<i>CYP2A6</i> and <i>ERCC1</i> polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients

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>

Adenosine triphosphate-based chemotherapy response assay-guided chemotherapy in unresectable colorectal liver metastasis

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>

한국의 HIV-1 감염의 분자역학

이주실,김은영,남정구,기미경,최병선,김성순,강춘,구본기,신영오 국립보건연구원 1998 국립보건원보 Vol.35 No.-

한국인 Long Term Non Progressors로부터 분리된 HIV-1 env 및 nef 유전자와 이들의 면역 유전학적 특성 분석에 의한 질병진전 요인 규명

이주실,강춘,김성순,박근용,고운영,기미경,최병선,남정구,서순덕,이성래,구본기,박혜경,도경미,김태규,최희백,조현일,김요숙,김지영,이해정,안수진 국립보건연구원 1999 국립보건원보 Vol.36 No.-

국내 HIV/AIDS 발견이후 HIV 유행주의 분자역학적 변이 분석

이주실,김성순,남정구,전수경,변승옥,최병선,박미선,김옥진,서순덕 국립보건연구원 2000 국립보건원보 Vol.37 No.-

Inhibitory effect of obovatol on nitric oxide production and activation of NF-κB/MAP kinases in lipopolysaccharide-treated RAW 264.7cells

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.

The long-term relationship between dietary pantothenic acid (vitamin B₅) intake and C-reactive protein concentration in adults aged 40 years and older

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>

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

<i>S100A9</i> and <i>EGFR</i> gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy

Kim, W. T.,Kim, J.,Yan, C.,Jeong, P.,Choi, S. Y.,Lee, O. J.,Chae, Y. B.,Yun, S. J.,Lee, S. C.,Kim, W. J. Oxford University Press 2014 Annals of Oncology Vol.25 No.5

<P>In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC. Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings. Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623-13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy. The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.</P>

ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding

Jeon, B.N.,Yoon, J.H.,Han, D.,Kim, M.K.,Kim, Y.,Choi, S.H.,Song, J.,Kim, K.S.,Kim, K.,Hur, M.W. Elsevier Science 2017 Biochimica et biophysica acta. Gene regulatory mec Vol.1860 No.9

Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.