Fibronectin expression in carcinoma cells correlates with tumor aggressiveness and poor clinical outcome in patients with invasive breast cancer

Bae, Y.K.,Kim, A.,Kim, M.K.,Choi, J.E.,Kang, S.H.,Lee, S.J. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.10

Fibronectin (FN), a large heterodimeric glycoprotein, can be found in soluble form in plasma or in insoluble form as an extracellular matrix protein. Cellular FN is produced by various types of benign and malignant epithelial and mesenchymal cells and is widely distributed in malignant tumors. We evaluated FN expression in cancer cells (epithelial FN; E-FN) and intratumor stroma (stromal FN, S-FN) of 1596 invasive breast cancer samples using immunohistochemistry on tissue microarrays. Correlations of FN expression with clinicopathologic factors and patient survival were investigated. Among 1512 informative cases, E-FN expression was observed in 355 (23.5%) cases, and S-FN expression showed no/weak staining in 362 (23.9%), moderate staining in 744 (49.2%), and strong staining in 406 (26.9%) cases. E-FN expression was correlated with advanced pT (P < .001) and pN (P < .001), histologic type (P = .006), high histologic grade (P < .001), lymphovascular invasion (P < .001), hormone receptor negativity (P < .001), and human epidermal growth factor receptor-2 (HER2) positivity (P < .001). Strong S-FN expression showed an association with advanced pN (P = .002), histologic type (P < .001), high histologic grade (P < .001), lymphovascular invasion (P < .001), and HER2 positivity (P < .001). Patients with E-FN expression showed worse overall survival (P < .001) and disease-free survival (P < .001) than did those with negative expression of FN. E-FN expression was an independent prognostic factor, especially in the hormone receptor-positive group. Expression of S-FN did not have a significant effect on patient survival. In conclusion, E-FN expression could be a promising prognostic marker in patients with invasive breast cancer.

Enhanced tumor protection by AdIL-12 plus E7 protein codelivery in a human papillomavirus 16 (E6/E7)-associated tumor challenge model

류상우 ( S. W. Rhu ),( S. J. Oh ),( J. W. Lee ),( E. K. Park ),( J. W. Lee ),( J. I. Sin ),( S. M. Bae ),( J. O. Lee ),( J. M. Lee ),( S. E. Namkoong ),( W. S. Ahn ) 대한산부인과학회 2002 대한산부인과학회 학술대회 Vol.88 No.-

pH-Responsive globular poly(ethylene glycol) for photodynamic tumor therapy

Ku, E.B.,Lee, D.J.,Na, K.,Choi, S.W.,Youn, Y.S.,Bae, S.K.,Oh, K.T.,Lee, E.S. Elsevier 2016 Colloids and Surfaces B Vol.148 No.-

<P>In this study, we report the development of extremely small-sized globular poly(ethylene glycol) (gPEG) that can specifically recognize tumor acidic pH. gPEG coupled with chlorin e6 (Ce6, a photosensitizing drug) and 2,3-dimethylmaleic acid (DMA, as a pH-responsive moiety) (gPEG-Ce6-DMA, particle size: 3-4 nm in diameter) was easily dispersed in phosphate buffered saline (PBS) without any of the nanoparticle fabrication steps. We observed that gPEG-Ce6-DMA displayed pH-dependent zeta-potential changes due to coupling (at pH 7.4) or decoupling (at pH 6.8-6.0) of DMA. As a result, the uptake of gPEG-Ce6-DMA was significantly increased in tumors at acidic pH, likely due to the decoupling of DMA (backing cationic primary amines). As a result, the preferential cellular uptake of gPEG-Ce6-DMA at acidic pH allowed for a significant enhancement of in vitro/in vivo photodynamic tumor cell ablation under light illumination. (C) 2016 Elsevier B.V. All rights reserved.</P>

Effects of E. Coli lipopolysaccharide on the pharmacokinetics of ipriflavone and its metabolites, M1 and M5, after intravenous and oral administration of ipriflavone to rats: Decreased metabolism of ipriflavone due to decreased expression of hepatic CYP1

Chung, Hye J.,Kang, Hee E.,Bae, Eun J.,Lee, Inchul,Kim, Sang G.,Lee, Myung G. Wiley Subscription Services, Inc., A Wiley Company 2008 journal of pharmaceutical sciences Vol.97 No.11

<P>It was reported that ipriflavone was primarily metabolized via hepatic CYP1A1/2 and 2C11 in rats. In the present study, the expression of CYP1A2 and 2C11 decreased in the liver, but increased in the intestine in rats pretreated with E. coli lipopolysaccharide (ECLPS; an animal model of inflammation). Thus, pharmacokinetic parameters of ipriflavone and its metabolites, M1 and M5, were evaluated in ECLPS rats. After intravenous administration (20 mg/kg) to ECLPS rats, the AUC of ipriflavone was significantly greater (26.7% increase) and CL<SUB>NR</SUB> of ipriflavone was significantly slower (19.9% decrease) than in the controls. This could have been due to decreased expression of hepatic CYP1A2 and 2C11 compared to the controls. After oral administration (200 mg/kg) to ECLPS rats, the AUC of ipriflavone was also significantly greater (130% increase) than in the controls. Although the expression of intestinal CYP1A2 and 2C11 increased in ECLPS rats, contribution of this increase to the significantly greater AUC of ipriflavone after oral administration of ipriflavone to ECLPS rats was not considerable. This could have also been due to a significantly decreased expression of hepatic CYP1A2 and 2C11 in ECLPS rats. The formation of M1 and M5 could be mediated via CYP1A2 and/or 2C11 in rats. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5024–5036, 2008</P>

Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT

Oh, W,Lee, E-W,Lee, D,Yang, M-R,Ko, A,Yoon, C-H,Lee, H-W,Bae, Y-S,Choi, C Y,Song, J Macmillan Publishers Limited 2010 Oncogene Vol.29 No.28

In this study, we identified posttranslational regulation of human telomerase reverse-transcriptase (hTERT) by the E3 ligase Hdm2. The telomerase activity generated by exogenous hTERT in U2OS cells was reduced on adriamycin treatment. The overexpressed levels of hTERT were also decreased under the same conditions. These processes were reversed by treatment with a proteasome inhibitor or depletion of Hdm2. Furthermore, intrinsic telomerase activity was increased in HCT116 cells with ablation of Hdm2. Immunoprecipitation analyses showed that hTERT and Hdm2 bound to each other in multiple domains. Ubiquitination analyses showed that Hdm2 could polyubiquitinate hTERT principally at the N-terminus, which was further degraded in a proteasome-dependent manner. An hTERT mutant with all five lysine residues at the N-terminus of hTERT that mutated to arginine became resistant to Hdm2-mediated ubiquitination and degradation. In U2OS cells, depletion of Hdm2 or addition of the Hdm2-resistant hTERT mutant strengthened the cellular protective effects against apoptosis. Similar results were obtained with the Hdm2-stable H1299 cell line. These observations indicate that Hdm2 is an E3 ligase of hTERT.

Methylome analysis reveals alterations in DNA methylation in the regulatory regions of left ventricle development genes in human dilated cardiomyopathy

Jo, B.S.,Koh, I.U.,Bae, J.B.,Yu, H.Y.,Jeon, E.S.,Lee, H.Y.,Kim, J.J.,Choi, M.,Choi, S.S. Academic Press 2016 Genomics Vol.108 No.2

<P>Dilated cardiomyopathy (DCM) is one of the main causes of heart failure (called cardiomyopathies) in adults. Alterations in epigenetic regulation (i.e., DNA methylation) have been implicated in the development of DCM. Here, we identified a total of 1828 differentially methylated probes (DMPs) using the Infinium 450K HumanMethylation Bead chip by comparing the methylomes between 18 left ventricles and 9 right ventricles. Alterations in DNA methylation levels were observed mainly in lowly methylated regions corresponding to promoter-proximal regions, which become hypermethylated in severely affected left ventricles. Subsequent mRNA microarray analysis showed that the effect of DNA methylation on gene expression regulation is not unidirectional but is controlled by the functional sub-network context. DMPs were significantly enriched in the transcription factor binding sites (TFBSs) we tested. Alterations in DNA methylation were specifically enriched in the cis-regulatory regions of cardiac development genes, the majority of which are involved in ventricular development (e.g., TBX5 and HAND1). (C) 2016 The Authors. Published by Elsevier Inc.</P>

Ligand Accessibility and Bioactivity of a Hormone–Dendrimer Conjugate Depend on pH and pH History

Kim, Sung Hoon,Madak-Erdogan, Zeynep,Bae, Sung Chul,Carlson, Kathryn E.,Mayne, Christopher G.,Granick, Steve,Katzenellenbogen, Benita S.,Katzenellenbogen, John A. American Chemical Society 2015 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.137 No.32

<P>Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells. In response to pH changes, however, these estrogen–dendrimer conjugates (EDCs) display a major morphological transition that alters the accessibility of the estrogen ligands that compromises the bioactivity of the EDC. A sharp break in dynamic behavior near pH 7 occurs for three different ligands on the surface of a PAMAM-G6 dendrimer: a fluorophore (tetramethylrhodamine [TMR]) and two estrogens (17α-ethynylestradiol and diphenolic acid). Collisional quenching and time-resolved fluorescence anisotropy experiments with TMR–PAMAM revealed high ligand shielding above pH 7 and low shielding below pH 7. Furthermore, when the pH was cycled from 8.5 (conditions of ligand–PAMAM conjugation) to 4.5 (e.g., endosome/lysosome) and through 6.5 (e.g., hypoxic environment) back to pH 8.5, the 17α-ethynylestradiol– and diphenolic acid–PAMAM conjugates experienced a dramatic, irreversible loss in cell stimulatory activity; dynamic NMR studies indicated that the hormonal ligands had become occluded within the more hydrophobic core of the PAMAM dendrimer. Thus, the active state of these estrogen–dendrimer conjugates appears to be metastable. This pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearing PAMAM dendrimers.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2015/jacsat.2015.137.issue-32/jacs.5b05952/production/images/medium/ja-2015-05952x_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja5b05952'>ACS Electronic Supporting Info</A></P>

Genetic Identification and Phylogenetic Analysis of Anaplasma and Ehrlichia Species in Haemaphysalis longicornis Collected from Jeju Island, Korea

Oh, Jae-Young,Moon, Bong-Chun,Bae, Bo-Kyoung,Shin, E-Hyun,Ko, Young-Hwan,Kim, Young-Joo,Park, Yong-Ho,Chae, Joon-Seok The Korean Society for Microbiology 2009 Journal of Bacteriology and Virology Vol.39 No.4

A total of 1,395 Haemaphysalis longicornis ticks collected from Jeju Island of Korea were examined by 16S rRNA gene-based nested PCR for the presence of infection with Anaplasma and Ehrlichia species. Template DNAs to detect the tick-borne pathogens were prepared from a total 506 tick pools. Eight genera of Anaplasma and six Ehrlichia by 16S rRNA gene PCR and sequencing analysis were identified. A. phagocytophilum was the most prevalent (27 [1.9%]) by nested PCR, followed by A. bovis (5 [0.4%]), E. chaffeensis (4 [0.2%]), and A. centrale (1 [0.1%]). In the phylogenetic analysis based on 16S rRNA sequences, eight genera of Anaplasma group (> 99.4% homology) and six Ehrlichia group (> 99.5% homology) were close to deposited A. marginale strains (AF309867, AF414874, and FJ226454) and Ehrlichia sp. (DQ324547), respectively. Three Anaplasma species groups A. phagocytophilum (group A), A. bovis (group B), and A. centrale (group C) and one Ehrlichia species E. chaffeensis (group D) were determined by comparing with Anaplasma and Ehrlichia related sequences. First, twenty-eight A. phagocytophilum clones belonging to group A were divided into 7 genotypes. The sequence similarity among genotypes A1 to A4 was very high (> 99.6%). Genotype B2 was close to A. bovis from Korea (99.7%). Genotype D1 was close to known E. chaffeensis strains (M73222, AF147752, and AY350424) and their similarity value was 99.7%. In conclusion, the genera of Anaplasma/Ehrlichia, A. phagocytophilum, and E. chaffeensis identified in predominant H. longicornis ticks were ubiquitous throughout the Jeju Island. The various native groups have been found through sequence identities and phylogenetic analysis.

Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations

Okada, Yukinori,Kim, Kwangwoo,Han, Buhm,Pillai, Nisha E.,Ong, Rick T.-H.,Saw, Woei-Yuh,Luo, Ma,Jiang, Lei,Yin, Jian,Bang, So-Young,Lee, Hye-Soon,Brown, Matthew A.,Bae, Sang-Cheol,Xu, Huji,Teo, Yik-Yin Oxford University Press 2014 Human Molecular Genetics Vol.23 No.25

<P>Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (<I>P</I><SUB>omnibus</SUB> = 6.9 × 10<SUP>−135</SUP>). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)—but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional <I>P</I><SUB>omnibus</SUB> = 2.2 × 10<SUP>−33</SUP>) and 74 (conditional <I>P</I><SUB>omnibus</SUB> = 1.1 × 10<SUP>−8</SUP>). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional <I>P</I> = 3.8 × 10<SUP>−6</SUP>) and HLA-DPβ1 (Phe9, conditional <I>P</I> = 3.0 × 10<SUP>−5</SUP>) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. <I>HLA-DRB1*09:01</I>) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.</P>

Blocking the immunosuppressive axis with small interfering RNA targeting interleukin (IL)‐10 receptor enhances dendritic cell‐based vaccine potency

Kim, J. H.,Kang, T. H.,Noh, K. H.,Bae, H. C.,Ahn, Y‐,H.,Lee, Y‐,H.,Choi, E. Y.,Chun, K‐,H.,Lee, S‐,J.,Kim, T. W. Blackwell Publishing Ltd 2011 Clinical and experimental immunology Vol.165 No.2

<P><B>Summary</B></P><P>Improving dendritic cell (DC) functions is highly promising for therapeutic intervention of diverse diseases, including cancer. Immunosuppressive cytokines such as interleukin (IL)‐10 produced by DCs themselves (autocrine) and other regulatory immune cells (paracrine) down‐regulate functional profiles of DCs through specific cell surface receptors such as IL‐10R. Here, we tried to improve DC functions using small interfering RNA (siRNA) technology to block an IL‐10R‐mediated immunosuppressive axis. DCs modified with siRNA targeting against IL‐10R or IL‐10 (DC/siIL‐10R or DC/siIL‐10) led to up‐regulation of major histocompatibility complex (MHC) class II, CD40 co‐stimulatory molecule, and IL‐12 proinflammatory cytokine after lipopolysacharide (LPS) stimulation compared to DC/siGFP. Notably, the LPS‐induced functional profiles of DC/siIL‐10R were strongly resistant to the addition of recombinant IL‐10, which mimicked paracrine IL‐10. In contrast, those of DC/siIL‐10 were reversed by adding exogenous IL‐10. Consistently, DC/siIL‐10R generated more human papilloma virus (HPV) E7‐specific CD8<SUP>+</SUP> T cells and stronger anti‐tumour effects against E7‐expressing TC‐1 tumour cells in vaccinated mice than DC/siGFP, as well as DC/siIL‐10. Taken together, these results provide the groundwork for future clinical translation of siRNA‐mediated strategy targeting IL‐10R to enhance DC‐based vaccine potency.</P>