Publications by authors named "Heuiran Lee"

85 Publications

AAV expressing an mTOR-inhibiting siRNA exhibits therapeutic potential in retinal vascular disorders by preserving endothelial integrity.

FEBS Open Bio 2021 Aug 24. Epub 2021 Aug 24.

Bio-Medical Institute of Technology, College of Medicine, University of Ulsan, Seoul, Korea.

Expanding on previous demonstrations of the therapeutic effects of adeno-associated virus (AAV) carrying small-hairpin RNA (shRNA) in downregulating the mechanistic target of rapamycin (mTOR) in in vivo retinal vascular disorders, vascular endothelial growth factor (VEGF)-stimulated endothelial cells were treated with AAV2-shmTOR to examine the role of mTOR inhibition in retinal angiogenesis. AAV2-shmTOR exposure significantly reduced mTOR expression in human umbilical vein endothelial cells (HUVECs) and decreased downstream signaling cascades of mTOR complex 1 (mTORC1) and mTORC2 under VEGF treatment. Moreover, the angiogenic potential of VEGF was significantly inhibited by AAV2-shmTOR, which preserved endothelial integrity by maintaining tight junctions between HUVECs. These data thus support previous in vivo studies and provide evidence that AAV2-shmTOR induces therapeutic effects by inhibiting the neovascularization of endothelial cells.
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http://dx.doi.org/10.1002/2211-5463.13281DOI Listing
August 2021

Optimal Ratio of Wnt3a Expression in Human Mesenchymal Stem Cells Promotes Axonal Regeneration in Spinal Cord Injured Rat Model.

J Korean Neurosurg Soc 2021 Sep 28;64(5):705-715. Epub 2021 May 28.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objective: Through our previous clinical trials, the demonstrated therapeutic effects of MSC in chronic spinal cord injury (SCI) were found to be not sufficient. Therefore, the need to develop stem cell agent with enhanced efficacy is increased. We transplanted enhanced Wnt3asecreting human mesenchymal stem cells (hMSC) into injured spines at 6 weeks after SCI to improve axonal regeneration in a rat model of chronic SCI. We hypothesized that enhanced Wnt3a protein expression could augment neuro-regeneration after SCI.

Methods: Thirty-six Sprague-Dawley rats were injured using an Infinite Horizon (IH) impactor at the T9-10 vertebrae and separated into five groups : 1) phosphate-buffered saline injection (injury only group, n=7); 2) hMSC transplantation (MSC, n=7); 3) hMSC transfected with pLenti vector (without Wnt3a gene) transplantation (pLenti-MSC, n=7); 4) hMSC transfected with Wnt3a gene transplantation (Wnt3a-MSC, n=7); and 5) hMSC transfected with enhanced Wnt3a gene (1.7 fold Wnt3a mRNA expression) transplantation (1.7 Wnt3a-MSC, n=8). Six weeks after SCI, each 5×105 cells/15 µL at 2 points were injected using stereotactic and microsyringe pump. To evaluate functional recovery from SCI, rats underwent Basso-Beattie-Bresnahan (BBB) locomotor test on the first, second, and third days post-injury and then weekly for 14 weeks. Axonal regeneration was assessed using growth-associated protein 43 (GAP43), microtubule-associated protein 2 (MAP2), and neurofilament (NF) immunostaining.

Results: Fourteen weeks after injury (8 weeks after transplantation), BBB score of the 1.7 Wnt3a-MSC group (15.0±0.28) was significantly higher than that of the injury only (10.0±0.48), MSC (12.57±0.48), pLenti-MSC (12.42±0.48), and Wnt3a-MSC (13.71±0.61) groups (p<0.05). Immunostaining revealed increased expression of axonal regeneration markers GAP43, MAP2, and NF in the Wnt3a-MSC and 1.7 Wnt3a-MSC groups.

Conclusion: Our results showed that enhanced gene expression of Wnt3a in hMSC can potentiate axonal regeneration and improve functional recovery in a rat model of chronic SCI.
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http://dx.doi.org/10.3340/jkns.2021.0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435649PMC
September 2021

Correlative Light and Electron Microscopy for Nanoparticle-Cell Interaction and Protein Localization.

Adv Exp Med Biol 2021 ;1310:115-132

Convergence Medicine Research Center (CREDIT), Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.

Various silica-based fluorescent nanoparticles ((Si-FNP)) with magnetic or metal cores represent a standard class of nanoparticles offering new opportunities for high-resolution cellular imaging and biomedicine applications, such as drug delivery. Their high solubility, homogeneity, biocompatibility, and chemical inertness Si-FNPs make them attractive probes for correlative light and electron microscopy (CLEM) studies, offering novel insights into nanoparticle-cell interactions in detail. In the present chapter, we present a procedure for imaging silica-based fluorescent magnetic core-shell nanoparticles (Si-FMNP) at the single-particle scale in cells. Our method facilitates the acquisition of information on the extracellular and intercellular distribution of nanoparticles and their various interactions with various cellular organelles when cells are cultured and electroporated by NPs. In addition, such information could facilitate the evaluation of the efficacy of nanocarriers designed for drug delivery.
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http://dx.doi.org/10.1007/978-981-33-6064-8_6DOI Listing
April 2021

miR-351-5p/Miro2 axis contributes to hippocampal neural progenitor cell death via unbalanced mitochondrial fission.

Mol Ther Nucleic Acids 2021 Mar 23;23:643-656. Epub 2020 Dec 23.

Department of Microbiology, University of Ulsan College of Medicine, Seoul 05505, Korea.

Adult hippocampal neurogenesis supports the structural and functional plasticity of the brain, while its decline is associated with neurodegeneration common in Alzheimer's disease (AD). Although the dysregulation of certain microRNAs (miRNAs) in AD have been observed, the effects of miRNAs on hippocampal neurogenesis are largely unknown. In this study, we demonstrated miR-351-5p as a causative factor in hippocampal neural progenitor cell death through modulation of the mitochondrial guanosine triphosphatase (GTPase), Miro2. Downregulation of Miro2 by siMiro2 induced cell death, similar to miR-351-5p, whereas ectopic Miro2 expression using an adenovirus abolished these effects. Excessively fragmented mitochondria and dysfunctional mitochondria were indexed by decreased mitochondrial potential, and increased reactive oxygen species were identified in miR-351-5p-induced cell death. Moreover, subsequent induction of mitophagy via Pink1 and Parkin was observed in the presence of miR-351-5p and siMiro2. The suppression of mitochondrial fission by Mdivi-1 completely inhibited cell death by miR-351-5p. miR-351-5p expression increased whereas the level of Miro2 decreased in the hippocampus of AD model mice, emulating expression in AD patients. Collectively, the data indicate the mitochondrial fission and accompanying mitophagy by miR-351-5p/Miro2 axis as critical in hippocampal neural progenitor cell death, and a potential therapeutic target in AD.
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http://dx.doi.org/10.1016/j.omtn.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848773PMC
March 2021

Real-time monitoring of oncolytic VSV properties in a novel in vitro microphysiological system containing 3D multicellular tumor spheroids.

PLoS One 2020 6;15(7):e0235356. Epub 2020 Jul 6.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.

As a new class of cancer therapeutic agents, oncolytic viruses (OVs) have gained much attention not only due to their ability to selectively replicate in and lyse tumor cells, but also for their potential to stimulate antitumor immune responses. As a result, there is an increasing need for in vitro modeling systems capable of recapitulating the 3D physiological tumor microenvironment. Here, we investigated the potential of our recently developed microphysiological system (MPS), featuring a vessel-like channel to reflect the in vivo tumor microenvironment and serving as culture spaces for 3D multicellular tumor spheroids (MCTSs). The MCTSs consist of cancer A549 cells, stromal MRC5 cells, endothelial HUVECs, as well as the extracellular matrix. 3D MCTSs residing in the MPS were infected with oncolytic VSV expressing GFP (oVSV-GFP). Post-infection, GFP signal intensity increased only in A549 cells of the MPS. On the other hand, HUVECs were susceptible to virus infection under 2D culture and IFN-β secretion was quite delayed in HUVECs. These results thus demonstrate that OV antitumoral characteristics can be readily monitored in the MPS and that its behavior therein somewhat differs compared to its activity in 2D system. In conclusion, we present the first application of the MPS, an in vitro model that was developed to better reflect in vivo conditions. Its various advantages suggest the 3D MCTS-integrated MPS can serve as a first line monitoring system to validate oncolytic virus efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337297PMC
September 2020

Evaluation of Bystander Infection of Oncolytic Virus using a Medium Flow Integrated 3D In Vitro Microphysiological System.

Adv Biosyst 2020 02 11;4(2):e1900143. Epub 2019 Dec 11.

Biomedical Engineering Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, 05505, Korea.

Replicable oncolytic viruses (OVs) induce tumor cell lysis and release viral progeny. The released progeny virions and cell debris can spread within surrounding tumor cells or blood vessels. These released molecules may also induce bystander damage in additional tumor cells through spreading within surrounding tumor cells or blood vessels. However, this effect has not been clearly demonstrated due to the difficulty of direct observation. Here, the bystander infection of OVs by vessel delivery and selective infection in 3D multicellular tumoroids (MCTs) in an in vitro microphysiological system (MPS) with integrated medium flow is demonstrated. This study uses replicable vesicular stomatitis virus (VSV)-green fluorescence protein (GFP) to identify the location of infection in 3D MCTs. Using this MPS, the oncoselective infection by VSV-GFP and the spreading by delivery of OVs through flow via block-to-block linkage of the primary infected MPS with uninfected 3D MCTs in an integrated MPS is observed. This MPS enables real-time monitoring and various analysis for the bystander infection of OVs. It is expected that the 3D in vitro MPS can be suitable to investigate the oncoselective spreading and bystander infection of OVs.
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http://dx.doi.org/10.1002/adbi.201900143DOI Listing
February 2020

Negative Regulation of IKK-Mediated IRF7 Phosphorylation by HSP70.

J Immunol 2020 05 13;204(9):2562-2574. Epub 2020 Mar 13.

Department of Microbiology, University of Ulsan College of Medicine, Seoul 05505, Korea; and

Immune reactions are controlled by the delicate spatiotemporal orchestration of multiple cells communicating by cytokines. Studies of cytokines that began with the discovery of IFN focused on positive regulatory mechanisms that induce secretion in response to harmful stimuli. However, there is a growing awareness that negative regulatory mechanisms that stop secretion of cytokines at specific times and spaces are also important for a successful immune reaction. Type I IFN is the primary cytokine in innate immunity. Although its induction is a prerequisite for the consequent adaptive immune reaction, its oversecretion can cause destructive tissue damage. IFN regulatory factor 7 (IRF7) is a master transcription factor of type I IFN, and multiple observations indicate the key role of IRF7 and the importance of its negative regulation. In this study, we found that the inducible heat shock protein 70 (HSP70) regulated the early type I IFN response by using mice knockout for HSP70. HSP70 dampened IRF7 activation; the inhibitory effect of HSP70 over IKKε-mediated IRF7 activation originated from simple competitive binding. This suggests the possibility of blocking the feed-forward loop between IRF7 and type I IFN in stress environments with increased expression of HSP70.
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http://dx.doi.org/10.4049/jimmunol.1900297DOI Listing
May 2020

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy.

Invest Ophthalmol Vis Sci 2020 02;61(2):45

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Purpose: Recent studies have shown that inhibitors of the mechanistic target of rapamycin (mTOR) play important roles in proliferating endothelial cells within the retinal vasculature. Here we explore the effects of inhibiting mTOR as a potential gene therapeutic against pathological retinal angiogenesis in a rat model of oxygen-induced retinopathy (OIR).

Methods: Sprague-Dawley pups were used to generate the OIR model, with a recombinant adeno-associated virus expressing an shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection on returning the rats to normoxia, with appropriate controls. Immunohistochemistry and TUNEL assays, as well as fluorescein angiography, were performed on transverse retinal sections and flat mounts, respectively, to determine the in vivo effects of mTOR inhibition.

Results: Compared with normal control rats, as well as OIR model animals that were either untreated (20.95 ± 6.85), mock-treated (14.50 ± 2.47), or injected with a control short hairpin RNA (shRNA)-containing virus vector (16.64 ± 4.92), rAAV2-shmTOR-GFP (4.28 ± 2.86, P = 0.00103) treatment resulted in dramatically reduced neovascularization as a percentage of total retinal area. These results mirrored quantifications of retinal avascular area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly greater therapeutic efficacy than the other treatments. The virus vector was additionally shown to reduce inflammatory cell infiltration into retinal tissue and possess antiapoptotic properties, both these processes having been implicated in the pathophysiology of angiogenic retinal disorders.

Conclusions: Taken together, these results demonstrate the strong promise of rAAV2-shmTOR-GFP as an effective and convenient gene therapy for the treatment of neovascular retinal diseases.
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http://dx.doi.org/10.1167/iovs.61.2.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329967PMC
February 2020

Effects of Stuffer DNA on the Suppression of Choroidal Neovascularization by a rAAV Expressing a mTOR-Inhibiting shRNA.

Mol Ther Methods Clin Dev 2019 Sep 3;14:171-179. Epub 2019 Jul 3.

Department of Microbiology, College of Medicine, University of Ulsan, Seoul 05505, Korea.

Choroidal neovascularization (CNV) is the defining characteristic of the wet subtype of age-related macular degeneration (AMD), which is a rapidly growing global health problem. Previously, we had demonstrated the therapeutic potential of gene therapy against CNV using short hairpin RNA (shRNA) delivered via recombinant adeno-associated virus (rAAV), which abrogates mammalian-to-mechanistic (mTOR) activity in a novel manner by simultaneously inhibiting both mTOR complexes. Both the target and use of gene therapy represent a novel treatment modality against AMD. Here, the xenogeneic GFP gene used as a reporter in previous studies was removed from the virus vector to further develop the therapeutic for clinical trials. Instead, a stuffer DNA derived from the 3' UTR of the human UBE3A gene was used to ensure optimal viral genome size for efficient rAAV assembly. The virus vector containing the stuffer DNA, rAAV2-shmTOR-SD, positively compares to one encoding the shRNA and a GFP expression cassette in terms of reducing CNV in a laser-induced mouse model, as determined by fundus fluorescein angiography. These results were confirmed via immunohistochemistry using anti-CD31, while a TUNEL assay showed that rAAV2-shmTOR-SD possesses anti-apoptotic properties as well. The qualities exhibited by rAAV2-shmTOR-SD demonstrate its potential as a human gene therapeutic for the treatment of wet AMD.
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http://dx.doi.org/10.1016/j.omtm.2019.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661460PMC
September 2019

CXCL10 production induced by high levels of IKKε in nasal airway epithelial cells in the setting of chronic inflammation.

Biochem Biophys Res Commun 2019 06 6;514(3):607-612. Epub 2019 May 6.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, South Korea; Bio-Medical Institute of Technology, Asan Medical Center, Seoul, South Korea. Electronic address:

The airway is the major entry route of pathogens due to continuous gas exchange with the environment. In particular, the nasal epithelial layer is the common site of airborne mucotropic virus infections. The inflammatory response to such infections must be tightly controlled due to its non-specific nature. Unrestrained inflammation breaks down the physiological mucosal defense system and leads to secondary bacterial or fungal infections. Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease that compromises quality of life. In spite of its importance in the initiation of inflammation, the role of interferon signaling in nasal airway epithelial cells is largely unknown. We analyzed the expression of interferon signaling genes using clinical lavage specimens and nasal airway epithelial cells collected from CRS patients and controls. Basal expression of IFNAs, IKBKE, STAT1, and some CXC chemokines was elevated in samples from CRS patients. In subsequent in vitro studies, we found IKKε to be the key molecule and augmented CXCL10 secretion. Based on our findings and review of the literature, we hypothesized that high levels of IKKε might induce intractable inflammation via CXCL10. We tested the hypothesis in an animal model and found not only that IKKε induced severe eosinophilic inflammation with CXCL10 over-production, but also that inhibition of IKKε resolved the inflammation.
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http://dx.doi.org/10.1016/j.bbrc.2019.04.173DOI Listing
June 2019

Relationship Between Neutralizing Antibodies Against Adeno-Associated Virus in the Vitreous and Serum: Effects on Retinal Gene Therapy.

Transl Vis Sci Technol 2019 Apr 9;8(2):14. Epub 2019 Apr 9.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: We determine the prevalence of neutralizing antibodies (NAbs) to adeno-associated virus (AAV) in the vitreous humor and serum of patients with vitreoretinal diseases and investigate the relationship between NAb titers in the vitreous humor and serum.

Methods: We analyzed NAbs to AAV serotypes 2, 5, 8, and 9 via in vitro neutralization in the vitreous humor and serum from 32 patients requiring vitrectomy for vitreoretinal diseases. The blood-retinal barrier (BRB) was evaluated for integrity based on preoperative examinations, with vitreous hemorrhage (VH) on funduscopy or dye leakage on fluorescein angiography observed indicating disruption.

Results: NAb levels were much lower in the vitreous humor than in the serum regardless of serotype. Patients with VH had higher levels of NAbs in the vitreous humor than those without VH. The NAb ratio (ratio between NAb titers in the serum and vitreous humor) was much lower in patients with epiretinal membrane with than in those without leakage. A significantly lower NAb ratio was noticed in patients with than in those without BRB disruptions.

Conclusions: The NAb ratio between levels in serum and vitreous humor varies according to the condition of the BRB. Therefore, in addition to measuring the serum NAb level, physicians should examine BRB integrity when planning retinal gene therapy.

Translational Relevance: This study provides substantial basis for retinal gene therapy using AAVs and how maintenance of BRB integrity in target diseases should be considered.
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http://dx.doi.org/10.1167/tvst.8.2.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467092PMC
April 2019

Development of a Pde6b Gene Knockout Rat Model for Studies of Degenerative Retinal Diseases.

Invest Ophthalmol Vis Sci 2019 04;60(5):1519-1526

Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: To describe the phenotypes of a newly developed Pde6b-deficient rat model of retinal degeneration.

Methods: Pde6b knockout rats were produced by CRISPR-Cpf1 technology. Pde6b knockout rats were evaluated for ocular abnormalities by comparison with wild-type eyes. Eyes were imaged using fundus photography and optical coherence tomography (OCT), stained by hematoxylin and eosin (H&E), and examined by TUNEL assay. Finally, eyes were functionally assessed by electroretinograms (ERGs).

Results: Pde6b knockout rats exhibited visible photoreceptor degeneration at 3 weeks of postnatal age. The fundus appearance of mutants was notable for pigmentary changes, vascular attenuation with an irregular vascular pattern, and outer retinal thinning, which resembled retinitis pigmentosa (RP) in humans. OCT showed profound retinal thinning in Pde6b knockout rats; the outer nuclear layer (ONL) was significantly thinner in Pde6b knockout rats, with relative preservation of the inner retina at 3 weeks of postnatal age. H&E staining confirmed extensive degeneration of the ONL, beginning at 3 weeks of postnatal age; no ONL remained in the retina by 16 weeks of postnatal age. Retinal sections of Pde6b knockout rats were highly positive for TUNEL, specifically in the ONL. In ERGs, Pde6b knockout rats showed no detectable a- or b-waves at 8 weeks of postnatal age.

Conclusions: The Pde6b knockout rat exhibits photoreceptor degeneration. It may provide a better model for experimental therapy for RP because of its slower progression and larger anatomic architecture than the corresponding mouse model. Further studies in this rat model may yield insights into effective therapies for human RP.
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http://dx.doi.org/10.1167/iovs.18-25556DOI Listing
April 2019

MicroRNA expression profiling of adult hippocampal neural stem cells upon cell death reveals an autophagic cell death-like pattern.

Biochem Biophys Res Commun 2019 02 3;509(3):674-679. Epub 2019 Jan 3.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, South Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address:

Adult hippocampal neural (HCN) stem cells promptly undergo irreversible autophagic cell death (ACD) if deprived of insulin in culture. Small, non-coding microRNAs (miRNA) play an important role in regulating biological processes, including proliferation and cell death. However, there have been no reports thus far regarding miRNA involvement in the induction of adult HCN stem cell death under insulin-deprived conditions, for which we performed a microarray-based analysis to examine the expression signature of miRNAs in adult rat HCN stem cells. Three independent specimens per culture condition either with or without insulin were prepared and a miRNA microarray analysis carried out. A total of 12 exhibited significantly altered expression levels upon cell death due to the absence of insulin when compared to HCN stem cells cultured with insulin present (cut-off limit; p < 0.05 and fold-change >1.3) The resulting volcano plot showed that, among these miRNAs, seven were upregulated and five were downregulated. The upregulated miRNAs were capable of modulating HCN stem cell death. Caspase-3 activity analysis, LC3 conversion, and TEM of autophagosome formation consistently suggested that ACD, not apoptosis, was most likely the mechanism affecting HCN cell death. As such, we have come to term these miRNAs, "HCN stem cell-specific autophagic cell death regulators." Taken together, our data suggest that the miRNA expression profile of HCN stem cells is altered during ACD occurring due to insulin deprivation and that differentially expressed miRNAs are involved in HCN stem cell viability. Detailed explorations of the underlying mechanisms regarding HCN stem cell viability modulation by these miRNAs would be beneficial in further understanding the physiological features of adult HCN stem cells and are currently being investigated.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.157DOI Listing
February 2019

Intravitreal Injection of AAV Expressing Soluble VEGF Receptor-1 Variant Induces Anti-VEGF Activity and Suppresses Choroidal Neovascularization.

Invest Ophthalmol Vis Sci 2018 11;59(13):5398-5407

Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: With anti-VEGF-based treatments for wet AMD requiring frequent injections, it is often burdensome to both patients and healthcare providers. To explore its possibility as a desirable alternative, we investigated the therapeutic potential of a recombinant adeno-associated virus 2 expressing a soluble variant of VEGF receptor-1 (rAAV2-sVEGFRv-1) in a laser-induced choroidal neovascularization (CNV) model, as CNV is a defining feature of AMD progression.

Methods: C57/B6 mice were intravitreally administered with rAAV2-sVEGFRv-1, rAAV2-GFP, or clinically used bevacizumab after CNV lesions were induced via laser photocoagulation. Immunostaining was performed with phalloidin and CD31 to measure CNV extensiveness, F4/80 and CD11b for inflammatory cell infiltration, and pan-cytokeratin to visualize fibrotic progression.

Results: rAAV2-sVEGFRv-1 (5.0 × 107 viral genomes) possesses antiangiogenic, anti-inflammatory, and antifibrotic properties. rAAV2-sVEGFRv-1 was demonstrated to significantly decrease retinal CNV lesion size (1336 ± 186) when compared to rAAV2-GFP-treated (2949 ± 437, P = 0.0043), mock-treated (3075 ± 265, P = 0.0013), and bevacizumab-treated models (995 ± 234). Infiltration by inflammatory cells significantly decreased with rAAV2-sVEGFRv-1 administration, while groups treated with rAAV2-GFP did not. Additionally, antiapoptotic activity was observed via TUNEL assay in rAAV2-sVEGFRv-1 (16.0 ± 3.6) and rAAV2-GFP (46.0 ± 7.5, P = 0.003). Overall, the rAAV2-sVEGFRv-1 viral vector was positively comparable to bevacizumab, indicating it as effective as approved therapeutics.

Conclusions: The ability of a low dose of rAAV2-sVEGFRv-1 to exert a therapeutically relevant anti-VEGF effect in a CNV model is demonstrated, and strongly suggests gene therapy as an effective and convenient treatment for sustained VEGF suppression.
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http://dx.doi.org/10.1167/iovs.18-24926DOI Listing
November 2018

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization.

Mol Ther Nucleic Acids 2017 Sep 1;8:26-35. Epub 2017 Jun 1.

Department of Biopharmacy, Chungbuk Health & Science University, Cheongju, Chungbuk 28150, Republic of Korea. Electronic address:

Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.
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http://dx.doi.org/10.1016/j.omtn.2017.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477068PMC
September 2017

In Vivo Fluorescence Retinal Imaging Following AAV2-Mediated Gene Delivery in the Rat Retina.

Invest Ophthalmol Vis Sci 2016 06;57(7):3390-6

Department of Microbiology, University of Ulsan, College of Medicine, Seoul, Korea 5Cellular Dysfunction Research Center, University of Ulsan, College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to evaluate longitudinal gene expression patterns by retinal imaging using a modified custom-built confocal laser-scanning microscope in experimental rats after intravitreal injection of recombinant adeno-associated virus 2 (rAAV2-green fluorescent protein [GFP]).

Methods: Ten 9-week-old Wistar rats were divided into two groups: experimental group (group 1) that received a rAAV2-GFP intravitreal injection and control group (group 2) that received a vehicle. After anesthesia using a Zoletil intraperitoneal injection, 8 μL rAAV2-GFP in group 1 or vehicle in group 2 was injected intravitreally using a 33-G Hamilton syringe. In vivo fluorescence retinal images were acquired under anesthesia at 2, 4, 6, and 13 days after rAAV or vehicle delivery.

Results: Differences in GFP fluorescence were identified starting from day 2 after the intravitreal injection of rAAV2-GFP in group 1. Between days 4 and 6, the intensity and area of fluorescence in the retina began to increase and peaked at day 13. Based on the pattern of GFP expression, the axon of the nerve fiber layer ganglion cell was identified. In group 2, eyes treated with the vehicle showed a small amount of autofluorescence in a limited area for up to 2 weeks, with no increase in intensity during this period.

Conclusions: In vivo retinal imaging confirmed gene expression within 2 weeks after the intravitreal injection of rAAV2-GFP. Gene transfer and expression in the rat retina occurs quickly in 2 days and appears to peak within 2 weeks of gene delivery. In vivo retinal imaging may be a useful noninvasive tool to continuously monitor gene expression in the retina over time.
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http://dx.doi.org/10.1167/iovs.15-18862DOI Listing
June 2016

In Vivo Fluorescence Retinal Imaging Following AAV2-Mediated Gene Delivery in the Rat Retina.

Invest Ophthalmol Vis Sci 2016 06;57(7):3390-6

Department of Microbiology, University of Ulsan, College of Medicine, Seoul, Korea 5Cellular Dysfunction Research Center, University of Ulsan, College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to evaluate longitudinal gene expression patterns by retinal imaging using a modified custom-built confocal laser-scanning microscope in experimental rats after intravitreal injection of recombinant adeno-associated virus 2 (rAAV2-green fluorescent protein [GFP]).

Methods: Ten 9-week-old Wistar rats were divided into two groups: experimental group (group 1) that received a rAAV2-GFP intravitreal injection and control group (group 2) that received a vehicle. After anesthesia using a Zoletil intraperitoneal injection, 8 μL rAAV2-GFP in group 1 or vehicle in group 2 was injected intravitreally using a 33-G Hamilton syringe. In vivo fluorescence retinal images were acquired under anesthesia at 2, 4, 6, and 13 days after rAAV or vehicle delivery.

Results: Differences in GFP fluorescence were identified starting from day 2 after the intravitreal injection of rAAV2-GFP in group 1. Between days 4 and 6, the intensity and area of fluorescence in the retina began to increase and peaked at day 13. Based on the pattern of GFP expression, the axon of the nerve fiber layer ganglion cell was identified. In group 2, eyes treated with the vehicle showed a small amount of autofluorescence in a limited area for up to 2 weeks, with no increase in intensity during this period.

Conclusions: In vivo retinal imaging confirmed gene expression within 2 weeks after the intravitreal injection of rAAV2-GFP. Gene transfer and expression in the rat retina occurs quickly in 2 days and appears to peak within 2 weeks of gene delivery. In vivo retinal imaging may be a useful noninvasive tool to continuously monitor gene expression in the retina over time.
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http://dx.doi.org/10.1167/iovs.15-18862DOI Listing
June 2016

Laser Photocoagulation Induces Transduction of Retinal Pigment Epithelial Cells by Intravitreally Administered Adeno-Associated Viral Vectors.

Hum Gene Ther Methods 2015 Oct;26(5):159-61

2 Department of Ophthalmology, Soonchunhyang University College of Medicine , Bucheon Hospital, Bucheon, South Korea.

Retinal transduction by intravitreally administered adeno-associated viral (AAV) vector is previously known to be extremely limited to the neural retina except AAV2 capsid type. Recently, we showed that prior laser photocoagulation enhances retinal transduction of intravitreally administered AAV vectors, including the outer retina and retinal pigment epithelium (RPE). Here, by performing short-pulse laser pretreatment on the mouse retina, we demonstrate RPE cells transduced by three different capsid types of AAV vectors, AAV2, AAV5, and AAV8, using RPE wholemounts. For all capsid types, laser pretreatment effectively induced the transduction of RPE cells in and around the laser site.
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http://dx.doi.org/10.1089/hgtb.2015.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615775PMC
October 2015

Suppression of stent-induced tissue hyperplasia in rats by using small interfering RNA to target matrix metalloproteinase-9.

Endoscopy 2014 Jun 25;46(6):507-12. Epub 2014 Apr 25.

Department of Microbiology, Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea.

Background And Study Aims: We evaluated the efficacy of small interfering RNA (siRNA) in targeting matrix metalloproteinase (MMP-9) to suppress stent-induced tissue hyperplasia in a rat esophageal model.

Methods: The silencing effect of the candidate siRNA (termed (MMP-9 siRNA) was evaluated in 9 L rat glial cells. Four groups of rats (n = 10, each group) were used: Eso-S, stent insertion only, comparison; Eso-R, stent insertion plus treatment with MMP-9 siRNA complexed with Chol-R9 for delivery, experimental; Eso-P, stent insertion plus treatment with pCMV-luc complexed with Chol-R9, for confirmation of Chol-R9 delivery effect; and Eso-N, no stent insertion and no treatment, controls. All rats were sacrificed at 3 weeks. The therapeutic efficacy of the MMP-9 siRNA/Chol-R9 complex was assessed.

Results: The most potent MMP-9 siRNA was selected. Compared with the Eso-S group, the Eso-R group showed significantly less tissue hyperplasia with a lower percentage of granulation tissue and smaller granulation tissue area, and also significantly lower MMP-9 level.

Conclusions: MMP-9 siRNA/Chol-R9 is effective for inhibiting stent-induced tissue hyperplasia in a rat esophageal model.
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http://dx.doi.org/10.1055/s-0034-1365495DOI Listing
June 2014

Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism.

Carcinogenesis 2014 Jul 17;35(7):1652-60. Epub 2014 Apr 17.

Department of Microbiology.

The assessment of the biological activity of capsaicin, the compound responsible for the spicy flavor of chili pepper, produced controversial results, showing either carcinogenicity or cancer prevention. The innate immune system plays a pivotal role in cancer pathology and prevention; yet, the effect of capsaicin on natural killer (NK) cells, which function in cancer surveillance, is unclear. This study found that capsaicin inhibited NK cell-mediated cytotoxicity and cytokine production (interferon-γ and tumor necrosis factor-α). Capsaicin impaired the cytotoxicity of NK cells, thereby inhibiting lysis of standard target cells and gastric cancer cells by modulating calcium mobilization in NK cells. Capsaicin also induced apoptosis in gastric cancer cells, but that effect required higher concentrations and longer exposure times than those required to trigger NK cell dysfunction. Furthermore, capsaicin inhibited the cytotoxicity of isolated NK cells and of an NK cell line, suggesting a direct effect on NK cells. Antagonists of transient receptor potential vanilloid subfamily member 1 (TRPV1), a cognate capsaicin receptor, or deficiency in TRPV1 expression failed to prevent the defects induced by capsaicin in NK cells expressing functional TRPV1. Thus, the mechanism of action of capsaicin on NK cells is largely independent of TRPV1. Taken together, capsaicin may have chemotherapeutic potential but may impair NK cell function, which plays a central role in tumor surveillance.
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http://dx.doi.org/10.1093/carcin/bgu091DOI Listing
July 2014

Laser photocoagulation enhances adeno-associated viral vector transduction of mouse retina.

Hum Gene Ther Methods 2014 Feb 28;25(1):83-91. Epub 2013 Dec 28.

1 Department of Ophthalmology, Soonchunhyang University , College of Medicine, Bucheon 420-767, Korea.

Laser photocoagulation is a well-established treatment modality for retinal disease. Discrete laser burns can be placed anywhere in the retina, singly or multiply, and the burn intensity is controllable. This study investigates the effect of prior laser photocoagulation on the retinal transduction properties of intravitreally administered adeno-associated viral (AAV) vectors. C57BL/6J mice were subjected to unilateral laser photocoagulation 48 hr before bilateral intravitreal injection of self-complementary cytomegaloviral enhanced green fluorescent protein (EGFP) vectors packaged in AAV type 2, 5, and 8 capsids. The eyes were enucleated 4 weeks after injection and examined by histochemistry and quantitative image analysis. Laser pretreatment resulted in substantially increased localized transduction around the burn site for all AAV capsid types. Without laser pretreatment, the vectors transduced only ganglion cells (AAV2) or sporadic cells around the optic nerve head (AAV5 and AAV8). Laser pretreatment increased AAV2 vector expression throughout the entire retina and focally at the burn site. Transduced cells at the burn site included retinal pigment epithelium (RPE), photoreceptors, Müller cells, inner nuclear layer cells, and retinal ganglion cells. The AAV5 vector showed increased RPE transduction at the burn site only. The AAV8 vector showed augmented expression in RPE, photoreceptors, and Müller cells around the burn site. Migrating RPE cells, present in the neural retina near the burn site, were also transduced by all three capsid types as evidenced by colocalization of EGFP and cytokeratin. Laser photocoagulation can be used to precisely direct AAV vector transduction to discrete locations in the retina. A combination of laser and AAV-mediated gene expression may allow the development of improved therapies for diabetic retinopathy, branch and central vein occlusion, and age-related macular degeneration.
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http://dx.doi.org/10.1089/hgtb.2013.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904656PMC
February 2014

Polytetrafluoroethylene-covered retrievable expandable nitinol stents for malignant esophageal obstructions: factors influencing the outcome of 270 patients.

AJR Am J Roentgenol 2012 Dec;199(6):1380-6

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Poongnap 2-dong, Songpa-gu, Seoul, 138-736, Republic of Korea.

Objective: The purpose of this study was to evaluate the clinical effectiveness of polytetrafluoroethylene (PTFE)-covered retrievable expandable nitinol stents in patients with malignant esophageal strictures and to identify prognostic factors associated with clinical outcomes.

Materials And Methods: From 2001 to 2010, 320 PTFE-covered stents were placed in 270 patients. Technical and clinical success, complications, survival, and stent patency were measures of clinical effectiveness. The relationships among complications and age, sex, stricture location, stricture length, chemotherapy alone, chemoradiotherapy, and malignancy source were examined. Independent prognostic factors of overall survival and stent patency were identified.

Results: Stent placement and removal were technically successful and tolerated without procedural complications, and 98% of patients achieved clinical success. The complication rate was 30%. Two removed stents exhibited covering membrane separation. Chemotherapy was associated with increased stent migration (p = 0.002). Stricture location and chemoradiotherapy were associated with esophagorespiratory fistula development (p = 0.033 and p < 0.001, respectively). Median and mean survival periods were 114 days (95% CI, 102-126 days) and 166 days (138-193 days). Chemotherapy and chemoradiotherapy were independent prognostic factors for survival (p = 0.050 and p = 0.032, respectively). The median and mean stent patency periods were 60 days (41-79 days) and 90 days (71-108 days). Chemoradiotherapy was the only independent prognostic factor for stent patency (p = 0.012).

Conclusion: The PTFE-covered stents were clinically effective. Membrane degradation was not evident, although 0.7% of the patients experienced covering membrane separation. Chemotherapy was associated with increased migration and prolonged survival. Chemoradiotherapy was associated with increased esophagorespiratory fistula formation and decreased stent patency.
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http://dx.doi.org/10.2214/AJR.10.6306DOI Listing
December 2012

Differentiation of human adipose tissue-derived stem cells into aggregates of insulin-producing cells through the overexpression of pancreatic and duodenal homeobox gene-1.

Cell Transplant 2013 1;22(6):1053-60. Epub 2012 Oct 1.

Laboratory of Stem Cell Biology and Cell Therapy, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

The pancreatic and duodenal homeobox gene 1 (Pdx-1) plays a key role in normal pancreas development and is required for maintaining the normal function of islets. In this study, we examined whether human adipose tissue-derived stem cells (hASCs) could differentiate into insulin-producing cells by exogenously expressed Pdx-1. hASCs were infected with recombinant adenovirus encoding the mouse Pdx-1 gene and differentiated under high-glucose conditions. Insulin transcript levels and the expression of key transcription factors required for pancreatic development including FoxA2, Nkx2.2, and NeuroD were significantly increased by exogenous Pdx-1 overexpression. The expression of Nkx6.1 was found only in Pdx-1-induced hASCs. In addition to transcripts for transcription factors involved in pancreatic development, transcripts for the GLP-1 receptor, glucokinase, and glucose transporter, which are required for maintaining the function of pancreatic β-cells, were observed only in Pdx-1-induced hASCs. Pdx-1-induced hASCs exhibited insulin secretion in response to glucose challenge in vitro. When Pdx-1-induced hASCs were transplanted into streptozotocin (STZ)-induced diabetic mice, they reduced blood glucose levels, although they did not restore normoglycemia. These results demonstrate that the expression of exogenous Pdx-1 is sufficient to induce pancreatic differentiation in vitro but does not induce the fully functional, mature insulin-producing cells that are required for restoring normoglycemia in vivo.
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http://dx.doi.org/10.3727/096368912X657215DOI Listing
February 2014

Antiviral protection against enterovirus 71 mediated by autophagy induction following FLICE-inhibitory protein inactivation.

Virus Res 2012 Oct 31;169(1):316-20. Epub 2012 Aug 31.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Even with the recent awareness of enterovirus 71 (EV71) as a major public health issue, there are no preventive or therapeutic agents that are effective against EV71 infection. Although FLICE-like inhibitory protein (FLIP) has been identified as a factor that modulates virus pathogenesis, there are no reports regarding its effects on EV71 infection. The aim of the present study was to identify whether FLIP influences EV71 pathogenesis and to understand the underlying mechanisms. Virus replication was markedly reduced in MRC5 cells preincubated with anti-FLIP peptides, and infected cells were rescued from the cytopathic effects of the virus. The anti-FLIP peptides induced autophagy by disrupting intrinsic FLIP functions. The antiviral activity of these peptides was reduced when autophagy was inhibited by treatment with siRNA targeted to beclin-1. Thus, the present study provides evidence that anti-FLIP peptides induce autophagy by inactivating cFLIP, and that this is associated with antiviral effects against EV71.
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http://dx.doi.org/10.1016/j.virusres.2012.08.016DOI Listing
October 2012

Acquisition of selective antitumoral effects of recombinant adeno-associated virus by genetically inserting tumor-targeting peptides into capsid proteins.

Oncol Lett 2011 Nov 8;2(6):1113-1119. Epub 2011 Aug 8.

Department of Microbiology, University of Ulsan College of Medicine, Seoul.

Recombinant adeno-associated virus serotype 5 (rAAV5) is considered to be a promising gene transfer vehicle. However, preferential gene delivery to the tumor remains a requirement for cancer treatment. We generated rAAV5 mutants bearing tumor marker-binding peptides and analyzed their properties as viral vectors, as well as their transduction efficiencies and preferential antitumoral potencies. All of the mutants were successfully produced. Transduction analyses showed that rAAV5 mutants harboring tumor-homing peptides, including RGD and TnC, transduced human cancer cells expressing corresponding receptors on their surfaces. RGDS peptides and TnC antibodies significantly suppressed transduction by rAAV5-RGD and rAAV5-TnC. Cytotoxicity was evident upon transfer of HSV-TK to cells by re-targeted rAAV5. These results provide evidence that rAAV5 vectors, genetically armed with tumor-targeting ligands, preferentially infect human cancer cells harboring the corresponding receptors, thereby inducing antitumoral effects. Further optimization of rAAV5 mutant viruses should thus facilitate practical exploitation of these vectors for gene-based cancer treatment.
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http://dx.doi.org/10.3892/ol.2011.376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406564PMC
November 2011

Usefulness of a guiding sheath for fluoroscopic colorectal stent placement.

Korean J Radiol 2012 Jan-Feb;13 Suppl 1:S83-8. Epub 2012 Apr 23.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.

Objective: To investigate the technical feasibility, clinical usefulness, and safety of a guiding sheath in fluoroscopic stent placement for patients with malignant colorectal obstructions.

Materials And Methods: Between June 2007 and January 2011, fluoroscopic placement of a dual colorectal stent was attempted in a total of 97 patients with malignant colorectal obstructions. A polytetrafluoroethylene guiding sheath was used in patients in whom a stent delivery system failed to reach the obstruction. Usefulness of the sheath was evaluated depending on whether the sheath could successfully assist the stent delivery system reach its area of interest.

Results: The guiding sheath was needed in 22 patients (15 men, 7 women; age range, 33-77 years; mean age, 59 years). The overall success rate for passing the sheath to the area of interest was 100%. There were no procedure-related deaths or major complications. The majority of the patients reported mild discomfort. In 2 of 22 patients with successful passing of the sheath to the area of interest, stent placement failed because of failure in the negotiation of a guide wire through the obstruction.

Conclusion: Using a guiding sheath seems to be easy, safe and useful in fluoroscopic stent placement for patients with malignant colorectal obstructions.
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http://dx.doi.org/10.3348/kjr.2012.13.S1.S83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341465PMC
September 2012

Multispecies-compatible antitumor effects of a cross-species small-interfering RNA against mammalian target of rapamycin.

Cell Mol Life Sci 2012 Sep 5;69(18):3147-58. Epub 2012 May 5.

Department of Microbiology, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil Songpa-Gu, Seoul, Korea.

Successful development of sequence-specific siRNA (small interfering RNA)-based drugs requires an siRNA design that functions consistently in different organisms. Utilizing the CAPSID program previously developed by our group, we here designed siRNAs against mammalian target of rapamycin (mTOR) that are entirely complementary among various species and investigated their multispecies-compatible gene-silencing properties. The mTOR siRNAs markedly reduced mTOR expression at both the mRNA and protein levels in human, mouse, and monkey cell lines. The reduction in mTOR expression resulted in inactivation of both mTOR complex I and II signaling pathways, as confirmed by reduced phosphorylation of p70S6K (70-kDa ribosomal protein S6 kinase), 4EBP1 (eIF4E-binding protein 1), and AKT, and nuclear accumulation of FOXO1 (forkhead box O1), with consequent cell-cycle arrest, proliferation inhibition, and autophagy activation. Moreover, interfering with mTOR activity in vivo using mTOR small-hairpin RNA-expressing recombinant adeno-associated virus led to significant antitumor effects in xenograft and allograft models. Thus, the present study demonstrates that cross-species siRNA successfully silences its target and readily produces multispecies-compatible phenotypic alterations-antitumor effects in the case of mTOR siRNA. Application of cross-species siRNA should greatly facilitate the development of siRNA-based therapeutic agents.
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http://dx.doi.org/10.1007/s00018-012-0998-1DOI Listing
September 2012

Antiviral effects of small interfering RNA simultaneously inducing RNA interference and type 1 interferon in coxsackievirus myocarditis.

Antimicrob Agents Chemother 2012 Jul 16;56(7):3516-23. Epub 2012 Apr 16.

Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Antiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5'-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5' end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.
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http://dx.doi.org/10.1128/AAC.06050-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393429PMC
July 2012

Dual-design expandable colorectal stent for a malignant colorectal obstruction: preliminary prospective study using new 20-mm diameter stents.

Korean J Radiol 2012 Jan-Feb;13(1):66-72. Epub 2011 Dec 23.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.

Objective: To evaluate the safety and effectiveness of a 20-mm diameter dual-design expandable colorectal stent for malignant colorectal obstruction.

Materials And Methods: The study series included 34 patients with malignant colorectal obstruction who underwent implantation of a 20-mm dual-design expandable colorectal stent in our department between March 2009 and June 2010. The 20-mm dual-design expandable colorectal stent was placed by using a 3.8-mm delivery system that had 28-mm diameter proximal and distal ends. Among the 34 patients, stent placement for palliation was performed in 20 patients, while stent placement for bridge to surgery was performed in 14 patients.

Results: A 97% (33 of 34) success rate was achieved for the stent placement. The perforation rate in the bridge to surgery group was 7% (1 of 14), compared to 0% (0 of 19) in palliative group. Migration occurred in one of 33 patients (3%) at 30 days after stent placement.

Conclusion: The placement of a 20-mm diameter dual-design stent appears to be clinically safe and effective for the management of colorectal obstruction, with low perforation and migration rates.
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http://dx.doi.org/10.3348/kjr.2012.13.1.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253405PMC
May 2012

Evaluation of the incidence of esophageal complications associated with balloon dilation and their management in patients with malignant esophageal strictures.

AJR Am J Roentgenol 2012 Jan;198(1):213-8

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Poongnap 2-dong, Songpa-gu, Seoul 138-736, Republic of Korea.

Objective: The objective of this study was to investigate the incidence of esophageal complications associated with balloon dilation and their management in patients with malignant esophageal strictures.

Materials And Methods: Fluoroscopically guided esophageal balloon dilation was performed in 89 patients with malignant esophageal strictures during a period of 15 years. Inclusion criteria were patients with unresected esophageal or gastric carcinoma showing short-segment stricture (≤4 cm) at the esophagogastric junction; patients who had previously received chemotherapy, radiation therapy, or both to manage malignant strictures; or patients who were scheduled for chemotherapy or radiation therapy to manage malignant strictures. Of these patients, 72 had esophageal cancer and 17 had stomach cancer. Esophageal rupture was categorized as intramural, transmural, or transmural with mediastinal leakage.

Results: A total of 120 procedures were performed, with each patient undergoing one to four procedures. Esophageal rupture occurred in 13 patients (15%): eight with intramural rupture, four with transmural rupture, and one with transmural rupture with mediastinal leakage. Improvements in dysphagia score were observed in 76 of 89 patients (85%) after balloon dilation. All esophageal ruptures were detected immediately after the procedure. Intramural and transmural ruptures were treated conservatively, whereas transmural rupture with mediastinal leakage was treated by temporary stent placement.

Conclusion: The overall prevalence of esophageal rupture was 15%. All intramural and transmural ruptures were successfully managed conservatively, whereas transmural rupture with mediastinal leakage was treated by temporary stent placement. We found no relationship between rupture incidence and balloon diameter.
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http://dx.doi.org/10.2214/AJR.11.6468DOI Listing
January 2012
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