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Youn, Seock-Won,Lee, Sae-Won,Lee, Jaewon,Jeong, Han-Kyul,Suh, Jung-Won,Yoon, Chang-Hwan,Kang, Hyun-Jae,Kim, Hak-Zoo,Koh, Gou-Young,Oh, Byung-Hee,Park, Young-Bae,Kim, Hyo-Soo American Society of Hematology 2011 Blood Vol.117 No.16
<B>Abstract</B><P>Recruitment and adhesion of bone marrow (BM)-derived circulating progenitor cells to ischemic tissue are important for vasculogenesis and tissue repair. Recently, we found cartilage oligomeric matrix protein (COMP)-Ang1 is a useful cell-priming agent to improve the therapeutic efficacy of progenitor cells. However, the effect and the underlying mechanisms of COMP-Ang1 on recruitment of BM-derived progenitor cells (BMPCs) to foci of vascular injury have not been well defined. Here, we found that COMP-Ang1 is a critical stimulator of stromal cell-derived factor 1 (SDF-1), the principal regulator of BM-cell trafficking. Furthermore, SDF-1 stimulation by COMP-Ang1 was blocked by small-interfering RNA (siRNA) against hypoxia-inducible factor-1α (HIF-1α). COMP-Ang1 increased the synthesis of HIF-1α by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting the COMP-Ang1 signal to the downstream mTOR/HIF-1α/SDF-1 pathway was the enhanced binding of the Tie2 receptor with integrin-linked kinase (ILK), an upstream activator of mTOR. In the mouse ischemic model, local injection of COMP-Ang1 stimulated the incorporation of BMPCs into ischemic limb, thereby enhancing neovasculogenesis and limb salvage. Collectively, our findings identify the COMP-Ang1/HIF-1α/SDF-1 pathway as a novel inducer of BMPC recruitment and neovasculogenesis in ischemic disease.</P>
( Do Youn Oh ),( Yu Jung Kim ),( Yung Jue Bang ),( Jee Hyun Kim ),( In Sil Choi ),( Sae Won Han ),( Seock Ah Im ),( Kyung Hun Lee ),( Tae You Kim ),( Keun Wook Lee ),( Tae Yong Kim ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1
Background: To investigate the effi cacy of gemcitabine plus UFT (uracil-tegafur) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC) Methods: This single-arm phase 2 study was conducted at 3 institutions in Korea. Patients with MCRC refractory to fiuoropyrimidine, oxaliplatin and irinotecan were enrolled. Gemcitabine 800 mg/m2 was administered intravenously on days 1, 8 and 15.UFT 200 mg/m2/day was taken orally in 3 divided doses on days 1-21. Cycles were repeated every 4 weeks and tumor evaluation was carried out every 8 weeks. The primary endpoint of this study was 8-week progression-free survival (PFS) rate. Results: Forty-one patients were enrolled. Fourteen patients received gemcitabine/UFT as a third-line treatment and 37 patients as a 4th-line or later-line therapy. Toxicities were easily manageable and non-hematologic toxicities of = grade 3 were rare. The most common toxicity of = grade 3 was neutropenia (20.0%). One patient showed partial response (response rate, 2.4%) and 14 (34.1%) showed stable disease. The 8-week PFS rate was 42.3%. The median PFS was 1.7 months [95% confi dence interval (CI), 1.6-1.8 months] and the median OS was 9.2 months (95% CI, 5.8-12.6 months). Conclusions: Overall effi cacy of gemcitabine/UFT in refractory MCRC was unsatisfactory. However, we could found a minor proportion of patients who showed prolonged tumor stabilization to gemcitabine/UFT. Further studies are warranted to identify a patient subgroup that might have benefi ts from gemcitabine/UFT therapy.
Kim, Jin Won,Im, Seock-Ah,Kim, Miso,Cha, Yongjun,Lee, Kyung-Hun,Keam, Bhumsuk,Kim, Min A,Han, Sae-Won,Oh, Do-Youn,Kim, Tae-You,Kim, Woo Ho,Bang, Yung-Jue Potamitis Press 2012 Anticancer research Vol.32 No.4
<P>We aimed to clarify the prognostic significance of HER2 positivity in advanced gastric cancer.</P>
Han, Sae-Won,Jeon, Yoon Kyung,Lee, Kyung-Hun,Keam, Bhumsuk,Hwang, Pil Gyu,Oh, Do-Youn,Lee, Se-Hoon,Kim, Dong-Wan,Im, Seock-Ah,Chung, Doo Hyun,Heo, Dae Seog,Bang, Yung-Jue,Kim, Tae-You Lippincott Williams Wilkins, Inc. 2007 PHARMACOGENETICS AND GENOMICS Vol.17 No.5
OBJECTIVE: Limited availability of tumoral tissue in non-small-cell lung cancer and presence of epidermal growth factor receptor mutation-independent responses call for investigation of other molecular predictive marker of gefitinib responsiveness. Therefore, CA repeat polymorphism in intron 1 was analyzed for its association with gefitinib responsiveness together with epidermal growth factor receptor mutation in Korean patients. PATIENTS AND METHODS: For 86 advanced non-small-cell lung cancer patients treated with gefitinib, epidermal growth factor receptor mutation was analyzed by direct sequencing (exons 18–21) from tumor tissue and CA repeat polymorphism was assessed by fragment length analysis from tumor and/or normal tissue. RESULTS: CA repeat status was identical in 33 patients with matched tumor and normal tissue. CA repeat was low (sum of both alleles ≤37) in 40 (46.5%) and high (sum ≥38) in 46 (53.5%) patients. Although epidermal growth factor receptor mutation was more frequent in high CA repeat patients [17.5% (7/40) in low vs. 28.3% (13/46) in high, P=0.18], response rate was higher in low CA repeat patients [25.0% (10/40) in low vs. 13.0% (6/46) in high, P=0.16]. In multivariate analysis, low CA repeat was associated with better objective response (odds ratio 7.1, 95% confidence interval 1.2–40.8; P=0.029) and time-to-progression (hazard ratio 0.54, 95% confidence interval 0.34–0.88; P=0.014), independent of the epidermal growth factor receptor mutational status. CA repeat status was not associated with epidermal growth factor receptor expression. CONCLUSION: Low number of CA repeats in intron 1 of epidermal growth factor receptor is associated with gefitinib responsiveness in non-small-cell lung cancer patients independent of epidermal growth factor receptor mutation.
Lee, Sae-Won,Jeong, Han-Kyul,Lee, Ji-Young,Yang, Jimin,Lee, Eun Ju,Kim, Su-Yeon,Youn, Seock-Won,Lee, Jaewon,Kim, Woo Jean,Kim, Kyu-Won,Lim, Jeong Mook,Park, Jong-Wan,Park, Young-Bae,Kim, Hyo-Soo WILEY-VCH Verlag 2012 EMBO molecular medicine Vol.4 No.9
<P>Hypoxic microenvironment plays an important role in determining stem cell fates. However, it is controversial to which direction between self-renewal and differentiation the hypoxia drives the stem cells. Here, we investigated whether a short exposure to hypoxia (termed ‘hypoxic-priming’) efficiently directed and promoted mouse embryonic stem cells (mESCs) to differentiate into vascular-lineage. During spontaneous differentiation of embryoid bodies (EBs), hypoxic region was observed inside EB spheroids even under normoxic conditions. Indeed, hypoxia-primed EBs more efficiently differentiated into cells of vascular-lineage, than normoxic EBs did. We found that hypoxia suppressed Oct4 expression via direct binding of HIF-1 to reverse hypoxia-responsive elements (rHREs) in the Oct4 promoter. Furthermore, vascular endothelial growth factor (VEGF) was highly upregulated in hypoxia-primed EBs, which differentiated towards endothelial cells in the absence of exogenous VEGF. Interestingly, this differentiation was abolished by the HIF-1 or VEGF blocking. <I>In vivo</I> transplantation of hypoxia-primed EBs into mice ischemic limb elicited enhanced vessel differentiation. Collectively, our findings identify that hypoxia enhanced ESC differentiation by HIF-1-mediated inverse regulation of Oct4 and VEGF, which is a novel pathway to promote vascular-lineage differentiation.</P>
Lee, Dae-Won,Han, Sae-Won,Cha, Yongjun,Rhee, Ye Young,Bae, Jeong Mo,Cho, Nam-Yun,Lee, Kyung-Hun,Kim, Tae-Yong,Oh, Do-Youn,Im, Seock-Ah,Bang, Yung-Jue,Jeong, Seung-Yong,Park, Kyu Joo,Kang, Gyeong Hoon BioMed Central 2015 CLINICAL EPIGENETICS Vol.7 No.-
<P><B>Background</B></P><P>Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.</P><P><B>Results</B></P><P>CIMP-high (≥5 methylated loci) and concurrent methylation in <I>NEUROG1</I> and <I>CDKN2A (p16)</I> were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in <I>NEUROG1</I> and <I>CDKN2A (p16)</I> was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction <I>p</I> value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (−) (<I>p</I> < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (<I>p</I> = 0.78).</P><P><B>Conclusions</B></P><P>Concurrent methylation in <I>NEUROG1</I> and <I>CDKN2A</I> is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.</P>