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Articles by J. W Lee
Total Records ( 9 ) for J. W Lee
  E Yoo , D.J Kim , D.I Kim , J. W Lee and S.H. Suh
 

BACKGROUND AND PURPOSE: Self-expandable stents are an effective tool for coil embolization of wide-neck intracranial aneurysms. The purpose of this study was to assess the feasibility and results of bailout stent positioning during rescue situations after deployment of ≥1 coil.

MATERIALS AND METHODS: Among 318 aneurysms treated by coil embolization in 267 patients, 16 patients who were treated by bailout stent deployment were retrospectively reviewed. Bailout procedures were performed to relieve potential parent artery compromise caused by the protruded coil loops or to prevent migration of the unstable coil basket. The size/location of the aneurysm, technical feasibility, successful stabilization rate, and procedure-related complications were evaluated.

RESULTS: The locations of the aneurysms were the internal carotid artery (n = 12) and basilar artery (n = 4). The mean aneurysm size was 8.3 mm (range, 3.5–19.4 mm) with hemorrhagic presentation in 3 patients. Relief/prevention of parent artery compromise was achieved by molding the encroached loops back into the sac (n = 11), scaffolding the aneurysmal neck in cases with an unstable coil basket (n = 4), and sidetacking the migrated loop to the parent vessel wall (n = 1). The procedure was technically successful in 87.5% (n = 14). Satisfactory molding or stabilization of the coil was seen in 75% (n = 12). Unsatisfactory molding of the protruded small coil loop was noted in 2 cases of small aneurysms. Acute in-stent thrombosis was successfully managed by thrombolysis (n = 1).

CONCLUSIONS: Bailout self-expandable stent deployment may be a feasible and effective method for relief/prevention of parent artery compromise or coil migration caused by prolapsed or unstable coil loops during embolization of aneurysms.

  G. Y Kim , J. W Lee , S. H Cho , J. M Seo and J. H. Kim
 

Objective— The leukotriene B4 (LTB4) receptor BLT2 is expressed in endothelium, but no clear physiological function for it has yet been identified, especially in vascular angiogenesis. The purpose of this study is to characterize the potential function of BLT2 in vascular endothelial growth factor (VEGF)-induced angiogenesis.

Methods and Results— VEGF significantly upregulates BLT2 expression in human umbilical vein endothelial cells (HUVECs), and BLT2 knockdown by siRNA or inhibition of BLT2 by a specific BLT2 antagonist LY255283 attenuates VEGF-induced angiogenesis, which was determined by its effect on the formation of tube-like structures and on transmigration. The role of BLT2 in VEGF-induced angiogenesis was more evident in vivo, where BLT2 inhibition by LY255283 almost completely blocked VEGF-induced vessel formation in Matrigel-plug assays. In addition, we found that VEGF upregulates synthesis of the BLT2 ligand, 12(S)-hydroxyeicosatetraenoic acid (HETE). siRNA knockdown of 12-lipoxygenase (12-LO) expression attenuates VEGF-induced angiogenesis in HUVECs, and the addition of 12(S)-HETE to the 12-LO knockdown-HUVECs restores VEGF-induced angiogenesis. The activation of BLT2 itself by either 12(S)-HETE or LTB4 evoked significant angiogenic phenotypes, both in vitro and in vivo.

Conclusion— Our findings indicate that BLT2 plays an essential role in mediating VEGF-induced angiogenesis.

  J. A Choi , J. W Lee , H Kim , E. Y Kim , J. M Seo , J Ko and J. H. Kim
 

Leukotriene B4 (LTB4) is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity LTB4 receptor, is significantly upregulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated in a BLT2-dependent manner in these breast cancer cells, suggesting that ‘Nox1-derived ROS’ lie downstream of BLT2. Consistent with the proposed role of ‘Nox1–ROS’ in pro-survival signaling, knockdown of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the ‘BLT2–Nox1–ROS’-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.

  S Kim , H. Y Kang , E. H Nam , M. S Choi , X. F Zhao , C. S Hong , J. W Lee , J. H Lee and Y. K. Park
 

TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid and other cancer tissues, although its oncogenic significance and molecular mechanisms are unknown. Previously, we have shown that TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition (EMT). In this study, we explored the molecular basis underlying TMPRSS4-mediated effects. We show that multiple downstream signaling pathways, including focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), Akt, Src and Rac1, are activated by TMPRSS4 expression and that FAK signaling and ERK activation are required for TMPRSS4-induced invasiveness and EMT, including cadherin switch. Inhibition of PI3K or Src reduced invasiveness and actin rearrangement mediated by TMPRSS4 without restoring E-cadherin expression. Downregulation of E-cadherin was required for TMPRSS4-mediated effects but was not sufficient to induce EMT and invasion. TMPRSS4 induced integrin 5 expression and its signal transduction, leading to invasiveness and EMT accompanied by downregulation of E-cadherin. Functional blocking confirmed that integrin 5β1 is a critical signaling molecule that is sufficient to induce TMPRSS4-mediated effects. Immunohistochemical analysis showed that TMPRSS4 expression was significantly higher in human colorectal cancer tissues from advanced stages than in that of early stage. Furthermore, upregulation of TMPRSS4 was correlated with enhanced integrin 5 expression. These observations implicate integrin 5 upregulation as a molecular mechanism by which TMPRSS4 induces invasion and contributes to cancer progression.

  L. S Mangala , V Zuzel , R Schmandt , E. S Leshane , J. B Halder , G. N Armaiz Pena , W. A Spannuth , T Tanaka , M. M.K Shahzad , Y. G Lin , A. M Nick , C. G Danes , J. W Lee , N. B Jennings , P. E Vivas Mejia , J. K Wolf , R. L Coleman , Z. H Siddik , G Lopez Berestein , S Lutsenko and A. K. Sood
 

Purpose: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models.

Experimental Design: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC).

Results: ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC50 levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH2-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis.

Conclusion: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance.

  H. S Eom , C. K Min , B. S Cho , S Lee , J. W Lee , W. S Min , C. C Kim , M Kim and Y. Kim
  Objective

Patients with multiple myeloma (MM) achieving high-quality responses, defined as a complete response (CR) and a very good partial response (VGPR) after transplant, benefit from high-dose therapy followed by autologous stem cell transplantation (ASCT). Induction pre-transplantation treatment with vincristine, doxorubicin and dexamethasone (VAD) is currently being replaced by new targeted agents with high anti-myeloma activity. The use of these novel agents may increase the CR + VGPR rate before ASCT, which may improve post-transplantation responses and survival.

Methods

We performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or VAD (n = 39) before collection of peripheral blood stem cells and ASCT.

Results

Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90%) of 30 and 31 (81.6%) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (P = 0.494). However, the high-quality response rate with VGPR or more in the bortezomib group was significantly higher compared with the VAD group (66.7% vs. 34.2%, respectively, P = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, P = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival (P = 0.498 and 0.835, respectively).

Conclusions

The results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.

  J. W Lee , H. D Han , M. M. K Shahzad , S. W Kim , L. S Mangala , A. M Nick , C Lu , R. R Langley , R Schmandt , H. S Kim , S Mao , J Gooya , C Fazenbaker , D Jackson , D. A Tice , C. N Landen , R. L Coleman and A. K. Sood
  Background

EphA2 is overexpressed in many types of human cancer but is absent or expressed at low levels in normal epithelial tissues. We investigated whether a novel immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) had antitumor activity against ovarian cancer cell lines and tumor models.

Methods

Specificity of 1C1-mcMMAF was examined in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells by antibody binding and internalization assays. Controls were phosphate-buffered saline (PBS), 1C1, or control IgG-mcMMAF. Viability and apoptosis were investigated in ovarian cancer cell lines and tumor models (10 mice per group). Antitumor activities were tested in the HeyA8-luc and SKOV3ip1 orthotopic mouse models of ovarian cancer. Endothelial cells were identified by use of immunohistochemistry and anti-CD31 antibodies. All statistical tests were two-sided.

Results

The 1C1-mcMMAF immunoconjugate specifically bound to EphA2-positive HeyA8 cells but not to EphA2-negative cells and was internalized by HeyA8 cells. Treatment with 1C1-mcMMAF decreased the viability of HeyA8-luc cells in an EphA2-specific manner. In orthotopic mouse models, treatment with 1C1-mcMMAF inhibited tumor growth by 85%–98% compared with that in control mice (eg, for weight of HeyA8 tumors, 1C1-mcMMAF = 0.05 g and control = 1.03 g; difference = 0.98 g, 95% confidence interval [CI] = 0.40 to 1.58 g; P = .001). Even in bulkier disease models with HeyA8-luc cells, 1C1-mcMMAF treatment, compared with control treatment, caused regression of established tumors and increased survival of the mice (eg, 1C1-mcMMAF vs control, mean = 60.6 days vs 29.4 days; difference = 31.2 days, 95% CI = 27.6 to 31.2 days; P = .001). The antitumor effects of 1C1-mcMMAF therapy, in SKOV3ip1 tumors, for example, were statistically significantly related to decreased proliferation (eg, 1C1-mcMMAF vs control, mean = 44.1% vs 55.8% proliferating cells; difference = 11.7%, 95% CI = 2.45% to 20.9%; P = .01) and increased apoptosis of tumor cells (eg, 1C1-mcMMAF vs control, mean = 8.6% vs 0.9% apoptotic cells; difference = 7.7%, 95% CI = 3.8% to 11.7%; P < .001) and of mouse endothelial cells (eg, 1C1-mcMMAF vs control, mean 2.8% vs 0.4% apoptotic endothelial cells; difference = 2.4%, 95% CI = 1.4% to 4.6%; P = .034).

Conclusion

The 1C1-mcMMAF immunoconjugate had antitumor activity in preclinical models of ovarian carcinoma.

  G. H Kim , K Park , S. Y Yeom , K. J Lee , G Kim , J Ko , D. K Rhee , Y. H Kim , H. K Lee , H. W Kim , G. T Oh , K. U Lee , J. W Lee and S. W. Kim
 

Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apolipoprotein E (apoE) transcripts as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low-density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-transgenic mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an antiatherogenic coactivator of LXRs in macrophages.

  A. Y Kim , Y. S Lee , K. H Kim , J. H Lee , H. K Lee , S. H Jang , S. E Kim , G. Y Lee , J. W Lee , S. A Jung , H. Y Chung , S Jeong and J. B. Kim
 

In obesity, dysregulation of adipocytokines is involved in several pathological conditions including diabetes and certain cancers. As a member of the adipocytokines, adiponectin plays crucial roles in whole-body energy homeostasis. Recently, it has been reported that the level of plasma adiponectin is reduced in several types of cancer patients. However, it is largely unknown whether and how adiponectin affects colon cancer cell growth. Here, we show that adiponectin suppresses the proliferation of colon cancer cells including HCT116, HT29, and LoVo. In colon cancer cells, adiponectin attenuated cell cycle progression at the G1/S boundary and concurrently increased expression of cyclin-dependent kinase inhibitors such as p21 and p27. Adiponectin stimulated AMP-activated protein kinase (AMPK) phosphorylation whereas inhibition of AMPK activity blunted the effect of adiponectin on the proliferation of colon cancer cells. Furthermore, knockdown of adiponectin receptors such as AdipoR1 and AdipoR2 relieved the suppressive effect of adiponectin on the growth of colon cancer cells. In addition, adiponectin repressed the expression of sterol regulatory element binding protein-1c, which is a key lipogenic transcription factor associated with colon cancers. These results suggest that adiponectin could inhibit the growth of colon cancer cells through stimulating AMPK activity.

 
 
 
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