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Choi, J. K.,Kim, K. H.,Park, S. R.,Choi, B. H. HUMANA PRESS INC 2014 Molecular neurobiology Vol.49 No.2
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic cytokine that plays a crucial role in regulating the proliferation, differentiation, and survival of hematopoietic cells. Recent studies have shown that GM-CSF also has anti-apoptotic effects and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. However, the mechanism underlying the anti-apoptotic function of GM-CSF is not well understood. In the present work, we examined the role of phosphoinositide 3-kinase (PI3K)-AKT signal pathway in the anti-apoptotic activity of GM-CSF in mouse neural progenitor cells (NPCs). In terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, the anti-apoptotic effect of GM-CSF (apoptotic population of approximately 8.17 %) on staurosporine-induced apoptosis of NPCs (31.09 %) was significantly blocked by LY294002, an inhibitor of PI3K signal (24.04 %). We found that the PI3K-AKT signal pathway induced by GM-CSF treatment activated nuclear factor kappa B (NF-kappa B) and increased the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in normoxic conditions. Analyses using specific small interfering RNAs (siRNAs) showed that NF-kappa B was an upstream molecule of HIF-1 alpha and activated its expression at the mRNA level. Further analyses using the siRNAs and chromatin immunoprecipitation (ChIP) showed that HIF-1 alpha was responsible for the induced expression of survivin, a member of the inhibitor of apoptosis proteins (IAPs). Each of the specific siRNAs for NF-kappa B, HIF-1 alpha, and survivin inhibited significantly the anti-apoptotic activity of GM-CSF on the staurosporine-induced apoptosis in NPCs in TUNEL assays. The results of this study showed the downstream signals and mechanism of PI3K/AKT-mediated anti-apoptotic activity of GM-CSF in NPCs, particularly revealing the role of the NF-kappa B-HIF-1 alpha-survivin cascade.
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Hur, H,Kim, N K,Kim, H G,Min, B S,Lee, K Y,Shin, S J,Cheon, J H,Choi, S H Nature Publishing Group 2012 The British journal of cancer Vol.106 No.1
<P><B>Background:</B></P><P>This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis.</P><P><B>Patients and methods:</B></P><P>Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared.</P><P><B>Results:</B></P><P>Between November 2008 and October 2010, a total 63 patients were randomised to Group A (<I>N</I>=32) or Group B (<I>N</I>=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) <I>vs</I> 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% <I>vs</I> 21.9%, <I>P</I>=0.027). The resectability of hepatic lesion was higher in Group B (35.5% <I>vs</I> 12.5%, <I>P</I>=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4–12) in Group A and 8 cycles (range 8–16) in Group B.</P><P><B>Conclusion:</B></P><P>This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis.</P>
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Seo, I.-T.,Park, H.-Y.,Dung, N.V.,Choi, M.-K.,Nahm, S.,Lee, H.-G.,Choi, B.-H. IEEE 2009 and Frequency Control Vol.56 No.11
<P>Various amounts of Nb<SUB>2</SUB>O<SUB>5</SUB> in the (Na<SUB>0.5</SUB>K<SUB>0.5</SUB>) NbO<SUB>3</SUB> (NKN) ceramic were replaced by V<SUB>2</SUB>O<SUB>5</SUB> to decrease its sintering temperature to below 950°C. A small V<SUB>2</SUB>O<SUB>5</SUB> content resulted in a dense microstructure with an increased grain size for the specimen sintered at 900°C due to the presence of a liquid phase. When V<SUB>2</SUB>O<SUB>5</SUB> was added to the NKN ceramics, their orthorhombic-to-tetragonal transition temperature increased from 178°C to around 200°C. However, their Curie temperature decreased from 402°C to around 330°C. The k<SUB>p</SUB>, <SUB>ε3</SUB> <SUP>T</SUP>/<SUB>ε0</SUB>, and Q<SUB>m</SUB> values increased with V<SUB>2</SUB>O<SUB>5</SUB> addition, probably due to the increased density and poling state, which was identified by the phase angle. The specimen with x = 0.05, sintered at 900°C for 8 h, exhibited the following piezoelectric properties: k<SUB>p</SUB> = 0.32, <SUB>ε3</SUB> <SUP>T</SUP>/<SUB>ε0</SUB> = 245, d<SUB>33</SUB> = 120 (pC/N), and Q<SUB>m</SUB> = 232.</P>
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Jung, S.,Kim, M.K.,Choi, B.Y. Elsevier 2017 Nutrition, metabolism, and cardiovascular diseases Vol.27 No.9
<P><B>Abstract</B></P> <P><B>Background and aims</B></P> <P>Low-grade inflammation, represented by minor C-reactive protein (CRP) elevation, has a critical role in the early stages of atherosclerosis, and pantothenic acid (PA) may have an antioxidant effect in inflammatory process. However, the long-term relationship between PA intake and CRP has not yet been studied. The objective of the present study was to evaluate the long-term relationship of PA intake to CRP concentration in healthy adults aged 40 years or older living in a rural area of South Korea.</P> <P><B>Methods and Results</B></P> <P>A total of 908 subjects (349 men, 559 women) with repeated data on dietary PA intake and CRP concentration were included in the final analysis. To represent the long-term effect of PA intake, both PA intake at the baseline and average PA intake were used as the exposure, and CRP concentration at the third visit and its change from the baseline to the third visit were used as the outcome. After adjustment for potential confounders, a significant inverse relationship between PA intake and CRP concentration at the third visit was observed (<I>P</I> for trend = 0.001, <I>β</I> = −0.07 (<I>P</I>-value = 0.001) for PA <SUB>baseline</SUB>; <I>P</I> for trend = <0.0001, <I>β</I> = −0.11 (<I>P</I>-value = 0.0004) for PA <SUB>average (baseline, 2nd, 3rd)</SUB>). Higher PA intake was significantly related to lower or attenuated increase in CRP concentration (<I>P</I> for trend = 0.002, <I>β</I> = −0.24 (<I>P</I>-value = 0.002) for PA <SUB>baseline</SUB>; <I>P</I> for trend = 0.001, <I>β</I> = −0.35 (<I>P</I>-value = 0.001) for PA <SUB>average (baseline, 2nd, 3rd)</SUB>).</P> <P><B>Conclusions</B></P> <P>In conclusion, dietary PA intake was inversely related to subsequent CRP concentration in both men and women aged 40 years or older in South Korea.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Higher baseline and average PA intakes were significantly related to lower CRP concentration at the end of follow-up. </LI> <LI> Higher average PA intakes were significantly related to lower CRP concentration or attenuated increase in CRP concentration. </LI> <LI> PA should not be overlooked in regard to its effects on inflammation, because it might have an antioxidant effect. </LI> </UL> </P>
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Choi, B.Y.,Yun, S.T.,Kim, K.H.,Choi, H.S.,Chae, G.T.,Lee, P.K. Elsevier 2014 Journal of geochemical exploration Vol.144 No.1
Naturally outflowing CO<SUB>2</SUB>-rich springs are a natural analogue of the seepage of sequestered CO<SUB>2</SUB> in geological storage sites. In Kangwon district of South Korea, two hydrochemically different types of CO<SUB>2</SUB>-rich springs (i.e., Ca-HCO<SUB>3</SUB>-type and Na-HCO<SUB>3</SUB>-type) occur together in a granitic terrain. Hydrochemical and water-isotope data (i.e., δ<SUP>18</SUP>O-δD and tritium) show that Na-HCO<SUB>3</SUB>-type springs have experienced significant silicate weathering processes over a long residence time at depths, while Ca-HCO<SUB>3</SUB>-type springs were formed by the mixing of Na-HCO<SUB>3</SUB>-type springs with shallow groundwater during ascent. In this study, diverse geochemical models including mixing, ion exchange and reaction path were investigated to verify the geochemical processes accounting for the occurrence of two contrasting types of CO<SUB>2</SUB>-rich springs. The mixing and ion exchange models reveal that Ca-HCO<SUB>3</SUB>-type springs are well explained by reverse cation exchange occurring during the mixing of Na-HCO<SUB>3</SUB>-type springs with shallow groundwater. The Na-HCO<SUB>3</SUB>-type springs are well explained by the reaction path modeling including the dissolution of silicate minerals (plagioclase, K-feldspar and biotite) and the precipitation of secondary minerals (calcite, kaolinite, muscovite and Mg-beidellite), implying that dissolved carbon is sequestered by calcite precipitation (i.e., mineral trapping). However, the concentrations of K in our modeling results are far below those of K observed in Na-HCO<SUB>3</SUB>-type springs, because of the precipitation of muscovite considered in the model, suggesting the partial disequilibrium state of the aquifer during the hydrolysis of K-feldspar under high P<SUB>CO'2</SUB> conditions. This result implies that to better predict long-term CO<SUB>2</SUB>-water-rock interactions in a geological storage site with abundant K-feldspar, the secondary K-bearing minerals should be carefully predicted, because a target aquifer can be far from chemical equilibrium during the storage period. This study shows that geochemical modeling can be effectively used to predict the hydrochemical changes of groundwater during long-term CO<SUB>2</SUB>-water-rock interactions and subsequent leakage toward surface in K-feldspar rich aquifer, although it should be included in a fully coupled computational approach between fluid flow, heat transfer and reactive mass transport processes in the future research.
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Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect
Choi, K-J,Kim, J-H,Lee, Y-S,Kim, J,Suh, B-S,Kim, H,Cho, S,Sohn, J-H,Kim, G E,Yun, C-O Nature Publishing Group 2006 Gene therapy Vol.13 No.13
Oncolytic adenoviral vectors are currently being developed as biologic anticancer agents. Coupling the lytic function of an oncolytic adenovirus (Ad) with its ability as a transgene delivery system represents a powerful extension of this methodology. A clear advantage is the amplification of a therapeutic gene, as replicating vectors would be able to infect and deliver the gene of interest to neighboring cells. Granulocyte–macrophage colony-stimulating factor (GM-CSF) is one of the most potent stimulators of a specific and long-lasting antitumor immunity and its important role in the maturation of antigen-presenting cells to induce T-cell activation has been well documented. Similarly, the B7 family has also been shown to play an integral role in mediating an antitumor response. Most tumor cells, however, lack the expression of these costimulatory molecules on their surface, thus escaping immune system recognition. To increase the antitumor effect of an oncolytic Ad, we have generated an E1B 55 kDa-deleted oncolytic adenoviral vector, YKL-GB, that expresses both GM-CSF and B7-1. The therapeutic efficacy of YKL-GB Ad was evaluated in immunocompetent mice bearing murine melanoma B16-F10 tumors. Significant inhibition of tumor growth was seen in mice treated with YKL-GB compared to those treated with the analogous vector, YKL-1. Moreover, YKL-GB oncolytic Ad demonstrated enhanced antitumor activity and higher incidences of tumor regression compared to a replication-incompetent Ad, dl-GB, which coexpresses GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against a tumor re-challenge. To establish that the observed antitumor effect is associated with the generation of a tumor-specific immune response, we carried out interferon-γ enzyme-linked immune spot assay. We observed that YKL-GB induced significantly higher immune cell activation than YKL-1. Furthermore, immunohistochemical studies demonstrated robust dendritic cells and CD4<SUP>+</SUP>/CD8<SUP>+</SUP> T-cell infiltration in these mice compared to the YKL-1-treated groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of the costimulatory and activation molecules. These findings demonstrate the effectiveness of enhancing the immune response against tumors with an oncolytic Ad expressing both GM-CSF and B7-1 and provide a potential therapeutic strategy for the management of neoplasia.Gene Therapy (2006) 13, 1010–1020. doi:10.1038/sj.gt.3302759; published online 9 March 2006
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Choi, M.S.,Lee, S.H.,Cho, H.S.,Kim, Y.,Yun, Y.P.,Jung, H.Y.,Jung, J.K.,Lee, B.C.,Pyo, H.B.,Hong, J.T. North-Holland ; Elsevier Science Ltd 2007 european journal of pharmacology Vol.556 No.1
The components of Magnolia obovata are known to have many pharmacological activities. In this study, we investigated the effects of obovatol, a neolignan compound isolated from the leaves of M. obovata, on nitric oxide (NO) production and NF-κB activity in lipopolysaccharide (LPS)-activated RAW 264.7 cells. The results show that obovatol (1-5 μM) significantly inhibited LPS-induced NO production in a concentration-dependent manner (IC<SUB>50</SUB>: 0.91 μM). Consistent with the inhibitory effect on NO production, obovatol inhibits the expression of inducible nitric oxide synthase and cyclooxygenase-2 expression. Furthermore, obovatol suppressed NF-κB (p50 and p65) translocation to the nucleus as well as IκB release resulting in the inhibition of the DNA binding activity of the NF-κB. Obovatol also inhibited c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signal, which are the most significantly involved signal in NO production and NF-κB activation. When the cells were treated with the combination of obovatol with U0126 (an ERK inhibitor) or SP600125 (a JNK inhibitor) as well as with SC-514 (an IKK2 inhibitor), much more inhibition of NO production was observed than that by obovatol alone. The present results suggest that obovatol has an inhibitory effect on NO production through the inhibition of NF-κB/MAPK activity, and thus can be used as an anti-inflammatory agent.
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Park, S R,Kong, S-Y,Nam, B-H,Choi, I J,Kim, C G,Lee, J Y,Cho, S J,Kim, Y W,Ryu, K W,Lee, J H,Rhee, J,Park, Y-I,Kim, N K Nature Publishing Group 2011 The British journal of cancer Vol.104 No.7
<P><B>Background:</B></P><P>We evaluated the association between polymorphisms of cytochrome P450 2A6 (<I>CYP2A6</I>)/excision repair cross-complementation group 1 (<I>ERCC1</I>)/X-ray repair cross-complementing group 1(<I>XRCC1</I>) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin.</P><P><B>Methods:</B></P><P>Among MGC patients (<I>n</I>=108), who received S-1 (40 mg m<SUP>−2</SUP> b.i.d., days 1–14) and cisplatin (60 mg m<SUP>−2</SUP>, day 1) every 3 weeks, we analysed the wild-type allele (<I>W</I>) and variants (<I>V</I>) of <I>CYP2A6</I> (<I>*4</I>, <I>*7, *9, *10</I>), and the polymorphisms of <I>ERCC1</I> (rs11615, rs3212986) and <I>XRCC1</I> (rs25487).</P><P><B>Results:</B></P><P>Patients having fewer <I>CYP2A6</I> variants had better response rates (<I>W</I>/<I>W vs W</I>/<I>V</I> other than <I>*1/*4 vs V</I>/<I>V</I> or <I>*1/*4</I>=66.7 <I>vs</I> 58.3 <I>vs</I> 32.3% <I>P</I>=0.008), time to progression (TTP) (7.2 <I>vs</I> 6.1 <I>vs</I> 3.5 months, <I>P</I>=0.021), and overall survival (23.2 <I>vs</I> 15.4 <I>vs</I> 12.0 months, <I>P</I>=0.004). <I>ERCC1 19442C</I>><I>A</I> (rs3212986) was also associated with response rate (<I>C/C</I>, 46.7% <I>vs C/A</I>, 55.3% <I>vs A/A</I>, 87.5%) (<I>P</I>=0.048) and TTP (4.4 <I>vs</I> 7.6 <I>vs</I> 7.9 months) (<I>P</I>=0.012). Patients carrying both risk genotypes of <I>CYP2A6</I> (<I>V</I>/<I>V</I> or <I>1/*4</I>) and <I>ERCC1 19442C</I>><I>A</I> (<I>C/C</I>) <I>vs</I> those carrying none showed an adjusted odds ratio of 0.113 (<I>P</I>=0.004) for response, and adjusted hazard ratios of 3.748 (<I>P</I>=0.0001) for TTP and 2.961 (<I>P</I>=0.006) for death.</P><P><B>Conclusion:</B></P><P>Polymorphisms of <I>CYP2A6</I> and <I>ERCC1 19442C</I>><I>A</I> correlated with the efficacy of S-1/cisplatin.</P>
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