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1.  Transcatheter Arterial Chemoembolization for Infiltrative Hepatocellular Carcinoma: Clinical Safety and Efficacy and Factors Influencing Patient Survival 
Korean Journal of Radiology  2014;15(4):464-471.
To evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) in patients with infiltrative hepatocellular carcinoma (HCC) and to identify the prognostic factors associated with patient survival.
Materials and Methods
Fifty two patients who underwent TACE for infiltrative HCC were evaluated between 2007 and 2010. The maximum diameter of the tumors ranged from 7 cm to 22 cm (median 15 cm). Of 46 infiltrative HCC patients with portal vein tumor thrombosis, 32 patients received adjuvant radiation therapy for portal vein tumor thrombosis after TACE.
The tumor response by European Association for the Study of the Liver criteria was partial in 18%, stable in 47%, and progressive in 35% of the patients. The median survival time was 5.7 months (Kaplan-Meier analysis). The survival rates were 48% at six months, 25% at one year, and 12% at two years. In the multivariable Cox regression analysis, Child-Pugh class (p = 0.02), adjuvant radiotherapy (p = 0.003) and tumor response after TACE (p = 0.004) were significant factors associated with patient survival. Major complications occurred in nine patients. The major complication rate was significantly higher in patients with Child-Pugh B than in patients with Child-Pugh A (p = 0.049, χ2 test).
Transcatheter arterial chemoembolization can be a safe treatment option in infiltrative HCC patients with Child Pugh class A. Child Pugh class A, radiotherapy for portal vein tumor thrombosis after TACE and tumor response are good prognostic factors for an increased survival after TACE in patients with infiltrative HCCs.
PMCID: PMC4105809  PMID: 25053906
HCC; TACE; Infiltrative; Survival
2.  Alternative Techniques for Cannulation of Biliary Strictures Resistant to the 0.035" System Following Living Donor Liver Transplantation 
Korean Journal of Radiology  2012;13(2):189-194.
To assess the clinical efficacy of alternative techniques for biliary stricture cannulation in patients undergoing living donor liver transplantation (LDLT), after cannulation failure with a conventional (0.035-inch guidewire) technique.
Subjects and Methods
Of 293 patients with biliary strictures after LDLT, 19 (6%) patients, 11 men and 8 women of mean age 48.5 years, had the failed cannulation of the stricture by conventional techniques. Recannulation was attempted by using two alternative methods, namely a micro-catheter set via percutaneous access and a snare (rendezvous) technique using percutaneous and endoscopic approaches.
Strictures were successfully cannulated in 16 (84%) of the 19 patients. A microcatheter set was used in 12 and a snare technique in four patients. Stricture cannulation failed in the remaining three patients, who finally underwent surgical revision.
Most technical failures using a conventional technique for biliary stricture cannulation after LDLT can be overcome by using a microcatheter set or a snare (rendezvous) technique.
PMCID: PMC3303902  PMID: 22438686
Living donor liver transplantation; Biliary complications; Endoscopy; Fluoroscopy
3.  The role of clusterin in retinal development and free radical damage 
The British Journal of Ophthalmology  2007;91(11):1541-1546.
To assess the role of clusterin in retinal vascular development and in free radical damage in vivo and in vitro.
The expression of clusterin, von Willebrand factor (vWF), flk‐1, heat shock protein 27 (Hsp27) and heat shock protein 70 (Hsp70) was examined in the retinas of developing mice and oxygen‐induced retinopathy (OIR) mice by immunofluorescence staining and western blot analysis. Hydrogen peroxide (H2O2)‐pretreated human retinal endothelial cells (HREC) and astrocytes were cultured in the presence or absence of exogenous clusterin, and then the cell viability was measured using the MTT assay and DAPI staining.
Clusterin was expressed mainly in the inner retina and co‐localised with vWF, an endothelial cell marker. During the mouse developmental process, clusterin expression was decreased, which was similar to the expression of flk‐1, vWF and Hsp27. Furthermore, in the OIR model, clusterin expression changed in a similar way to both vWF and Hsp27. Under hypoxic conditions, clusterin expression increased in HREC and astrocytes. In H2O2‐pretreated HREC and astrocytes, clusterin protected against apoptotic cell death.
These results suggest that clusterin is associated with protection from apoptotic retinal cell death in retinal development and in free radical damage.
PMCID: PMC2095423  PMID: 17475708
4.  Transcatheter Arterial Chemoembolization for Hepatic Recurrence after Curative Resection of Pancreatic Adenocarcinoma 
Gut and Liver  2010;4(3):384-388.
Despite curative resection, hepatic recurrences cause a significant reduction in survival in patients with primary pancreatic adenocarcinoma. Transcatheter arterial chemoembolization (TACE) has recently been used successfully to treat primary and secondary hepatic malignancy.
Between 2003 and 2008, 15 patients underwent TACE because of hepatic recurrence after curative resection of a pancreatic adenocarcinoma. The tumor response was evaluated based on computed tomography scans after TACE. The overall duration of patient survival was measured.
After TACE, a radiographically evident response occurred in six patients whose tumors demonstrated a tumor blush on angiography. Four patients demonstrated stabilization of a hypovascular mass. The remaining five patients demonstrated continued progression of hypovascular hepatic lesions. The median survival periods from the time of diagnosis and from the time of initial TACE were 9.6 and 7.5 months, respectively.
TACE may represent a viable therapeutic modality in patients with hepatic recurrence after curative resection of pancreatic adenocarcinoma.
PMCID: PMC2956353  PMID: 20981218
Pancreatic adenocarcinoma; Transcatheter arterial chemoembolization; Liver
5.  Structural Analysis of Different Incision Sizes and Stromal Hydration in Cataract Surgery Using Anterior Segment Optical Coherence Tomography 
To analyze healing changes of corneal wounds of different corneal incision sizes with or without stromal hydration in cataract surgery using anterior segment optical coherence tomography.
Cataract surgeries were performed by a single surgeon and 2.2- and 2.8-mm corneal incisions were made using a diamond blade (ME-759; Meyco, Biel-Bienne, Swiss). Patients were divided into four groups according to incision size (2.2 and 2.8 mm), and with/without stromal hydration. Fifteen eyes were assigned to each group and incision wounds were measured using anterior segment optical coherence tomography at 2 hours, 1 day, 1 week, 1 month, and 3 months postoperatively. Corneal thickness, incision length and incision angle were measured and existence of epithelial, endothelial gaping and Descemet's membrane detachment was evaluated.
Incision thickness was greater in the group with stromal hydration than in the group without on operation day (p < 0.05). Stromal hydration exerted greater influence in the 2.2-mm incision group than in the 2.8-mm incision group. Corneal thickness decreased more rapidly in the stromal hydration group than in the group with no hydration (p = 0.022). Endothelial gaping was greater in the 2.2-mm incision group than in the 2.8-mm incision group 1 day, 1 month, and 3 months after surgery (p = 0.035, p = 0.009, and p = 0.008, respectively). No other statistical significance was observed between the two groups (2.2 and 2.8 mm) during follow-up regarding corneal thickness, epithelial gaping and Descemet's membrane detachment.
Corneal wounds with a smaller incision could be more vulnerable to external stimuli such as stromal hydration and are less stable than those with a larger incision.
PMCID: PMC4309865  PMID: 25646057
Corneal pachymetry; Corneal stroma; Wounds and injuries
6.  Interaction between Pericytes and Endothelial Cells Leads to Formation of Tight Junction in Hyaloid Vessels 
Molecules and Cells  2013;36(5):465-471.
The hyaloid vessel is a transient vascular network that nourishes the lens and the primary vitreous in the early developmental periods. In hyaloid vessels devoid of the support of astrocytes, we demonstrate that tight junction proteins, zonula occludens-1 and occludin, are regularly expressed at the junction of endothelial cells. To figure out the factor influencing the formation of tight junctions in hyaloid vessels, we further progress to investigate the interactions between endothelial cells and pericytes, two representative constituent cells in hyaloid vessels. Interestingly, endothelial cells interact with pericytes in the early postnatal periods and the interaction between two cell types provokes the up-regulation of transforming growth factor β1. Further in vitro experiments demonstrate that transforming growth factor β1 induces the activation of Smad2 and Smad3 and the formation of tight junction proteins. Taken together, in hyaloid vessels, pericytes seem to regulate the formation of tight junctions by the interaction with endothelial cells even without the support of astrocytes. Additionally, we suggest that the hyaloid vessel is a valuable system that can be utilized for the investigation of cell-cell interaction in the formation of tight junctions in developing vasculatures.
PMCID: PMC3887934  PMID: 24213675
endothelial cells; hyaloid vasculature; pericytes; tight junction; transforming growth factor β1
7.  Distinct Dictation of Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality via Triggering TLR3 and TLR4 Signal Pathways 
PLoS Pathogens  2014;10(9):e1004319.
Japanese encephalitis (JE) is major emerging neurologic disease caused by JE virus. To date, the impact of TLR molecules on JE progression has not been addressed. Here, we determined whether each TLR modulates JE, using several TLR-deficient mouse strains (TLR2, TLR3, TLR4, TLR7, TLR9). Surprisingly, among the tested TLR-deficient mice there were contrasting results in TLR3−/− and TLR4−/− mice, i.e. TLR3−/− mice were highly susceptible to JE, whereas TLR4−/− mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation characterized by early infiltration of inflammatory CD11b+Ly-6Chigh monocytes along with profoundly increased viral burden, proinflammatory cytokine/chemokine expression as well as BBB permeability. In contrast, TLR4−/− mice showed mild CNS inflammation manifested by reduced viral burden, leukocyte infiltration and proinflammatory cytokine expression. Interestingly, TLR4 ablation provided potent in vivo systemic type I IFN innate response, as well as ex vivo type I IFN production associated with strong induction of antiviral PRRs (RIG-I, MDA5), transcription factors (IRF-3, IRF-7), and IFN-dependent (PKR, Oas1, Mx) and independent ISGs (ISG49, ISG54, ISG56) by alternative activation of IRF3 and NF-κB in myeloid-derived DCs and macrophages, as compared to TLR3−/− myeloid-derived cells which were more permissive to viral replication through impaired type I IFN innate response. TLR4 ablation also appeared to mount an enhanced type I IFN innate and humoral, CD4+ and CD8+ T cell responses, which were mediated by altered immune cell populations (increased number of plasmacytoid DCs and NK cells, reduced CD11b+Ly-6Chigh monocytes) and CD4+Foxp3+ Treg number in lymphoid tissue. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were closely coupled with reduced JE lethality. Collectively, these results suggest that a balanced triggering of TLR signal array by viral components during JE progression could be responsible for determining disease outcome through regulating negative and positive factors.
Author Summary
Japanese encephalitis (JE) is major emerging encephalitis, and more than 60% of global population inhabits JE endemic areas. The etiological virus is currently spreading to previously unaffected regions due to rapid changes in climate and demography. However, the impact of TLR molecules on JE progression has not been addressed to date. We found that the distinct outcomes of JE progression occurred in TLR3 and TLR4-dependent manner, i.e. TLR3−/− mice were highly susceptible, whereas TLR4−/− mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation manifested by early CD11b+Ly-6Chigh monocyte infiltration, high expression of proinflammatory cytokines, as well as increased BBB permeability. In contrast, TLR4 ablation provided potent type I IFN innate response in infected mice, as well as in myeloid-derived cells closely associated with strong induction of antiviral ISG genes, and also resulted in enhanced humoral, CD4+, and CD8+ T cell responses along with altered plasmacytoid DC and CD4+Foxp3+ Treg number. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were coupled with reduced JE lethality. Our studies provide an insight into the role of each TLR molecule on the modulation of JE, as well as its mechanism of neuroinflammation control during JE progression.
PMCID: PMC4154777  PMID: 25188232
8.  Safety and Efficacy of Transarterial Nephrectomy as an Alternative to Surgical Nephrectomy 
Korean Journal of Radiology  2014;15(4):472-480.
To evaluate the safety and efficacy of transarterial nephrectomy, i.e., complete renal artery embolization, as an alternative to surgical nephrectomy.
Materials and Methods
This retrospective study included 11 patients who underwent transarterial nephrectomy due to a high risk of surgical nephrectomy or their refusal to undergo surgery during the period from April 2002 to February 2013. Medical records and radiographic images were reviewed retrospectively to collect information regarding underlying etiologies, clinical presentations and embolization outcomes.
The underlying etiologies for transarterial nephrectomy included recurrent hematuria (chronic transplant rejection [n = 3], arteriovenous malformation or fistula [n = 3], angiomyolipoma [n = 1], or end-stage renal disease [n = 1]), inoperable renal or ureteral injury (n = 2), and ectopic kidney with urinary incontinence (n = 1). The technical success rate was 100%, while clinical success was achieved in eight patients (72.7%). Subsequent surgical nephrectomy was required for three patients due to an incomplete nephrectomy effect (n = 2) or necrotic pyelonephritis (n = 1). Procedure-related complications were post-infarction syndrome in one patient and necrotic pyelonephritis in another patient. Of four patients with follow-up CT, four showed renal atrophy and two showed partial renal enhancement. No patient developed a procedure-related hypertension.
Transarterial nephrectomy may be a safe and effective alternative to surgical nephrectomy in patients with high operative risks.
PMCID: PMC4105810  PMID: 25053907
Kidney; Embolization; Nephrectomy
9.  Percutaneous Radiologic Gastrostomy Using the One-Anchor Technique in Patients after Partial Gastrectomy 
Korean Journal of Radiology  2014;15(4):488-493.
The purpose of our study was to assess the feasibility of performing percutaneous radiologic gastrostomy (PRG) in patients who had undergone partial gastrectomy and to evaluate factors associated with technical success.
Materials and Methods
Nineteen patients after partial gastrectomy, who were referred for PRG between April 2006 and April 2012, were retrospectively analyzed. The remnant stomach was punctured using a 21-gauge Chiba-needle. A single anchor was used for the gastropexy and a 12-Fr or 14-Fr gastrostomy tube was inserted. Data were collected regarding the technical success, procedure time, and presence of any complications. Univariable analyses were performed to determine the factors related to the technical success.
Percutaneous radiologic gastrostomy was technically successful in 10 patients (53%), while a failed attempt and failure without an attempt were observed in 5 (26%) and 4 (21%) patients, respectively. Percutaneous radiologic jejunostomy was successfully performed in 9 patients who experienced technical failure. In the 10 successful PRG cases, the mean procedure time was 6.35 minutes. Major complications occurred in 2 patients, tube passage through the liver and pneumoperitonum in one and severe hemorrhage in the other. The technical success rate was higher in patients with Billroth I gastrectomy (100%, 6/6) than in patients with Billroth II gastrectomy (31%, 4/13) (p = 0.011).
Percutaneous radiologic gastrostomy can be successfully performed using the one-anchor technique in approximately half of the patients after partial gastrectomy.
PMCID: PMC4105812  PMID: 25053909
Percutaneous radiologic gastrostomy; Partial gastrectomy; Percutaneous radiologic jejunostomy
10.  Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α 
Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using β-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP. The effects of β-lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of β-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF-1α–mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF-1α in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP.
PMCID: PMC4119393  PMID: 24533641
β-lapachone; hypoxia-induced factor 1-α; oxygen-induced retinopathy; retinal neovascularization; retinopathy of prematurity; vascular endothelial growth factor
11.  Gallotannin suppresses calcium oxalate crystal binding and oxalate-induced oxidative stress in renal epithelial cells 
Calcium oxalate monohydrate (COM) crystals bind avidly to the surface of proliferating and migrating renal endothelial cells, perhaps a key event in kidney stone formation. Oxalate-induced pre-oxidative stress can further promote crystal attachment cells. Natural products including gallotannins found in green teas have been studied as potentially novel treatments to prevent crystal retention and kidney stone formation. Gallotannin significantly inhibited COM crystal growth and binding to MDCK I renal epithelial cells at non-toxic concentrations and also delayed renal cell migration in a wound healing assay. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that gallotannin significantly attenuated oxalate-induced mRNA expression of monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22phox and p47phox in human primary renal epithelial cells (HRCs). Gallotannin also reduced HRC production of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as enhanced antioxidant enzyme superoxide dismutase (SOD) activity in response to oxalate. Taken together, our findings suggest that gallotannin can contribute to nephrolithiasis prevention via direct effects on renal epithelial cells including suppression of COM binding and MCP-1 and OPN expression, along with augmenting antioxidant activity.
PMCID: PMC3910304  PMID: 22466558
gallotannin; renal epithelial cells; calcium oxalate monohydrate; MCP-1; osteopontin; ROS; SOD
12.  Covered Stent Placement for the Treatment of Malignant Superior Vena Cava Syndrome: Is Unilateral Covered Stenting Safe and Effective? 
Korean Journal of Radiology  2014;15(1):87-94.
To evaluate the safety and efficacy of unilateral covered stent placement in patients with malignant superior vena cava (SVC) syndrome.
Materials and Methods
Between October 2008 and November 2012, expanded polytetrafluoroethylene-covered stent placement for malignant SVC syndrome was performed in 40 consecutive patients (35 men and five women; mean age, 61.4 years; range, 35-81 years). All covered stents were unilaterally placed within the SVC or across the venous confluence when needed to relieve venous obstruction and prevent tumor overgrowth, regardless of patency of contralateral brachiocephalic veins.
Stent placement was technically successful in all patients. There were no major complications. Of the 37 patients symptomatic prior to stent placement, 34 (92%) experienced complete symptomatic relief 1-8 days after stent placement. Of the 29 patients who underwent covered stent placement across the venous confluence, nine patients had patent contralateral brachiocephalic veins prior to stent placement. However, no sign of SVC obstruction or contralateral upper extremity venous thrombosis was observed during the follow-up period. Kaplan-Meier analysis revealed median patient survival of 163 days. Stent occlusion occurred in four (10%) of 40 patents. Cumulative stent patency rates at 1, 3, 6, and 12 months were 95%, 92%, 86%, and 86%, respectively.
Unilateral covered stent placement appears to be a safe and effective method for treating malignant SVC syndrome, despite the location of SVC occlusion.
PMCID: PMC3909867  PMID: 24497797
Malignant superior vena cava syndrome; Covered stent
13.  The Effect of Bevacizumab versus Ranibizumab in the Treatment of Corneal Neovascularization: A Preliminary Study 
To compare the short term effects of bevacizumab and ranibizumab injections on the regression of corneal neovascularization (NV).
Sixteen eyes of 16 patients with corneal NV were randomly assigned for an injection with 2.5 mg of bevacizumab (group 1, n = 8) or 1 mg of ranibizumab (group 2, n = 8) through subconjunctival and intrastromal routes. The patients were prospectively followed-up for one month after the injections. Corneal NV areas, as shown on corneal slit-lamp photographs stored in JPEG format, were calculated using Image J software before the injection, one week after the injection, and one month after the injection. The corneal NV areas were compared before and after the injections.
Seven women and nine men, with an average age of 51 years, presented with corneal NV secondary to herpetic keratitis (7 cases), graft rejection (6), chemical burn (1), pemphigoid (1), and recurrent ulcer (1). In group I, the preoperative corneal NV area (8.75 ± 4.33%) was significantly decreased to 5.62 ± 3.86% one week after the injection and to 6.35 ± 3.02% one month after the injection (p = 0.012, 0.012, respectively). The corneal NV area in group 2 also exhibited a significant change, from 7.37 ± 4.33% to 6.72 ± 4.16% one week after the injection (p = 0.012). However, no significant change was observed one month after the injection. The mean decrease in corneal NV area one month after injection in group 1 (28.4 ± 9.01%) was significantly higher than in group 2 (4.51 ± 11.64%, p = 0.001).
Bevacizumab injection resulted in a more effective and stable regression of corneal NV compared to the ranibizumab injection. The potency and dose of these two drugs for the regression of corneal NV require further investigation.
PMCID: PMC3730064  PMID: 23908568
Bevacizumab; Corneal neovascularization; Ranibizumab
14.  Orthotopic transplantation of retinoblastoma cells into vitreous cavity of zebrafish for screening of anticancer drugs 
Molecular Cancer  2013;12:71.
With high throughput screening, novel therapeutic agents can be efficiently identified. Unfortunately, researchers only resort to in vitro cell viability assays for screening of anticancer drugs for retinoblastoma, the most common intraocular cancer in the childhood. Current available animal models of retinoblastoma require more than 2 weeks for tumour formation and the investigation of the efficacy of therapeutic agents. In this study, we established a novel orthotopic transplantation model of retinoblastoma in zebrafish as an in vivo animal model for screening of anticancer drugs.
We injected retinoblastoma cells into the vitreous cavity of zebrafish at 48 hours after fertilization. Eyeballs of zebrafish were scanned daily under the confocal laser microscope, and the tumor population was quantitatively analyzed by measuring the mean intensity of green fluorescent protein (GFP). Transplanted retinoblastoma cells were isolated to perform further analyses including Western blotting and reverse transcriptase-polymerase chain reaction to confirm that retinoblastoma cells maintained their characteristics as tumor cells even after transplantation and further isolation. To figure out the potential of this model for screening of anticancer drugs, zebrafish were cultured in Ringer’s solution containing carboplatin and melphalan after the injection of retinoblastoma cells.
The degree of the tumor population was dependent on the number of retinoblastoma cells injected and maintained stably for at least 4 days. Transplanted retinoblastoma cells maintain their proliferative potential and characteristics as retinoblastoma cells after isolation. Interestingly, systemic application of carboplatin and melphalan demonstrated significant reduction in the tumor population, which could be quantitatively analyzed by the estimation of the mean intensity of GFP.
This orthotopic retinoblastoma model in zebrafish is expected to be utilized for the screening of anticancer drugs for the treatment of retinoblastoma.
PMCID: PMC3707771  PMID: 23835085
Anticancer drug screen; Orthotopic transplantation; Retinoblastoma; Zebrafish
15.  Animal models of diabetic retinopathy: doors to investigate pathogenesis and potential therapeutics 
Effective and validated animal models are valuable to investigate the pathogenesis and potential therapeutics for human diseases. There is much concern for diabetic retinopathy (DR) in that it affects substantial number of working population all around the world, resulting in visual deterioration and social deprivation. In this review, we discuss animal models of DR based on different species of animals from zebrafish to monkeys and prerequisites for animal models. Despite criticisms on imprudent use of laboratory animals, we hope that animal models of DR will be appropriately utilized to deepen our understanding on the pathogenesis of DR and to support our struggle to find novel therapeutics against catastrophic visual loss from DR.
PMCID: PMC3694455  PMID: 23786217
Animal model; Diabetic retinopathy; Macular edema; Pathologic angiogenesis; Vascular permeabilit
16.  Human Apolipoprotein(a) Kringle V Inhibits Ischemia-Induced Retinal Neovascularization via Suppression of Fibronectin-Mediated Angiogenesis 
Diabetes  2012;61(6):1599-1608.
Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focused on the treatment of retinal neovascularization. In this study, we demonstrated the inhibitory effect of recombinant human apolipoprotein(a) kringle V (rhLK8) in an animal model of ischemia-induced retinal neovascularization. rhLK8 induced no definite toxicity on endothelial cells and retinal tissues at the therapeutic dosage. Interestingly, rhLK8 showed antiangiogenic effect, particularly on fibronectin-mediated migration of endothelial cells. Further experiments demonstrated high binding affinity of rhLK8 to α3β1 integrin, and suppression of it might be the mechanism of antiangiogenic effect of rhLK8. Furthermore, rhLK8 inhibited phosphorylation of focal adhesion kinase, resulting in suppression of activation of consequent p130CAS-Jun NH2-terminal kinase. Taken together, our data suggested the possible application of rhLK8 in the treatment of retinal neovascularization by suppression of fibronectin-mediated angiogenesis.
PMCID: PMC3357289  PMID: 22427380
17.  Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells 
Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells. Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.
PMCID: PMC3684033  PMID: 23818927
18.  Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells 
Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H2O2-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H2O2) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H2O2-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H2O2-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H2O2-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H2O2-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H2O2-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H2O2-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.
PMCID: PMC3518788  PMID: 23243457
19.  Role of Heat Shock Protein 47 in Transdifferentiation of Human Tenon's Fibroblasts to Myofibroblasts 
BMC Ophthalmology  2012;12:49.
Heat shock protein 47 (Hsp47) is a well-known molecular chaperone in collagen synthesis and maturation. The aim of this study is to investigate its putative role in the transdifferentiation of Tenon’s fibroblasts to myofibroblasts.
Primary cultured human Tenon’s fibroblasts were exposed to transforming growth factor-β1 (TGF-β1) for up to 48 hours. The mRNA levels of Hsp47 and α smooth muscle actin (αSMA) were determined by quantitative real time RT-PCR. After delivery of small interfering RNA (siRNA) molecules targeting Hsp47 into the cells, the expression of Hsp47 and αSMA proteins was determined by western immunoblotting.
TGF-β1 increased the mRNA expressions of both Hsp47 and αSMA in human Tenon’s fibroblasts, as determined by quantitative real time RT-PCR. However, it induced the protein expression of only αSMA but not Hsp47, as determined by western immunoblots. When siRNAs specific for Hsp47 were introduced into those cells, the TGF-β1-induced expression of αSMA was significantly attenuated on western immunoblots; after 48 hours of exposure to TGF-β1, the relative densities of immunobands were 11.58 for the TGF-β1 only group and 2.75 for the siRNA treatment group, compared with the no treatment control group (p < 0.001).
Our data suggest that Hsp47 may be related to the TGF-β1-induced transdifferentiation of human Tenon’s fibroblasts to myofibroblasts.
PMCID: PMC3490793  PMID: 22967132
Fibroblast; Fibrosis; Heat shock protein; Myofibroblast; Transforming growth factor-β
20.  Enhancement of Th1-biased protective immunity against avian influenza H9N2 virus via oral co-administration of attenuated Salmonella enterica serovar Typhimurium expressing chicken interferon-α and interleukin-18 along with an inactivated vaccine 
Control of currently circulating re-assorted low-pathogenicity avian influenza (LPAI) H9N2 is a major concern for both animal and human health. Thus, an improved LPAI H9N2 vaccination strategy is needed to induce complete immunity in chickens against LPAI H9N2 virus strains. Cytokines play a crucial role in mounting both the type and extent of an immune response generated following infection with a pathogen or after vaccination. To improve the efficacy of inactivated LPAI H9N2 vaccine, attenuated Salmonella enterica serovar Typhimurium was used for oral co-administration of chicken interferon-α (chIFN-α) and chicken interleukin-18 (chIL-18) as natural immunomodulators.
Oral co-administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18, prior to vaccination with inactivated AI H9N2 vaccine, modulated the immune response of chickens against the vaccine antigen through enhanced humoral and Th1-biased cell-mediated immunity, compared to chickens that received single administration of S. enterica serovar Typhimurium expressing either chIFN-α or chIL-18. To further test the protective efficacy of this improved vaccination regimen, immunized chickens were intra-tracheally challenged with a high dose of LPAI H9N2 virus. Combined administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18 showed markedly enhanced protection compared to single administration of the construct, as determined by mortality, clinical severity, and feed and water intake. This enhancement of protective immunity was further confirmed by reduced rectal shedding and replication of AIV H9N2 in different tissues of challenged chickens.
Our results indicate the value of combined administration of chIFN-α and chIL-18 using a Salmonella vaccine strain to generate an effective immunization strategy in chickens against LPAI H9N2.
PMCID: PMC3425080  PMID: 22776696
Attenuated Salmonella vaccine; Chicken interferon-α; Chicken interleukin-18; Avian influenza H9N2; Oral delivery
21.  Correction: Inhibitory Activity of Bevacizumab to Differentiation of Retinoblastoma Cells 
PLoS ONE  2012;7(5):10.1371/annotation/008b05a8-229b-4aca-94ae-91e6dd5ca5ba.
PMCID: PMC3355184
22.  Inhibitory Activity of Bevacizumab to Differentiation of Retinoblastoma Cells 
PLoS ONE  2012;7(3):e33456.
Vascular endothelial growth factor (VEGF) is a major regulator in retinal and choroidal angiogenesis, which are common causes of blindness in all age groups. Recently anti-VEGF treatment using anti-VEGF antibody has revolutionarily improved the visual outcome in patients with vaso-proliferative retinopathies. Herein, we demonstrated that bevacizumab as an anti-VEGF antibody could inhibit differentiation of retinoblastoma cells without affection to cellular viability, which would be mediated via blockade of extracellular signal-regulated kinase (ERK) 1/2 activation. The retinoblastoma cells expressed VEGFR-2 as well as TrkA which is a neurotrophin receptor associated with differentiation of retinoblastoma cells. TrkA in retinoblastoma cells was activated with VEGF treatment. Interestingly even in the concentration of no cellular death, bevascizumab significantly attenuated the neurite formation of differentiated retinoblastoma cells, which was accompanied by inhibition of neurofilament and shank2 expression. Furthermore, bevacizumab inhibited differentiation of retinoblastoma cells by blockade of ERK 1/2 activation. Therefore, based on that the differentiated retinoblastoma cells are mostly photoreceptors, our results suggest that anti-VEGF therapies would affect to the maintenance or function of photoreceptors in mature retina.
PMCID: PMC3310877  PMID: 22457763
23.  Incidence and Management of Bleeding Complications Following Percutaneous Radiologic Gastrostomy 
Korean Journal of Radiology  2012;13(2):174-181.
Upper gastrointestinal (GI) bleeding is a serious complication that sometimes occurs after percutaneous radiologic gastrostomy (PRG). We evaluated the incidence of bleeding complications after a PRG and its management including transcatheter arterial embolization (TAE).
Materials and Methods
We retrospectively reviewed 574 patients who underwent PRG in our institution between 2000 and 2010. Eight patients (1.4%) had symptoms or signs of upper GI bleeding after PRG.
The initial presentation was hematemesis (n = 3), melena (n = 2), hematochezia (n = 2) and bloody drainage through the gastrostomy tube (n = 1). The time interval between PRG placement and detection of bleeding ranged from immediately after to 3 days later (mean: 28 hours). The mean decrease in hemoglobin concentration was 3.69 g/dL (range, 0.9 to 6.8 g/dL). In three patients, bleeding was controlled by transfusion (n = 2) or compression of the gastrostomy site (n = 1). The remaining five patients underwent an angiography because bleeding could not be controlled by transfusion only. In one patient, the bleeding focus was not evident on angiography or endoscopy, and wedge resection including the tube insertion site was performed for hemostasis. The other four patients underwent prophylactic (n = 1) or therapeutic (n = 3) TAEs. In three patients, successful hemostasis was achieved by TAE, whereas the remaining one patient underwent exploration due to persistent bleeding despite TAE.
We observed an incidence of upper GI bleeding complicating the PRG of 1.4%. TAE following conservative management appears to be safe and effective for hemostasis.
PMCID: PMC3303900  PMID: 22438684
Percutaneous radiologic gastrostomy; Bleeding; Transcatheter arterial embolization
24.  Dual-Design Expandable Colorectal Stent for a Malignant Colorectal Obstruction: Preliminary Prospective Study Using New 20-mm Diameter Stents 
Korean Journal of Radiology  2011;13(1):66-72.
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.
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.
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.
PMCID: PMC3253405  PMID: 22247638
Colorectal cancer; Stent; Dual-design; Expandable
25.  Intravenously Administered Anti-recoverin Antibody Alone Does Not Pass through the Blood-Retinal Barrier 
Cancer-associated retinopathy is a paraneoplastic retinal degeneration which may primarily result from auto-immune mediated apoptosis. It has been hypothesized that high titer of auto-antibodies are able to cross the blood-retinal barrier (BRB) and to enter retinal cells to activate apoptotic pathway which has been already well-established. However, it still remains to be elucidated whether auto-antibodies could cross BRB in the retina. Herein, we demonstrated that intravenously administrated anti-recoverin antibodies could not pass through BRB and not lead to retinal cell death.
Anti-recoverin antibody was intravenously injected to C57BL/6 mice, which were sacrificed 1 and 7 days to obtain eye. Vascular endothelial growth factor was intravitreally injected to induce BRB breakdown, which was confirmed by fluorescein angiography and western blotting for zonula occludens (ZO)-1, ZO-2 and occludin. To investigate the location of anti-recoverin antibody in the retina, immunofluorescein was performed. The retinal toxicity of intravenous anti-recoverin antibody was evaluated by histological examination and transferase-mediated dUTP nick-end labeling. Immunofluorescein staining for glial fibrillary acidic protein was done to address glial activation as well.
Intravenously administrated anti-recoverin antibodies were exclusively distributed on retinal vessels which were co-localized with CD31, and led to neither increase of glial fibrillary acidic protein expression, as an indicator of retinal stress, nor apoptotic retinal cell death. Moreover, even in the condition of vascular endothelial growth factor-induced BRB breakdown, anti-recoverin antibodies could not migrate across BRB and still remained on retinal vessels without retinal cytotoxicity.
Our results suggest that high titer of intravascular anti-recoverin antibodies could not penetrate into the retina by themselves, and BRB breakdown mediated by dysregulation of tight junction might not be sufficient to allow anti-recoverin antibodies to pass through BRB.
PMCID: PMC3102823  PMID: 21655045
Anti-recoverin antibody; Blood-retinal barrier; Cancer-associated retinopathy; Intravenous administration; Retina

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