, TBB reduced the expression of type II collagen and stimulated the accumulation of β‑catenin, phenotypic markers of chondrocyte differentiation and dedifferentiation, respectively. It was also observed that the abrogation of CK2 activity by CK2 small interfering RNA induced phenotypes of chondrocyte senescence. The association between HO‑1 and cellular senescence was also examined in CK2 inhibitor‑treated chondrocytes. Pretreatment with 3‑morpholinosydnonimine hydrochloride, an inducer of the HO‑1 expression, or overexpression of the HO‑1 gene significantly delayed chondrocyte senescence. These results show that CK2 is associated with chondrocyte differentiation and cellular senescence and that this is due to regulation of the expression of HO‑1. Furthermore, the findings suggest that CK2 is crucial as an anti‑aging factor during chondrocyte senescence.
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http://dx.doi.org/10.3892/ijmm.2018.4016DOI Listing
February 2019

Preparation and Properties of WC-Based Alloy Coatings with Controlled Co and Cr via High Velocity Oxy-Fuel Spray Technique.

J Nanosci Nanotechnol 2018 Mar;18(3):2049-2053

Department of Materials Process Engineering, Inha University, Incheon 22212, Republic of Korea.

WC based alloy coatings included different mass percent of Co and Cr have been synthesized on high carbon steel by using a facile high velocity oxy-fuel spray method. The mechanical nature of the coating films has been investigated by micro vickers hardness and fracture toughness. X-ray diffraction (XRD) and EDX analyses indicate that the three different samples (WC-10Co-4Cr, WC-17Co, and WC-12Co) consist of pure WC, W, Cr, and Co constituents as well as W2C and Co6W6C phases. The SEM and image analysis results show that WC-10Co-4Cr condition has higher porosity than those of WC-17Co, and WC-12Co coatings. WC-17Co coating showed the highest value in the hardness and fracture toughness test among three different samples. The obtained results revealed that the mechanical properties of WC based alloy coatings synthesized by a facile high velocity oxy-fuel spray method is very sensitive to Co content.
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http://dx.doi.org/10.1166/jnn.2018.14974DOI Listing
March 2018

Effect of the Spray Distance on the Properties of High Velocity Oxygen-Fuel (HVOF) Sprayed WC-12Co Coatings.

J Nanosci Nanotechnol 2018 Mar;18(3):1931-1934

Department of Materials Engineering, Inha University, Incheon 22212, Republic of Korea.

In this study influence of spray distance on the properties of WC-12Co coatings deposited by HVOF was investigated. WC-12Co coating was sprayed at spray distance of 300, 385 and 450 mm. From microstructure observation, it is confirmed that the porosity of coatings increases with increasing the spray distance. The X-ray diffraction patterns indicate that the coatings consist of pure WC, W, and Co as well as W2C and Co6W6C phases. The increase of the spray distance accelerated the decarburization of coatings. From micro hardness tests, it was found that the hardness and the fracture toughness decreased with increasing spray distance. These mechanical properties would be related with not only porosity but also the degree of decarburization.
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http://dx.doi.org/10.1166/jnn.2018.14990DOI Listing
March 2018

Effects of Heat Treatment on Interfacial Behavior and Bonding Strength of Surface Activated Bonding Ti-Al Laminate.

J Nanosci Nanotechnol 2018 Mar;18(3):1847-1850

Department of Materials Engineering, Inha University, Incheon 22212, Republic of Korea.

The surface activated bonding (SAB) method generally has the advantage of high bonding strength, low contact resistance, and high microstructural stability at room temperature. In this study, Ti-Al laminates were produced by surface activated bonding with aluminum and titanium foils. Heat treatment was conducted at the temperature range from 200 to 550 °C in vacuum. The bonding strength Ti-Al laminates was measured by a peel test, and the interfacial characteristics were investigated microstructural observation. The results showed that the bonding strength was the highest with heat treatment at 400 °C, microstructure observation revealed that the bonding strength of the Ti-Al laminate was influenced by the interfacial characteristics.
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http://dx.doi.org/10.1166/jnn.2018.14992DOI Listing
March 2018

Decoction of Turcz. Root Bark Ameliorates Skin Lesions and Inhibits Inflammatory Reactions in Mice with Contact Dermatitis.

Pharmacogn Mag 2017 Jul-Sep;13(51):483-487. Epub 2017 Jul 19.

Division of Pharmacology, School of Korean Medicine, Pusan National University, Gyeongnam, Korea.

Background: The root bark of Turcz. (Dictamni Radicis Cortex) has been widely used to treat skin diseases in Korea, and its anti-inflammatory efficacies were recently reported.

Objective: The paper aims to investigate the inhibitory effects of decoction of Dictamni Radicis Cortex (DDRC) in mice with contact dermatitis (CD).

Materials And Methods: We investigated the effects of DDRC on skin lesion characteristics such as crust, scales, incrustation and petechiae, the erythema and melanin indexes, skin thickness, histopathologic changes, and cytokine production in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced CD mice.

Results: Topical application of DDRC ameliorated crust, scales, incrustation, and induced by DNFB. In addition, DDRC lowered the erythema index significantly ( < 0.05). DDRC effectively inhibited enlargement of skin thickness ( < 0.05). Histopathologic observation showed that DDRC inhibited epidermal hyperplasia, hyperkeratosis, and spongiotic changes. Finally, DDRC decreased production levels of IFN-γ, TNF-α and IL-6 induced by repeated application of DNFB ( < 0.05).

Conclusion: These data suggest that DDRC can be used in the treatment of inflammatory skin diseases including CD. Moreover, these results are closely related to the decreasing production of TNF-α IFN-γ and IL-6 in inflamed tissues.

Summary: DDRC ameliorated skin lesions such as crust, scales, incrustation and petechiae, and lowered erythema index on skin surface in CD miceDDRC inhibited enlargement of dorsal skin and prevented epidermal hyperplasia, hyperkeratosis, and spongiotic changes in inflamed tissuesDDRC reduced the levels of TNF-α, IFN-γ, and IL-6 in inflamed tissues of CD miceDDRC did not affect spleen/body weight ratio in CD mice. DDRC: decoction of Dictamni Radicis Cortex, CD: contact dermatitis, DNFB: 1-fluoro-2,4-dinitrofluorobenzene, AOO: acetone and olive oil, DEX: dexamethasone, CBA: cytometric bead array.
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http://dx.doi.org/10.4103/0973-1296.211034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551369PMC
July 2017

Diclofenac Inhibits 27-hydroxycholesterol-induced Differentiation of Monocytic Cells into Mature Dendritic Cells.

Immune Netw 2017 Jun 20;17(3):179-185. Epub 2017 Jun 20.

Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.

We investigated whether diclofenac could influence the development of antigen-presenting cells in an oxygenated cholesterol-rich environment by determining its effects on the 27-hydroxycholesterol (27OHChol)-induced differentiation of monocytic cells into mature dendritic cells (mDCs). Treatment of human THP-1 monocytic cells with diclofenac antagonized the effects of 27OHChol by attenuating dendrite formation and cell attachment and promoting endocytic function. Diclofenac inhibited the transcription and surface expression of the mDC markers of CD80, CD83, and CD88, and reduced the 27OHChol-induced elevation of surface levels of MHC class I and II molecules to the basal levels in a dose-dependent manner. It also reduced the expression of CD197, a molecule involved in DC homing and migration. These results indicate that diclofenac inhibits the differentiation of monocytic cells into mDCs, thereby potentially modulating adaptive immune responses in a milieu rich in cholesterol oxidation products.
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http://dx.doi.org/10.4110/in.2017.17.3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484648PMC
June 2017

27-Hydroxycholesterol upregulates the production of heat shock protein 60 of monocytic cells.

J Steroid Biochem Mol Biol 2017 09 24;172:29-35. Epub 2017 May 24.

Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address:

Investigating differentially expressed proteins in a milieu rich in cholesterol oxidation products, we found via mass spectrometry-based proteomics that surface levels of heat shock protein 60 (HSP60) were upregulated on monocytic cells in the presence of 27-hydroxycholesterol (27OHChol). The elevated levels of cytoplasmic membrane HSP60 were verified via Western blot analysis and visualized by confocal microscopy. Treatment with 27OHChol also resulted in increased levels of cellular HSP60 without altering its transcription. Cholesterol, however, did not affect cell-surface levels and cellular amount of HSP60. GSK 2033, an LXR antagonist, inhibited expression of live X receptor α, but not of HSP60, induced by 27OHChol. Treatment with 27OHChol also resulted in increased release of HSP60 from monocytic cells, but the release was significantly reduced by inhibitors of endoplasmic reticulum-Golgi protein trafficking, brefeldin A and monensin. Results of the current study indicate that 27OHChol upregulates not only cell-surface and cellular levels of HSP60 but also its release from monocytic cells, thereby contributing to activation of the immune system.
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http://dx.doi.org/10.1016/j.jsbmb.2017.04.015DOI Listing
September 2017

PI3K and ERK signaling pathways are involved in differentiation of monocytic cells induced by 27-hydroxycholesterol.

Korean J Physiol Pharmacol 2017 May 21;21(3):301-308. Epub 2017 Apr 21.

Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.

27-Hydroxycholesterol induces differentiation of monocytic cells into mature dendritic cells, mDCs. In the current study we sought to determine roles of the PI3K and the ERK pathways in the 27OHChol-induced differentiation. Up-regulation of mDC-specific markers like CD80, CD83 and CD88 induced by stimulation with 27OHChol was significantly reduced in the presence of LY294002, an inhibitor of PI3K, and U0126, an inhibitor of ERK. Surface expression of MHC class I and II molecules elevated by 27OHChol was decreased to basal levels in the presence of the inhibitors. Treatment with LY294002 or U0126 resulted in recovery of endocytic activity which was reduced by 27OHChol. CD197 expression and cell adherence enhanced by 27OHChol were attenuated in the presence of the inhibitors. Transcription and surface expression of CD molecules involved in atherosclerosis such as CD105, CD137 and CD166 were also significantly decreased by treatment with LY294002 and U0126. These results mean that the PI3K and the ERK signaling pathways are necessary for differentiation of monocytic cells into mDCs and involved in over-expression of atherosclerosis-associated molecules in response to 27OHChol.
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http://dx.doi.org/10.4196/kjpp.2017.21.3.301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409116PMC
May 2017

Generation of therapeutic immunoconjugates via Residue-Specific Conjugation Technology (RESPECT) utilizing a native cysteine in the light chain framework of Oryctolagus cuniculus.

Cancer Biol Ther 2017 05 10;18(5):347-357. Epub 2017 Apr 10.

a Morphotek Inc. , Exton , PA , USA.

The conjugation of toxins, dyes, peptides, or proteins to monoclonal antibodies is often performed via free thiol groups generated by either partial reduction methods or engineering free cysteine residues into the antibody sequence. Antibodies from the rabbit Oryctolagus cuniculus have an additional intrachain disulfide bond, whereby the light chain variable kappa domain is bridged to the constant kappa region between cysteine residues at positions 80 and 171, respectively. Chimerization of rabbit antibodies with human constant domains allows for the generation of a free thiol group at the light chain position 80 (C80) that can be used for site-specific conjugation. An efficient process for the purification and simultaneous removal of cysteinylation at the C80 site was developed. The unpaired C80 was shown to be efficiently conjugated using several different maleimido-based ligands. REsidue SPEcific Conjugation Technology (RESPECT) antibody-drug conjugates prepared using rabbit-human chimeric anti-human mesothelin rabbit antibodies and maleimido-PEG-auristatin conjugated to C80 were shown to be highly potent and specific in vitro and effective in vivo in reduction of tumor growth in a highly aggressive mesothelin-expressing xenograft tumor model.
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http://dx.doi.org/10.1080/15384047.2017.1312232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499757PMC
May 2017

7α-Hydroxycholesterol induces monocyte/macrophage cell expression of interleukin-8 via C5a receptor.

PLoS One 2017 21;12(3):e0173749. Epub 2017 Mar 21.

Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.

We investigated effects of 7-oxygenated cholesterol derivatives present in atherosclerotic lesions, 7α-hydroxycholesterol (7αOHChol), 7β-hydroxycholesterol (7βOHChol), and 7-ketocholesterol (7K), on IL-8 expression. Transcript levels of IL-8 and secretion of its corresponding gene product by monocytes/macrophages were enhanced by treatment with 7αOHChol and, to a lesser extent, 7K, but not by 7βOHChol. The 7-oxygenated cholesterol derivatives, however, did not change transcription of the IL-8 gene in vascular smooth muscle cells. 7αOHChol-induced IL-8 gene transcription was inhibited by cycloheximide and Akt1 downregulation, but not by OxPAPC. Expression of C5a receptor was upregulated after stimulation with 7αOHChol, but not with 7K and 7βOHChol, and a specific antagonist of C5a receptor inhibited 7αOHChol-induced IL-8 gene expression in a dose dependent manner. Pharmacological inhibitors of PI3K and MEK almost completely inhibited expression of both IL-8 and cell-surface C5a receptor induced by 7αOHChol. These results indicate that 7-oxygenated cholesterol derivatives have differential effects on monocyte/macrophage expression of IL-8 and C5a receptor and that C5a receptor is involved in 7αOHChol-induced IL-8 expression via PI3K and MEK.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360241PMC
August 2017

Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

Biochem Biophys Res Commun 2016 09 26;478(3):1456-61. Epub 2016 Aug 26.

Department of Pharmacology, Pusan National University - School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address:

27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products.
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http://dx.doi.org/10.1016/j.bbrc.2016.08.145DOI Listing
September 2016

Dexamethasone Suppresses Oxysterol-Induced Differentiation of Monocytic Cells.

Oxid Med Cell Longev 2016 31;2016:2915382. Epub 2016 May 31.

Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea.

Oxysterol like 27-hydroxycholesterol (27OHChol) has been reported to induce differentiation of monocytic cells into a mature dendritic cell phenotype. We examined whether dexamethasone (Dx) affects 27OHChol-induced differentiation using THP-1 cells. Treatment of monocytic cells with Dx resulted in almost complete inhibition of transcription and surface expression of CD80, CD83, and CD88 induced by 27OHChol. Elevated surface levels of MHC class I and II molecules induced by 27OHChol were reduced to basal levels by treatment with Dx. A decreased endocytosis ability caused by 27OHChol was recovered by Dx. We also examined effects of Dx on expression of CD molecules involved in atherosclerosis. Increased levels of surface protein and transcription of CD105, CD137, and CD166 by treatment with 27OHChol were significantly inhibited by cotreatment with Dx. These results indicate that Dx inhibits 27OHChol-induced differentiation of monocytic cells into a mature dendritic cell phenotype and expression of CD molecules whose levels are associated with atherosclerosis. In addition, we examined phosphorylation of AKT induced by 27OHChol and effect of Dx, where cotreatment with Dx inhibited the phosphorylation of AKT. The current study reports that Dx regulates oxysterol-mediated dendritic cell differentiation of monocytic cells.
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http://dx.doi.org/10.1155/2016/2915382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906206PMC
May 2017

7α-Hydroxycholesterol induces inflammation by enhancing production of chemokine (C-C motif) ligand 2.

Biochem Biophys Res Commun 2015 Nov 19;467(4):879-84. Epub 2015 Oct 19.

Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address:

We investigated pro-inflammatory activity of 7-oxygenated cholesterol derivatives present in atherosclerotic lesions. Treatment of THP-1 monocyte/macrophage with 7α-hydroxycholesterol (7αOHChol) resulted in increased gene transcription of CCL2 and production of its corresponding protein. The conditioned medium isolated from THP-1 cells treated with 7αOHChol enhanced migration of monocytic cells, and migration was inhibited in the presence of CCL2-neutralizing antibody. In contrast, 7β-hydroxycholesterol (7βOHChol) or 7-ketocholesterol (7K) did not induce expression of CCL2, and the conditioned medium isolated from THP-1 cells exposed to 7βOHChol or 7K did not affect migration of monocytic cells. 7αOHChol also enhanced production of MMP-9. Inhibition of MEK or PI3K resulted in significantly attenuated expression of CCL2, along with that of MMP-9, induced by 7αOHChol. We propose that elevated concentration of a certain type of 7-oxygenated cholesterol derivative, like 7αOHChol, leads to inflammation via upregulation of CCL2 and MMP-9 in macrophages in the artery, thereby promoting progression of atherosclerosis, and the ERK and the PI3K pathways are involved in the process.
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http://dx.doi.org/10.1016/j.bbrc.2015.10.050DOI Listing
November 2015

27-Oxygenated cholesterol induces expression of CXCL8 in macrophages via NF-κB and CD88.

Biochem Biophys Res Commun 2015 Aug 15;463(4):1152-8. Epub 2015 Jun 15.

Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address:

We attempted to determine the effects of a milieu rich in cholesterol molecules on expression of chemokine CXCL8. A high-cholesterol diet led to an increased transcription of the IL-8 gene in the arteries and elevated levels of CXCL8 in sera of ApoE(-/-) mice, compared with those of wild-type C57BL/6 mice. Treatment of THP-1 monocyte/macrophage cells with 27-hydroxycholesterol (27OHChol) resulted in transcription of the IL-8 gene and increased secretion of its corresponding gene product whereas cholesterol did not induce expression of CXCL8 in THP-1 cells. 27OHChol-induced transcription of the IL-8 gene was blocked by cycloheximide, but not by polymyxin B. Treatment of THP-1 cells with 27OHChol caused translocation of p65 NF-κB subunit into the nucleus and up-regulation of CD88. Inhibition of NF-κB and CD88 using SN50 and W-54011, respectively, resulted in reduced transcription of the IL-8 gene and attenuated secretion of CXCL8 induced by 27OHChol. We propose that oxidatively modified cholesterol like 27OHChol, rather than cholesterol, is responsible for sustained expression of CXCL8 in monocytes/macrophages in atherosclerotic arteries.
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http://dx.doi.org/10.1016/j.bbrc.2015.06.075DOI Listing
August 2015

Pro-apoptotic action of macrophage inhibitory cytokine 1 and counteraction of activating transcription factor 3 in carrageenan-exposed enterocytes.

Toxicol Lett 2014 Nov 30;231(1):1-8. Epub 2014 Aug 30.

Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea; Department of Microbiology and Immunology and Medical Research Institute, Pusan National University, Pusan, South Korea; Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Busan, South Korea. Electronic address:

Carrageenan (CGN), a widely used food additive, has been shown to injure the epithelial barrier in animal models. This type of damage is a clinical feature of inflammatory bowel disease (IBD) in humans. In the present study, the effects of CGN on pro-apoptotic responses associated with macrophage inhibitory cytokine 1 (MIC-1) regulation in human enterocytes were evaluated. CGN up-regulated the expression of MIC-1 that promoted epithelial cell apoptosis. Although MIC-1 induction was dependent on pro-apoptotic p53 protein, the pro-survival protein activating transcription factor 3 (ATF3) was negatively regulated by p53 expression. However, MIC-1 enhanced the expression of the pro-survival protein ATF3 in enterocytes exposed to CGN. Functionally, MIC-1-mediated epithelial cell apoptosis was counteracted by the pro-survival action of ATF3 in response to CGN exposure. These findings demonstrated that the counterbalance between MIC-1 and ATF3 is critical for deciding the fate of enterocytes under the food chemical stress.
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http://dx.doi.org/10.1016/j.toxlet.2014.08.022DOI Listing
November 2014

Induction of heme oxygenase‑1 expression protects articular chondrocytes against cilostazol‑induced cellular senescence.

Int J Mol Med 2014 Nov 29;34(5):1335-40. Epub 2014 Aug 29.

Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626‑870, Republic of Korea.

Chondrocyte senescence is associated with the aging and degeneration of cartilage, and eventually leads to joint destruction. The aim of this study was to elucidate the mechanisms responsible for the cytoprotective effects of heme oxygenase‑1 (HO‑1) on chondrocytes in cartilage. Chondrocyte senescence was induced using cilostazol and measured using a specific senescence‑associated β‑galactosidase (SA‑β‑gal) staining assay. Cilostazol altered the expression of type Ⅱ collagen and β‑catenin, which are phenotypic markers of the differentiation and dedifferentiation of chondrocytes. Cilostazol also significantly induced HO‑1 expression, and the induction of HO‑1 expression was affected by a significant increase in reactive oxygen species (ROS) production caused by cilostazol treatment. Of note, pre‑treatment with 3‑morpholinosydnonimine hydrochloride (SIN‑1), an inducer of HO‑1 expression, markedly attenuated cilostazol‑induced chondrocyte senescence, and thus, we examined whether HO‑1 directly modulates chondrocyte senescence induced by cilostazol. The upregulation of HO‑1 was found to suppress cilostazol‑induced cellular senescence. In addition, the inhibition of HO‑1 activity with the iron chelator, desferrioxamine (DFO), or HO‑1 siRNA increased cilostazol‑induced chondrocyte senescence. Based on these results, it can be concluded that HO‑1 is associated with the suppression of chondrocyte senescence, and that the enforced overexpression of HO‑1 protects chondrocytes against stress‑induced senescence.
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http://dx.doi.org/10.3892/ijmm.2014.1918DOI Listing
November 2014

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity.

Cancer Biol Ther 2013 Nov 28;14(11):1032-8. Epub 2013 Aug 28.

Morphotek Inc.; Exton, PA USA.

Because of its high mortality rate, ovarian cancer is a leading cause of death among women and a highly unmet medical need. New therapeutic agents that are effective and well tolerated are needed and cancer antigen-specific monoclonal antibodies that have direct pharmacologic effects or can stimulate immunological responses represent a promising class of agents for the treatment of this disease. The human folate receptor α (FOLR1), which is overexpressed in ovarian cancer but largely absent in normal tissues, appears to play a role in the transformed phenotype in ovarian cancer, cisplatin sensitivity, and growth in depleted folate conditions and therefore has potential as a target for passive immunotherapy. The anti-FOLR1 monoclonal antibody MORAb-003 (farletuzumab) was previously shown to elicit antibody dependent cellular cytotoxicity (ADCC) and inhibit tumor growth of human tumor xenografts in nude mice. Because of its promising preclinical profile, farletuzumab has been evaluated in clinical trials as a potential therapeutic agent for ovarian cancer. In this report, we demonstrated that farletuzumab's antitumor effect against an experimental model of ovarian cancer is mediated by its ADCC activity.
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http://dx.doi.org/10.4161/cbt.26106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925658PMC
November 2013

Effect of the state of distribution of supported Pt nanoparticles on effective Pt utilization in polymer electrolyte fuel cells.

Phys Chem Chem Phys 2013 Jul 29;15(27):11236-47. Epub 2013 May 29.

Fuel Cell Nanomaterials Center, University of Yamanashi, 6-43 Miyamae, Kofu 400-0021, Japan.

In polymer electrolyte fuel cells, it is essential to minimize Pt loading, particularly at the cathode, without serious loss of performance. From this point of view, we will report an advanced concept for the design of high performance catalysts and membrane-electrode assemblies (MEAs): first, the evaluation of Pt particle distributions on both the interior and exterior walls of various types of carbon black (CB) particles used as supports with respect to the "effective surface (ES)"; second, control of both size and location of Pt particles by means of a new preparation method (nanocapsule method); and finally, a new evaluation method for the properties of MEAs based on the Pt utilization (UPt), mass activity (MA), and effectiveness of Pt (EfPt), based on the ES concept. The amounts of Pt catalyst particles located in the CB nanopores were directly evaluated using the transmission electron microscopy, scanning electron microscopy and corresponding three-dimensional images. By use of the nanocapsule method and optimization of the ionomer, increased MA and EfPt values for the MEA were achieved. The improvement in the cathode performance can be attributed to the sharp particle-size distribution for Pt and the highly uniform dispersion on the exterior surface of graphitized carbon black (GCB) supports.
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http://dx.doi.org/10.1039/c3cp51801aDOI Listing
July 2013

Pneumomediastinum after functional endoscopic sinus surgery under general anesthesia -A case report-.

Korean J Anesthesiol 2013 Apr 22;64(4):367-72. Epub 2013 Apr 22.

Department of Anesthesiology and Pain Medicine, St. Mary's Medical Center, Busan, Korea.

The occurrences of pneumothorax and pneumomediastinum are rare, but considered to be potentially life-threatening conditions in patients undergoing functional endoscopic sinus surgery under general anesthesia. Tracheobronchial rupture may results in serious complications, such as pneumothorax and pneumomediastinum. It may occur accidentally by endotracheal tube when the patient's neck is flexed or extended. We report the case of a 48-year-old female patient who developed massive subcutaneous emphysema, pneumothorax, pneumomediastinum and pneumoperitoneum seven hours after functional endoscopic sinus surgery under general anesthesia.
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http://dx.doi.org/10.4097/kjae.2013.64.4.367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640172PMC
April 2013

Popliteal sciatic nerve block versus spinal anesthesia in hallux valgus surgery.

Korean J Anesthesiol 2013 Apr 22;64(4):321-6. Epub 2013 Apr 22.

Department of Anesthesiology and Pain Medicine, St. Mary's Medical Center, Busan, Korea.

Background: We compared clinical properties and patient satisfaction between spinal anesthesia and popliteal sciatic nerve block (PSNB) for hallux valgus surgery.

Methods: Forty patients undergoing hallux valgus surgery were divided into spinal group (spinal anesthesia with 2.5 ml of 0.5% bupivacaine [n = 20]) and PSNB group (PSNB with 30 ml of 0.75% ropivacaine mixed with 10 ml of normal saline solution using a nerve stimulator [n = 20]). The PSNB group used a patient-controlled-analgesia (PCA) pump for postoperative pain control. The quality and side effects were compared between the two groups. A questionnaire was used to evaluate patient satisfaction with the use of anesthetic techniques and postoperative pain control in the PSNB group. This study was assessed 3 days postoperatively by a blinded observer.

Results: Procedure time and time from anesthesia until start of sugery were significantly shorter in the spinal group than those in the PSNB group (P < 0.01). Anesthesia-related complications such as hypotension, bradycardia, shivering, nausea/vomitting, post-dural puncture headache (PDPH) and urinary retension were observed in 15%, 10%, 5%, 5%, 10%, and 20% of patients in the spinal group, respectively. PSNB was not associated with these complications. Patient satisfaction was slightly higher for PSNB than for spinal anesthesia. In the PSNB group, patient satisfaction with postoperative pain-control was 95% above ordinary satisfaction.

Conclusions: Despite the long duration of the procedure, PSNB is relatively safe, provides an adequate level of anesthesia, effectively controls postoperative pain and reduces side effects. Therefore, PSNB could be a potential anesthetic technique for hallux valgus surgery.
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http://dx.doi.org/10.4097/kjae.2013.64.4.321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640164PMC
April 2013

p53 interferes with microtubule-stabilizing agent-induced apoptosis in prostate and colorectal cancer cells.

Int J Mol Med 2013 Jun 5;31(6):1388-94. Epub 2013 Apr 5.

Department of Anatomy and Cell Biology, Dong-A University, Busan, Republic of Korea.

Taxanes are microtubule-stabilizing agents that have anticancer activity against several types of human solid tumors. Although the primary mechanism of action of these drugs is well understood, the signaling pathways that confer resistance to these agents in certain types of cancer remain poorly understood. In particular, the association of p53 with the mechanism(s) of taxane-mediated cell death is still controversial. In this study, we showed that p53 has a profound inhibitory effect on docetaxel (Doc)-induced apoptosis in prostate and colorectal cancer cells and that caspases play a critical role in this process. Doc induced prostate cancer cell apoptosis at high levels in p53-null PC3 cells, at intermediate levels in p53-mutant DU145 cells and at low levels in p53 wild-type LNCaP cells. While transient overexpression of p53 in PC3 cells suppressed Doc-induced apoptosis, knockdown of p53 in LNCaP cells increased apoptosis. This finding was further confirmed using an isogenic pair of colorectal cancer cell lines, HCT-116 p53-/- and p53+/+, indicating that p53 inhibits induction of apoptosis by Doc. To our knowledge, this is the first report describing that chemical or genetic knockout of p53 enhances the susceptibility of both prostate and colorectal cancer cells to Doc-induced apoptosis. These results may suggest an approach to stratify patients for regimens involving Doc.
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http://dx.doi.org/10.3892/ijmm.2013.1333DOI Listing
June 2013

27-hydroxycholesterol induces production of tumor necrosis factor-alpha from macrophages.

Biochem Biophys Res Commun 2013 Jan 13;430(2):454-9. Epub 2012 Dec 13.

Department of Pharmacology, Pusan National University - School of Medicine, Yangsan 626-870, Republic of Korea.

Enhanced production of TNF-α from macrophages promotes development and instability of atherosclerotic plaques, but involvement of lipid component in TNF-α production has not been clarified in atherosclerosis. We attempted to determine whether cholesterol oxidation products (oxysterols) could modify TNF-α production. Treatment of THP-1 cells with 27-hydroxycholesterol (27OHChol) or 7α-hydroxycholesterol (7αOHChol) resulted in a profound increase in TNF-α transcription, while treatment with an identical concentration of cholesterol and 7-ketochoelsterol did not lead to any change in TNF-α expression. Treatment with 27OHChol resulted in increased synthesis, as well as secretion, of TNF-α, while 7αOHChol led to increased synthesis of TNF-α without affecting secretion of the cytokine. Co-treatment with 7αOHChol or 27OHChol and LPS resulted in synergistically enhanced or augmented secretion of TNF-α. Treatment with TO-901317, pertussis toxin, PP2, and LY294002 resulted not only in attenuated transcription of TNF-α induced by 27OHChol and 7αOHChol, but also secretion of TNF-α enhanced by 27OHChol. This is the first report demonstrating enhanced production of TNF-α in macrophages by treatment with oxysterols which are detected in abundance in atheromatous lesions; in addition, results of the current study provide evidence indicating that certain types of oxysterols contribute to development of atherosclerosis by promoting production of proinflammatory cytokines.
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http://dx.doi.org/10.1016/j.bbrc.2012.12.021DOI Listing
January 2013

Protein kinase CK2 mediates peroxynitrite-induced heme oxygenase-1 expression in articular chondrocytes.

Int J Mol Med 2012 Jun 23;29(6):1039-44. Epub 2012 Mar 23.

Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea.

Heme oxygenase-1 (HO-1) is induced as an adaptive mechanism against oxidative stress in chondrocytes, which play an important role in the maintenance and degradation of cartilage. In the present study, we examined the role of protein kinase casein kinase (CK2) on peroxynitrite-induced expression of HO-1 in primary articular chondrocytes. 3-Μorpholinosydnonimine hydrochloride (SIN-1) has been shown to mediate cell death by activating apoptosis-related molecules in cells. In this study, we used a low concentration of SIN-1 that did not induce apoptosis to elucidate the mechanism by which SIN-1 upregulates HO-1 expression. In chondrocytes, SIN-1 induced HO-1 expression with spontaneous downregulation in a different manner than with high concentrations of SIN-1. Importantly, SIN-1 treatment of chondrocytes increased CK2 activation. Additionally, inhibition of CK2 with 4,5,6,7-tetrabromobenzotriazole (TBB) or siRNA did not induce HO-1 expression and reduced NF-E2-related factor 2 (Nrf2) accumulation in chondrocytes. Therefore, we examined whether CK2 directly regulates Nrf2, which is a transcription factor that regulates the expression of HO-1. Indeed, TBB treatment inhibited phosphorylation and nuclear translocation of Nrf2 in SIN-1-treated cells. Moreover, using an immunoprecipitation assay, we confirmed that SIN-1 treatment enhanced the interaction between CK2 and Nrf2. Taken together, our findings suggest that peroxynitrite activates Nrf2 via CK2 signaling, leading to the upregulation of HO-1 in primary chondrocytes.
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http://dx.doi.org/10.3892/ijmm.2012.949DOI Listing
June 2012

Cilostazol induces cellular senescence and confers resistance to etoposide-induced apoptosis in articular chondrocytes.

Int J Mol Med 2012 Apr 23;29(4):619-24. Epub 2012 Jan 23.

Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea.

We recently reported that cilostazol protects chondrocytes against stress-induced apoptosis and prevents cartilage destruction in an osteoarthritis (OA) model. In the present study, we elucidate the mechanism underlying the protective effect induced by cilostazol against stress-induced apoptosis in chondrocytes. Cilostazol significantly reduced the expression of type II collagen and stimulated the accumulation of β-catenin in primary rat articular chondrocytes. Moreover, cilostazol-induced chondrocytes showed induction of senescent phenotypes, such as changes in cell morphology, decrease in cell proliferation and increase in specific senescence-associated β-galactosidase (SA-β-gal) staining. Moreover, dedifferentiated chondrocytes obtained by serial subculture showed cellular senescence that increased with passage number. In addition, the percentage of terminal dUTP nick end-labeling (TUNEL)-positive cells was higher when chondrocytes were treated with cilostazol and the apoptosis inducer etoposide than when the cells were treated with etoposide alone. Our findings suggest that cilostazol induces dedifferentiation and senescence in rat articular chondrocytes and renders them resistant to etoposide-induced apoptosis.
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http://dx.doi.org/10.3892/ijmm.2012.892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577138PMC
April 2012

Characterization of the human folate receptor alpha via novel antibody-based probes.

Oncotarget 2011 Dec;2(12):1227-43

Morphotek Inc., 210 Welsh Pool Road, Exton, PA 19342, USA.

Folate receptor alpha (FRA) is a cell surface protein whose aberrant expression in malignant cells has resulted in its pursuit as a therapeutic target and marker for diagnosis of cancer. The development of immune-based reagents that can reproducibly detect FRA from patient tissue processed by varying methods has been difficult due to the complex post-translational structure of the protein whereby most reagents developed to date are highly structure-sensitive and have resulted in equivocal expression results across independent studies. The aim of the present study was to generate novel monoclonal antibodies (mAbs) using modified full length FRA protein as immunogen in order to develop a panel of mAbs to various, non-overlapping epitopes that may serve as diagnostic reagents able to robustly detect FRA-positive disease. Here we report the development of a panel of FRA-specific mAbs that are able to specifically detect FRA using an array of diagnostic platforms and methods. In addition, the methods used to develop these mAbs and their diverse binding properties provide additional information on the three dimensional structure of FRA in its native cell surface configuration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282080PMC
http://dx.doi.org/10.18632/oncotarget.412DOI Listing
December 2011
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