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1.  Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b induced early apoptosis in A549 lung cancer cells 
Urokinase receptor interacts with α5β1-integrin and enhances cancer cell proliferation and metastasis. Activation of α5β1-integrin requires caveolin-1 and is regulated by uPAR, which upregulates persistently the activated ERK necessary for tumor growth. In this study, we show that the ganglioside GT1b induces proapoptotic signaling through two uPAR-ERK signaling pathways in A549 lung cancer cells. GT1b downregulated the expression of α5β1 integrin, caveolin-1, fibronectin, FAK, and ERK, whereas GT1b upregulated the expression of p53 and uPAR, suggesting GT1b mediated depletion of caveolin-1 in uPAR-expressing A549 cells also disrupts uPAR/integrin complexes, resulting in downregulation of fibronectin-α5β1-integrin-ERK signaling. Following p53 siRNA treatment, FAK and ERK expression was recovered, meaning the presence of reentry uPAR-FAK-ERK signaling pathway. These findings reveal that GT1b is involved in both caveolin-1-dependent uPAR-α5β1-integrin-ERK signaling and caveolin-1-independent uPAR-FAK-ERK signaling. These results suggest a novel function of GT1b as a dual regulator of ERK by modulating caveolin-1 and p53.
PMCID: PMC4266713  PMID: 25520869
Lung cancer; ganglioside GT1b; uPAR; caveolin-1; ERK; p53
2.  Extraneural Metastases of Glioblastoma without Simultaneous Central Nervous System Recurrence 
Glioblastoma multiforme (GBM) is well known as the most common malignant primary brain tumor. It could easily spread into the adjacent or distant brain tissue by infiltration, direct extension and cerebro-spinal fluid dissemination. The extranueural metastatic spread of GBM is relatively rare but it could have more progressive disease course. We report a 39-year-old man who had multiple bone metastases and malignant pleural effusion of the GBM without primary site recurrence.
PMCID: PMC4231629  PMID: 25408938
Glioblastoma multiforme; Neoplasm metastasis; Spinal neoplasms; Pleural effusion; Malignant
3.  Ventriculolumbar Perfusion Chemotherapy With Methotrexate for Treating Leptomeningeal Carcinomatosis: A Phase II Study 
The Oncologist  2014;19(10):1044-1045.
The efficacy of ventriculolumbar perfusion (VLP) chemotherapy with methotrexate (MTX) was evaluated for treatment of leptomeningeal carcinomatosis (LMC).
The primary outcome was the response rate of increased intracranial pressure (ICP), which was available for comparison from historical data on conventional intraventricular chemotherapy. Secondary endpoints were response rates of other LMC symptoms and overall survival of patients. Artificial cerebrospinal fluid (CSF) premixed with MTX was continuously perfused intraventricularly through a preinstalled intraventricular reservoir and drained via lumbar catheter for 72 hours. The VLP was repeated twice at 3-day intervals for each cycle.
Forty-five of 65 patients had increased ICP, and 32 patients (71%) showed response after VLP chemotherapy, including 31 patients with normalization of ICP. Altered mentation improved in 7 of 21 patients (33%). Cauda equina symptoms responded in 5 of 27 patients (19%), including 4 patients who became ambulatory from a bedridden state. Median overall survival was 187 days, and the 1-year survival rate was 27%. All side effects, including nausea, vomiting, confusion, and sleep disturbance, were tolerable and transient except for two cases of CSF infection.
VLP chemotherapy with MTX provided better control of increased ICP, improved symptom response, and prolonged survival at a cost of acceptable toxicity in patients with LMC.
PMCID: PMC4200999  PMID: 25209375
4.  Angiogenin Reduces Immune Inflammation via Inhibition of TANK-Binding Kinase 1 Expression in Human Corneal Fibroblast Cells 
Mediators of Inflammation  2014;2014:861435.
Angiogenin (ANG) is reportedly multifunctional, with roles in angiogenesis and autoimmune diseases. This protein is involved in the innate immune system and has been implicated in several inflammatory diseases. Although ANG may be involved in the anti-inflammatory response, there is no evidence that it has direct anti-inflammatory effects. In this study we sought to determine whether ANG has an anti-inflammatory effect in human corneal fibroblasts (HCFs) exposed to media containing tumor necrosis factor-alpha (TNF-α). We found that ANG reduced the mRNA expression of interleukin-1 beta (IL-1β), -6, -8 and TNF-α receptors (TNFR) 1 and 2. In contrast, ANG increased the mRNA expression of IL-4 and -10. Protein levels of TANK-binding kinase 1 (TBK1) were reduced by ANG in HCFs treated with TNF-α. Moreover, ANG diminished the expression of IL-6 and -8 and monocyte chemotactic protein- (MCP-) 1. The protein expression of nuclear factor-κB (NF-κB) was downregulated by ANG treatment. These findings suggest that ANG suppressed the TNF-α-induced inflammatory response in HCFs through inhibition of TBK1-mediated NF-κB nuclear translocation. These novel results are likely to play a significant role in the selection of immune-mediated inflammatory therapeutic targets and may shed light on the pathogenesis of immune-mediated inflammatory diseases.
PMCID: PMC4016892  PMID: 24860242
5.  Palatal Implants for Persistent Snoring and Mild Obstructive Sleep Apnea After Laser-Assisted Uvulopalatoplasty 
Laser-assisted uvulopalatoplasty (LAUP) was widely performed in 1990s as a surgical therapeutic procedure to improve snoring or mild obstructive sleep apnea (OSA). However, LAUP is not currently recommended as a treatment for OSA because the evidence for its efficacy is insufficient. Little is known about alternative minimally invasive surgery in patients who refuse continuous positive airway pressure or oral appliance after failed LAUP. We present a case of successful surgical treatment of persistent snoring and mild OSA with palatal implants after LAUP. This case suggests that palatal implants may be offered as an alternative surgical procedure for selective patients with persistent or recurrent snoring or mild OSA after LAUP.
PMCID: PMC3932353  PMID: 24587885
Obstructive sleep apnea; Snoring; Palate; Implants
6.  Temozolomide Salvage Chemotherapy for Recurrent Anaplastic Oligodendroglioma and Oligo-Astrocytoma 
To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA).
A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m2/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed.
TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01).
For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.
PMCID: PMC3921276  PMID: 24527191
Anaplastic oligodendroglioma; Anaplastic oligoastrocytoma; Chemotherapy; Recurrence; Temozolomide
7.  Effect of Isolated Uvulopalatopharyngoplasty on Subjective Obstructive Sleep Apnea Symptoms 
The aims of this study were 1) to evaluate the effect of isolated uvulopalatopharyngoplasty (UPPP) on subjective obstructive sleep apnea (OSA) symptoms in adult patients regardless of the response to surgery, and ultimately 2) to investigate the differences in changes in subjective OSA symptoms between successful and unsuccessful surgery groups.
Twenty consecutive adult patients who underwent isolated UPPP were enrolled. Pre- and postoperative subjective OSA symptoms (snoring, witnessed apnea, daytime sleepiness, morning headache, daytime fatigue, restless sleep, difficulty with morning arousal) and polysomnographic data were evaluated in all subjects. Changes in subjective OSA symptoms before and after surgery were investigated in the successful (n=11) and unsuccessful (n=9) groups. Surgical success was defined as a reduction of at least 50% in the preoperative apnea-hypopnea index (AHI) and a postoperative AHI less than 20 per hour.
After isolated UPPP, all subjective OSA symptoms changed significantly in the patients, especially in the successful group. In the unsuccessful group, snoring, witnessed apnea and daytime fatigue changed significantly, while other symptoms did not change significantly after surgery.
Isolated UPPP may improve subjective OSA symptoms in adult patients whom surgery was successful or unsuccessful. However, after isolated UPPP, the improvements in subjective OSA symptoms in the unsuccessful group may be different from those in the successful group.
PMCID: PMC3781229  PMID: 24069519
Adult; Obstructive sleep apnea; Polysomnography; Surgery; Symptom
8.  Cerebral Microbleeds: Their Associated Factors, Radiologic Findings, and Clinical Implications 
Journal of Stroke  2013;15(3):153-163.
Cerebral microbleeds (CMBs) are tiny, round dark-signal lesions that are most often detected on gradient-echo MR images. CMBs consist of extravasations of blood components through fragile microvascular walls characterized by lipohyalinosis and surrounding macrophages. The prevalence of CMBs in elderly subjects with no history of cerebrovascular disease is around 5%, but is much higher in patients with ischemic or hemorrhagic stroke. Development of CMBs is closely related to various vascular risk factors; in particular, lobar CMBs are thought to be associated with cerebral amyloid angiopathy. The presence of CMBs has been hypothesized to reflect cerebral-hemorrhage-prone status in patients with hypertension or amyloid microangiopathy. Stroke survivors with CMBs have been consistently found to have an elevated risk of subsequent hemorrhagic stroke or an antithrombotic-related hemorrhagic complication, although studies have failed to establish a link between CMBs and hemorrhagic transformation after thrombolytic treatment. A large prospective study is required to clarify the clinical significance of CMBs and their utility in a decision-making index.
PMCID: PMC3859003  PMID: 24396809
Cerebral microbleed; Ischemic stroke; Intracerebral hemorrhage; Antithrombotics; Gradient-echo MRI
9.  Impact of CHADS2 Score on Neurological Severity and Long-Term Outcome in Atrial Fibrillation-Related Ischemic Stroke 
Background and Purpose
The CHADS2 (an acronym for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism) score is a widely used system for estimating the risk of stroke in patients with atrial fibrillation. However, how the CHADS2 score is related to stroke severity and outcome in patients with strokes due to atrial fibrillation has not yet been elucidated.
We enrolled patients with atrial fibrillation who visited our stroke center within 7 days after the onset of acute ischemic stroke between October 2002 and September 2008. CHADS2 scores were categorized into three groups: 0 points, low risk; 1 or 2 points, intermediate risk; and 3-6 points, high risk. Poor neurological state was defined as follows: a National Institutes of Health Stroke Scale (NIHSS) score of ≥2, and a modified Rankin Scale (mRS) score of ≥3 at discharge. Mortality information was ascertained as at December 2008.
A cohort of 298 patients with atrial-fibrillation-related stroke was included in this study. A high-risk CHADS2 score at admission was a powerful predictor of poor neurological outcome [for NIHSS: odds ratio (OR), 4.17; 95% confidence interval (CI), 1.76-9.87; for mRS: OR, 2.97; 95% CI, 1.23-7.16] after controlling for all possible confounders. In addition, a high-risk CHADS2 score was an independent predictor of all causes of death during the follow-up [hazard ratio (HR), 3.01; 95% CI, 1.18-7.65] and vascular death (HR, 12.25; 95% CI, 1.50-99.90).
Although the CHADS2 score was originally designed to distinguish patients with a future risk of stroke, our study shows that it may also be used to predict poor neurological outcome after atrial-fibrillation-related stroke.
PMCID: PMC3540283  PMID: 23323132
atrial fibrillation; ischemic stroke; CHADS2 score; neurological severity; outcome
10.  Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3K/AKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines 
PLoS ONE  2012;7(10):e47449.
Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistance to radiation occurs in most patients, and the underlying molecular mechanisms of radio-resistance are not fully understood. Here, we demonstrated that microRNA 21 (miR-21), a well-known onco-microRNA in malignant glioma, is one of the major players in radio-resistance. Radio-resistance in different malignant glioma cell lines measured by cytotoxic cell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio-sensitization of U373 and U87 cells, whereas overexpression of miR-21 lead to a decrease in radio-sensitivity of LN18 and LN428 cells. Anti-miR-21 sustained γ-H2AX DNA foci formation, which is an indicator of double-strand DNA damage, up to 24 hours and suppressed phospho-Akt (ser473) expression after exposure to γ-irradiation. In a cell cycle analysis, a significant increase in the G2/M phase transition by anti-miR-21 was observed at 48 hours after irradiation. Interestingly, our results showed that anti-miR-21 increased factors associated with autophagosome formation and autophagy activity, which was measured by acid vesicular organelles, LC3 protein expression, and the percentage of GFP-LC3 positive cells. Furthermore, augmented autophagy by anti-miR-21 resulted in an increase in the apoptotic population after irradiation. Our results show that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a novel phenomenon for the acquisition of radio-resistance.
PMCID: PMC3471817  PMID: 23077620
11.  Branch Atheromatous Plaque: A Major Cause of Lacunar Infarction (High-Resolution MRI Study) 
Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI).
HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke.
The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images.
HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.
PMCID: PMC3468813  PMID: 23060895
High-resolution MRI; Lacunar infarction; Branch atheromatous disease
12.  Chemotherapy for Malignant Gliomas Based on Histoculture Drug Response Assay : A Pilot Study 
The Histoculture Drug Response Assay (HDRA), which measures chemosensitivity using minced tumor tissue on drug-soaked gelfoam, has been expected to overcome the limitations of in vitro chemosensitivity test in part. We analyzed interim results of HDRA in malignant gliomas to see if the test can deserve further clinical trials.
Thirty-three patients with malignant gliomas were operated and their tumor samples were examined for the chemosensitivity to 10 chosen drugs by HDRA. The most sensitive chemotherapy regimen among those pre-established was chosen based on the number of sensitive drugs or total inhibition rate (IR) of the regimen. The response was evaluated by 3 month magnetic resonance image.
Among 13 patients who underwent total resection of the tumor, 12 showed no evidence of disease and one patient revealed progression. The response rate in 20 patients with residual tumors was 55% (3 complete and 8 partial responses). HDRA sensitivity at the cut-off value of more than one sensitive drug in the applied regimen showed a sensitivity of 100%, specificity of 60% and predictability of 70%. Another cut-off value of >80% of total IR revealed a sensitivity of 100%, specificity of 69%, and predictability of 80%. For 12 newly diagnosed glioblastoma patients, median progression-free survival of the HDRA sensitive group was 21 months, while that of the non-sensitive group was 6 months (p=0.07).
HDRA for malignant glioma was inferred as a feasible method to predict the chemotherapy response. We are encouraged to launch phase 2 clinical trial with chemosensitivity on HDRA.
PMCID: PMC3259462  PMID: 22259689
Chemotherapy; Drug sensitivity tests; Malignant glioma
13.  Spontaneous Carotid Cavernous Fistula in a Case with Protein S Deficiency that Newly Developed Ophthalmoplegia after Embolization 
Carotid cavernous fistula (CCF) is an abnormal communication between the carotid artery and the cavernous sinus. The pathogenesis of spontaneous CCF remains unclear, although sinus thrombosis is known to be a predisposing factor for dural arteriovenous fistula. Because spontaneous CCFs are mainly of the dural type, we considered that thrombogenic conditions, such as, protein S deficiency might be associated with CCF.
Case Report
A 42-year-old woman complained of conjunctival injection and retro-orbital pain that first appeared 1-month before visiting our hospital. She had no history of head trauma or intracranial surgery. Exophthalmos and chemosis were observed in her left eye, which also had lower visual acuity and higher intraocular pressure than the right eye. Magnetic resonance images and cerebral angiography revealed a left dural CCF. Her protein S was low, at 41% (normal range: 70-140%), but other hematologic values related to coagulation were normal. Her symptoms were relieved after initial transvenous coil embolization. However, a newly developed sixth-nerve palsy was detected 4 days after initial embolization. Follow-up angiography revealed a minimal shunt, and thus transvenous coil embolization was repeated. Two days later, the ophthalmoplegia started reducing, and 1-month later it had almost disappeared.
To the best of our knowledge, this is the first report of spontaneous dural CCF in a Korean patient with concurrent protein S deficiency. Interestingly, transient sixth-nerve palsy developed after transvenous coil embolization in this patient. This additional symptom caused by the residual fistula was relieved after additional transarterial embolization.
PMCID: PMC3212604  PMID: 22087212
carotid cavernous fistula; protein S deficiency; transvenous embolization; sixth-nerve palsy; complication
14.  Surgical Outcomes of Hemorrhagic Metastatic Brain Tumors 
Hemorrhagic metastatic brain tumors are not rare, but little is known about the surgical outcome following treatment. We conducted this study to determine the result of the surgical outcome of hemorrhagic metastatic brain tumors.
Materials and Methods
From July 2001 to December 2008, 21 patients underwent surgery for hemorrhagic metastatic brain tumors at our institution. 15 patients had lung cancer, 3 had hepatocellular carcinoma, and the rest had rectal cancer, renal cell carcinoma, and sarcoma. 20 patients had macroscopic hemorrhage in the tumors, and one patient had intracerebral hemorrhage surrounding the tumor. A retrospective clinical review was conducted focusing on the patterns of presenting symptoms and signs, as well as local recurrence following surgery.
Among 21 hemorrhagic brain metastases, local recurrence developed in two patients. The 12 month progression free survival rate was 86.1%. Mean time to progression was 20.8 months and median survival time after surgery was 11.7 months.
The results of our study showed that hemorrhagic metastatic brain tumors rarely recurred after surgery. Surgery should be considered as a good treatment option for hemorrhagic brain metastasis, especially in cases with increased intracranial pressure or severe neurologic deficits.
PMCID: PMC3138913  PMID: 21811426
Neoplasm metastasis; Brain; Hemorrhage; Local neoplasm recurrences; Surgery
15.  Clinical Implications of Mandible and Neck Measurements in Non-Obese Asian Snorers: Ansan City General Population-Based Study 
Anthropometric abnormalities of the mandible and neck may contribute to snoring in non-obese Asians. The study evaluated the clinical implications of mandible and neck measurements in non-obese Asian snorers.
The external mandible and neck measurements (neck circumference, two lengths of neck, mandibular body angle, and lengths of mandibular ramus and body) were compared between snorers and non-snorers in a sample of 2,778 non-obese Koreans (1,389 males, 1,389 females) aged 40 to 69 years (mean, 48.47±7.72 years).
The overall prevalence of snoring was 64.7% (899/1,389) and 48.3% (671/1,389) in non-obese male and female subjects, respectively. In non-obese males, snorers had significantly a greater neck circumference (P<0.0001) and shorter mandibular body length (P=0.0126) than non-snorers. In non-obese females, snorers had significantly greater neck circumferences (P=0.0165), compared with non-snorers. However, there were no statistically significant differences in other variables between non-snorers and snorers.
Anthropometric abnormalities of the mandible and neck, including thick neck circumference in both genders and small mandible size in males, may be relevant contributing factors to snoring in non-obese Asian snorers.
PMCID: PMC3062226  PMID: 21461062
Asian; Population; Snoring; Mandible; Neck
16.  Optimal Continuous Positive Airway Pressure Level in Korean Patients with Obstructive Sleep Apnea Syndrome 
The aim of this study was to investigate optimal continuous positive airway pressure (CPAP) level, to examine the factors affecting optimal CPAP level, and to develop a predictive equation for optimal CPAP level in Korean patients with obstructive sleep apnea syndrome (OSAS).
A total of 202 patients with OSAS who underwent successful manual titration for CPAP treatment were included in this study. Correlations between the optimal CPAP level and baseline data including anthropometric and polysomnographic variables were analyzed. A predictive equation for optimal CPAP level was developed based on anthropometric and polysomonographic data.
The mean optimal CPAP level in 202 patients with OSAS was 7.8±2.3 cm H2O. The mean optimal CPAP level in the mild, moderate, and severe OSAS groups was 6.0±1.3, 7.4±1.9, and 9.1±2.1 cm H2O, respectively. The apneahypopnea index (AHI) (r=0.595, P<0.001), arousal index (r=0.542, P<0.001), minimal SaO2 (r=-0.502, P<0.001), body mass index (BMI) (r=0.494, P<0.001), neck circumference (r=0.265, P<0.001), and age (r=-0.164, P=0.019) were significantly correlated with optimal CPAP level. The best predictive equation according to stepwise multiple linear regression analysis was: Optimal CPAP level (cm H2O)=0.681+(0.205×BMI)+(0.040×AHI). Forty-two percent of the variance in the optimal CPAP level was explained by this equation (R2=0.42, P<0.001).
A predictive equation for optimal CPAP level in Korean patients with OSAS was developed using AHI and BMI, which can be easily measured during the diagnostic process.
PMCID: PMC3010540  PMID: 21217962
Obstructive sleep apnea syndrome; Continuous positive airway pressure; Polysomnography; Body mass index
17.  Epidemiology of Primary Brain and Central Nervous System Tumors in Korea 
The aim of this report is to provide accurate nationwide epidemiologic data on primary central nervous system (CNS) tumors in Korea. Despite its importance, there are no accurate statistics on primary CNS tumors in Korea. We analyzed primary CNS tumors diagnosed in 2005 from the nationwide registry.
Data on primary CNS tumors diagnosed in 2005 were collected from the Korean Central Cancer Registry and the Korean Brain Tumor Society. Crude and age-standardized rates were calculated in terms of gender, age, and histological type. Tumors of uncertain histology were investigated individually at the corresponding hospitals and had their diagnoses confirmed.
A total of 5,692 patients diagnosed with primary CNS tumors in 2005 were included in this study. CNS tumors occurred in females more often than in males (female to male, 1.43 : 1). The most common tumor was meningioma (31.2%). Glioblastoma accounted for 30.7% of all gliomas, and 19.3% of all malignant primary CNS tumors. In children under 19 years of age, both germ cell tumor and embryonal/primitive/medulloblastoma were the most common tumors.
This article is the first nationwide primary CNS tumor epidemiology report in Korea. Data from this study should provide valuable information regarding the understanding of primary CNS tumors epidemiology in Korea.
PMCID: PMC2941858  PMID: 20856664
Epidemiology; Brain; Central nervous system; Tumor; Registry; Korea
18.  Role of hyaluronan in glioma invasion 
Cell Adhesion & Migration  2008;2(3):202-207.
Gliomas are the most common primary intracranial tumors. Their distinct ability to infiltrate into the extracellular matrix (ECM) of the brain makes it impossible to treat these tumors using surgery and radiation therapy. A number of different studies have suggested that hyaluronan (HA), the principal glycosaminoglycan (GAG) in the ECM of the brain, is the critical factor for glioma invasion. HA-induced glioma invasion was driven by two important molecular events: matrix metalloproteinase (MMP) secretion and upregulation of cell migration. MMP secretion was triggered by HA-induced focal adhesion kinase (FAK) activation, which transmits its signal through ERK activation and nuclear factor kappa B (NFκB) translocation. Another important molecular event is osteopontin (OPN) expression. OPN expression by AKT activation triggers cell migration. These results suggest that HA-induced glioma invasion is tightly regulated by signaling mechanisms, and a detailed understanding of this molecular mechanism will provide important clues for glioma treatment.
PMCID: PMC2634087  PMID: 19262113
hyaluronan; matrix metalloproteinase; osteopontin; emodin; invasion; glioma
19.  Silent Microbleeds and Hemorrhagic Conversion of an Embolic Infarction 
We report a patient with multiple simultaneous embolic infarctions with localized hemorrhagic conversion. A 75-year-old male patient had several silent microbleeds (SMBs) exclusively in the cerebral cortex, and underwent angioplasty and stenting for bilateral carotid stenosis. He subsequently experienced embolic infarctions in the cortex and the striatum: the cortical infarction, where an SMB had been present, showed hemorrhagic conversion, whereas the striatal infarction did not. This case suggests that SMBs are indicators of an underlying hemorrhage-prone state.
PMCID: PMC2686849  PMID: 19513282
Ischemic stroke; Stroke assessment; Microbleeds; Hemorrhage
20.  Radiation-induced Necrosis Deteriorating Neurological Symptoms and Mimicking Progression of Brain Metastasis after Stereotactic-guided Radiotherapy 
Although radiation-induced necrosis (RIN) is not a tumor in itself, the lesion progressively enlarges with mass effects and diffuse peritumoral edema in a way that resembles neoplasm. To identify the RIN that mimics progression of brain metastasis, we performed surgical resections of symptomatic RIN lesions.
Meterials and Methods
From June 2003 to December 2005, 7 patients received stereotactic-guided radiotherapy (SRT) for metastatic brain tumor, and they later underwent craniotomy and tumor resection due to the progressive mass effects and the peritumoral edema that caused focal neurological deficit. On MR imaging, a ring-like enhanced single lesion with massive peritumoral edema could not be distinguished from progression of brain metastasis.
Four patients had non-small cell lung cancer, 2 patients had colorectal cancer and 1 patient had renal cell carcinoma. The mean tumor volume was 8.7 ml (range: 3.0~20.7 ml). The prescribed dose of SRT was 30 Gy with 4 fractions for one patient, 18 Gy for two patients and 20 Gy for the other four patients. The four patients who received SRT with a dose of 20 Gy had RIN with or without microscopic residual tumor cells.
Early detection of recurrent disease after radiotherapy and identifying radiation-induced tissue damage are important for delivering adequate treatment. Therefore, specific diagnostic tools that can distinguish RIN from progression of metastatic brain tumor need to be developed.
PMCID: PMC2739359  PMID: 19746231
Radiation-induced necrosis; Stereotactic guided radiotherapy; Brain metastasis
21.  Planar heterojunction perovskite solar cells with superior reproducibility 
Scientific Reports  2014;4:6953.
Perovskite solar cells (PeSCs) have been considered one of the competitive next generation power sources. To date, light-to-electric conversion efficiencies have rapidly increased to over 10%, and further improvements are expected. However, the poor device reproducibility of PeSCs ascribed to their inhomogeneously covered film morphology has hindered their practical application. Here, we demonstrate high-performance PeSCs with superior reproducibility by introducing small amounts of N-cyclohexyl-2-pyrrolidone (CHP) as a morphology controller into N,N-dimethylformamide (DMF). As a result, highly homogeneous film morphology, similar to that achieved by vacuum-deposition methods, as well as a high PCE of 10% and an extremely small performance deviation within 0.14% were achieved. This study represents a method for realizing efficient and reproducible planar heterojunction (PHJ) PeSCs through morphology control, taking a major step forward in the low-cost and rapid production of PeSCs by solving one of the biggest problems of PHJ perovskite photovoltaic technology through a facile method.
PMCID: PMC4223662  PMID: 25377945
22.  Histamine Promotes the Release of Interleukin-6 via the H1R/p38 and NF-κB Pathways in Nasal Fibroblasts 
Based on the close relationship between histamine and interleukin 6 (IL-6), we hypothesized that histamine may regulate the production of cytokines, such as IL-6, during allergic inflammation. Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.
Experiments were performed using nasal fibroblasts from 8 normal patients. RT-PCR was used to identify the major histamine receptors expressed in nasal fibroblasts. Fibroblasts were then treated with histamine with or without histamine-receptor antagonists, and monitored for IL-6 production using an ELISA. Four potential downstream signaling molecules, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB, were evaluated by Western blot, and a luciferase reporter assay.
Elevated expression was seen for all histamine receptors, with IL-6 protein levels increasing significantly following histamine stimulation. Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the expression level of phosphorylated p38 (pp38), pERK, and pJNK, as well as NF-κB induction. The H1R antagonist actively suppressed pp38 and NF-κB expression in histamine-induced nasal fibroblasts, but not pERK and pJNK. The p38 inhibitor strongly attenuated IL-6 production in histamine-stimulated nasal fibroblasts.
The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.
PMCID: PMC4214978  PMID: 25374757
Nose; fibroblast; histamine; IL-6; allergic rhinitis
23.  Overexpression of Human GATA-1 and GATA-2 Interferes with Spine Formation and Produces Depressive Behavior in Rats 
PLoS ONE  2014;9(10):e109253.
Functional consequences to which vertebrate GATA transcription factors contribute in the adult brain remain largely an open question. The present study examines how human GATA-1 and GATA-2 (hGATA-1 and hGATA-2) are linked to neuronal differentiation and depressive behaviors in rats. We investigated the effects of adeno-associated viral expression of hGATA-1 and hGATA-2 (AAV-hGATA1 and AAV-hGATA2) in the dentate gyrus (DG) of the dorsal hippocampus on dendrite branching and spine number. We also examined the influence of AAV-hGATA1 and AAV-hGATA2 infusions into the dorsal hippocampus on rodent behavior in models of depression. Viral expression of hGATA-1 and hGATA-2 cDNA in rat hippocampal neurons impaired dendritic outgrowth and spine formation. Moreover, viral-mediated expression of hGATA-1 and hGATA-2 in the dorsal hippocampus caused depressive-like deficits in the forced swim test and learned helplessness models of depression, and decreased the expression of several synapse-related genes as well as spine number in hippocampal neurons. Conversely, shRNA knockdown of GATA-2 increased synapse-related gene expression, spine number, and dendrite branching. The results demonstrate that hGATA-1 and hGATA-2 expression in hippocampus is sufficient to cause depressive like behaviors that are associated with reduction in spine synapse density and expression of synapse-related genes.
PMCID: PMC4207676  PMID: 25340772
24.  Scopoletin from Cirsium setidens Increases Melanin Synthesis via CREB Phosphorylation in B16F10 Cells 
In this study, we isolated scopoletin from Cirsium setidens Nakai (Compositae) and tested its effects on melanogenesis. Scopoletin was not toxic to cells at concentrations less than 50 µM and increased melanin synthesis in a dose-dependent manner. As melanin synthesis increased, scopoletin stimulated the total tyrosinase activity, the rate-limiting enzyme of melanogenesis. In a cell-free system, however, scopoletin did not increase tyrosinase activity, indicating that scopoletin is not a direct activator of tyrosinase. Furthermore, Western blot analysis showed that scopoletin stimulated the production of microphthalmia-associated transcription factor (MITF) and tyrosinase expression via cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Based on these results, preclinical and clinical studies are needed to assess the use of scopoletin for the treatment of vitiligo.
PMCID: PMC4146632  PMID: 25177162
Cirsium setidens; CREB; MITF; Scopoletin; Tyrosinase
25.  The anti-tumor activator sMEK1 and paclitaxel additively decrease expression of HIF-1α and VEGF via mTORC1-S6K/4E-BP-dependent signaling pathways 
Oncotarget  2014;5(15):6540-6551.
Recently, we found that sMEK1 effectively regulates pro-apoptotic activity when combined with a traditional chemotherapeutic drug. Therefore, combinational therapeutic strategies targeting critical molecular and cellular mechanisms are urgently required. In this present work, we evaluated whether sMEK1 enhanced the pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. Combined with a chemotherapeutic drug, sMEK1 showed an additive effect on the suppression of ovarian cancer cell growth by inducing cell cycle arrest and apoptosis and regulating related gene expression levels or protein activities. In addition, the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was strongly inhibited by the combined treatment, showing de-repression of the tuberous sclerosis complex (TSC) and suppression of ras homolog enriched in the brain (Rheb) and mTOR and raptor in aggressive ovarian carcinoma cells and mouse xenograft models. Treatment with sMEK1 and paclitaxel reduced phosphorylation of ribosomal S6 kinase (S6K) and 4E-binding protein (4E-BP), two critical downstream targets of the mTOR-signaling pathway. Furthermore, both sMEK1 and paclitaxel significantly inhibited the expression of signaling components downstream of S6K/4E-BP, such as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), both in vitro and in vivo. Therefore, our data suggest that the combination of sMEK1 and paclitaxel is a promising and effective targeted therapy for chemotherapy-resistant or recurrent ovarian cancers.
PMCID: PMC4171649  PMID: 25153728
sMEK1 anti-activator; cell cycle arrest; caspase activity; traditional chemotherapeutic agent; ovarian cancer

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