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1.  A Case of Habitual Neck Compression Induced Electroencephalogram Abnormalities: Differentiating from Epileptic Seizures Using a Tc-99m HMPAO SPECT 
Self-induced hypoxia has been reported particularly in adolescents, and it can result in neurological injury. Here, we present a case of electroencephalogram (EEG) abnormalities induced by habitual neck compression differentiated from epileptic seizures by Tc-99m HMPAO SPECT. A 19-year-old male was admitted for evaluation of recurrent generalized tonic-clonic seizures. No interictal EEG abnormality was detected; however, abnormal slow delta waves were found immediately after habitual right neck compression. To differentiate EEG abnormalities due to a hemodynamic deficit induced by habitual neck compression from an epileptic seizure, Tc-99m HMPAO SPECT was performed immediately after right carotid artery compression. Abnormal delta waves were triggered, and cerebral hypoperfusion in the right internal carotid artery territory was detected on Tc-99m HMPAO SPECT. The slow delta wave detected on the EEG resulted from the cerebral hypoperfusion because of the habitual neck compression.
PMCID: PMC4028483  PMID: 24900157
Habitual neck compression; Tc-99m HMPAO SPECT; Electroencephalogrm; Seizure
2.  Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling 
Scientific Reports  2015;5:8264.
Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8−/− mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8−/− mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8+/− mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.
PMCID: PMC4317695  PMID: 25652335
3.  The usefulness of bone SPECT/CT imaging with volume of interest analysis in early axial spondyloarthritis 
The role of conventional bone scintigraphy in diagnosing early axial spondyloarthritis (SpA) is yet controversial. Single positron emission computed tomography (SPECT) plus CT is an imaging modality that adds better anatomical information to scintigraphy of the sacroiliac (SI) joint. Our aim was to investigate the usefulness of bone SPECT/CT with volume of interest (VOI) analysis in early axial SpA patients.
Twenty patients (male: female ratio = 12:8; age range = 17–65 years) presenting with inflammatory back pain meeting the Amor criteria of early axial SpA were recruited from a single center in South Korea. Bone scintigraphy was performed 180 min after intravenous injection of 1110 MBq of Tc-99 m-HDP, followed by bone SPECT/CT. The ratio between the entire SI joint and sacrum (SIS ratio) was measured by both bone SPECT/CT and bone scintigraphy. Data from 13 controls were also evaluated. Receiver operating characteristic (ROC) curve was plotted for further analysis, and the correlation between the SIS ratio and SI joint grade by plain radiography was assessed.
The SIS ratio of early axial SpA patients vs. control subjects was significantly increased in bone SPECT/CT (p < 0.001). However, no significant difference was detected in bone scintigraphy. ROC curve analysis showed a significant difference in the area under curve (AUC) of bone SPECT/CT vs. bone scintigraphy (0.862 vs. 0.523, respectively; p < 0.001). With a cut-off SIS ratio of 1.50, ROC curve analysis showed a sensitivity of 80.0% and specificity of 84.6% in bone SPECT/CT. The SIS ratio measured in SPECT/CT, but not that measured in bone scintigraphy, was significantly increased with a higher grade of SI joint changes in plain radiography (p = 0.014).
Bone SPECT/CT is more useful than conventional bone scintigraphy in identifying sacroiliitis in early axial SpA patients, even with mild SI joint changes in plain radiography. By combining CT, we can accurately delineate the sacrum and SI joint uptake with our VOI method.
PMCID: PMC4328061  PMID: 25649319
SPECT/CT; Bone scintigraphy; Sacroiliitis; SIS ratio; Axial spondyloarthritis
4.  Benign Colorectal Stricture: An Answer to the Balloon or Stent Question? 
Gut and Liver  2015;9(1):3-4.
PMCID: PMC4282847  PMID: 25547085
5.  Usefulness of C-Reactive Protein as a Disease Activity Marker in Crohn’s Disease according to the Location of Disease 
Gut and Liver  2015;9(1):80-86.
C-reactive protein (CRP) is a serologic activity marker in Crohn’s disease (CD), but it may be less useful in evaluating CD activity in ileal CD patients. We aimed to investigate the usefulness of CRP as a disease activity marker in CD according to disease location.
Korean CD patients in a single hospital were evaluated. Factors associated with elevated CRP concentration at the time of diagnosis of CD and the association between the physician’s prediction regarding upcoming surgery and the sites of the lesions directly related to surgery were analyzed.
Of 435 CD patients, 25.7%, 6.9%, and 67.4% had ileal, colonic, and ileocolonic CD, respectively. Multivariate analysis revealed that an elevated erythrocyte sedimentation rate, reduced serum albumin, CD activity index (CDAI) >220, and ileocolonic/colonic location were associated with an elevated CRP level and that the CRP level was significantly correlated with the CDAI in all CD patients (γ=0.466, p<0.01). However, the correlation coefficient was dependent on the location, with values of 0.395, 0.456, and 0.527 in patients with an ileal, ileocolonic, and colonic disease location, respectively. Surgery for ileal lesions was less predictable than surgery for ileocolonic or colonic lesions during follow-up.
CRP is less useful as a disease activity marker in patients with ileal CD than those with ileocolonic or colonic CD.
PMCID: PMC4282861  PMID: 25170056
Crohn disease; C-reactive protein; Inflammation
6.  Extremely Low Frequency Magnetic Field Modulates the Level of Neurotransmitters 
This study was aimed to observe that extremely low frequency magnetic field (ELF-MF) may be relevant to changes of major neurotransmitters in rat brain. After the exposure to ELF-MF (60 Hz, 2.0 mT) for 2 or 5 days, we measured the levels of biogenic amines and their metabolites, amino acid neurotransmitters and nitric oxide (NO) in the cortex, striatum, thalamus, cerebellum and hippocampus. The exposure of ELF-MF for 2 or 5 days produced significant differences in norepinephrine and vanillyl mandelic acid in the striatum, thalamus, cerebellum and hippocampus. Significant increases in the levels of serotonin and 5-hydroxyindoleacetic acid were also observed in the striatum, thalamus or hippocampus. ELF-MF significantly increased the concentration of dopamine in the thalamus. ELF-MF tended to increase the levels of amino acid neurotransmitters such as glutamine, glycine and γ -aminobutyric acid in the striatum and thalamus, whereas it decreased the levels in the cortex, cerebellum and hippocampus. ELF-MF significantly increased NO concentration in the striatum, thalamus and hippocampus. The present study has demonstrated that exposure to ELF-MFs may evoke the changes in the levels of biogenic amines, amino acid and NO in the brain although the extent and property vary with the brain areas. However, the mechanisms remain further to be characterized.
PMCID: PMC4297757  PMID: 25605992
Amino acid; Biogenic amines; Extremely low frequency magnetic field; Neurotransmitters; Nitric oxide
7.  Effects of ramp slope on physiological characteristic and performance time of healthy adults propelling and pushing wheelchairs 
[Purpose] This study examined the effects of ramp slope (1:12, 1:10, 1:8, and 1:6) on physiological characteristics and performance times of wheelchair users and the performance times of caregivers to determine which slope would be the best for wheelchairs, in order to propose a ramp slope that incorporates a universal design. [Subjects and Methods] Twenty-four healthy subjects were enrolled in this study. Fifteen of these subjects also volunteered to participate as caregivers. A wooden ramp with an adjustable slope was constructed. As manual wheelchair users, the participants performed propulsion of a wheelchair up the ramp at a self-selected pace. Four ramp slopes (1:12, 1:10, 1:8, and 1:6) were used, and the participants sequentially ascended them in order from the gentlest to the steepest slope. The caregivers also pushed a wheelchair up the ramp at a self-selected pace. The blood pressure and pulse of participants after the ascent, as well as the performance times of the caregivers and manual wheelchair users, were measured on each of the different ramp slopes. The measured data, pulse, blood pressure, and performance time, were analyzed using repeated ANOVA. [Results] Systolic blood pressure was significantly higher after ascending the 1:6 slope than after ascending the 1:12 and 1:8 slopes. Diastolic blood pressure was significantly higher after ascending the 1:6 slope than after ascending the 1:12 and 1:8 slopes. The participants’ pulses tended to increase significantly with an increase in slope. An assessment of the propulsion performance times revealed significant differences among the slopes. [Conclusion] Considering the results of the wheelchair users and caregivers, the 1:12 and 1:10 slopes are suitable ramp slopes for wheelchairs.
PMCID: PMC4305601  PMID: 25642025
Wheelchair; Ramp slope; Physiological characteristics
8.  Accuracy of Biometry for Intraocular Lens Implantation Using the New Partial Coherence Interferometer, AL-scan 
To compare the refractive results of cataract surgery measured by applanation ultrasound and the new partial coherence interferometer, AL-scan.
Medical records of 76 patients and 104 eyes who underwent cataract surgery from January 2013 to June 2013 were retrospectively reviewed. Biometries were measured using ultrasound and AL-scan and intraocular lens power was calculated using the SRK-T formula. Automatic refraction examination was done 1 month after the operation, and differences between the ultrasound group and AL-scan group were compared and analyzed by mean absolute error.
Mean axial length measured preoperatively by the ultrasound method was 23.53 ± 1.17 mm while the lengths measured using the AL-scan were 0.03 mm longer than that of the ultrasound group (23.56 ± 1.15 mm). However, there was not a significant difference in this finding (p = 0.638). Mean absolute error was 0.34 ± 0.27 diopters in the ultrasound group and 0.36 ± 0.31 diopters in AL-scan group, which showed no significant difference (p = 0.946) in precision of predicting postoperative refraction.
Although the difference was not statistically significant, intraocular lens calculations done by the AL-scan were nearly similar in predicting postoperative refraction compared to those of applanation ultrasound, however more precise measurements may be obtained if the axial length is longer than 24.4 mm. Except in the case of opacity in the media, which makes obtaining measurements with the AL-scan difficult, AL-scan could be a useful biometry in cataract surgery.
PMCID: PMC4239462  PMID: 25435746
Biometry; Interferometery; Phacoemulsification; Ultrasonography
9.  Usefulness of the Computed Tomography Venography for Evaluation of Leg Edema Including Deep Vein Thrombosis in Rehabilitation Patients 
Annals of Rehabilitation Medicine  2014;38(6):812-820.
To investigate the usefulness of computed tomography venography (CTV) for evaluation of leg swelling, especially deep vein thrombosis (DVT), in rehabilitation patients.
A hundred twenty-three patients, who had performed CTV performed because of suspected DVT in our clinic, were enrolled. We performed chart reviews retrospectively and categorized CTV findings as follows: DVT distal to inguinal ligament and no compression lesion; DVT proximal to inguinal ligament and no compression lesion; DVT distal to inguinal ligament and anatomical variant (for example, May-Thurner syndrome); DVT due to compression of mass (cancer or cyst); DVT and other incidental abnormal finding; and no DVT and other possible causes of leg swelling.
DVTs were found in 65 (53%) patients. DVTs were found at distal level (thigh or lower leg) to inguinal ligament in 47 patients. DVTs were found at proximal to inguinal ligament, usually undetectable with duplex ultrasonography, in 6 patients. DVTs caused by external compression, such as femoral vein and cancer mass, were found in 12 patients (10%), which are also not easily detected with duplex ultrasonography. Other various causes of leg edema without DVT were found in 22 (18%) patients.
CTV can evaluate more extensively venous problems in the pelvis and abdomen and detect other possible causes of leg swelling. Therefore, CTV can be a useful tool not only for easy detection of DVT but also for evaluating differential diagnosis of leg edema in rehabilitation patients.
PMCID: PMC4280378  PMID: 25566481
Computed tomography; Edema; Venography; Venous thrombosis
10.  Chest Wall Pain as the Presenting Symptom of Leptomeningeal Carcinomatosis 
Annals of Rehabilitation Medicine  2014;38(6):861-864.
Leptomeningeal metastasis (LMM), also referred to as leptomeningeal carcinomatosis, results from diffuse infiltration of the leptomeninges by malignant cells originating from extra-meningeal primary tumors. It occurs in approximately 5%-10% of patients with solid tumor. Among solid tumors, the most common types leading to infiltration of the leptomeninges are breast cancer, lung cancer, and melanoma. Patients with LMM may present various signs and symptoms. Herein, we report a rare case with initial presentation of isolated chest wall pain. Computed tomography of the chest with contrast revealed a 2.5-cm nodule over the left upper lung. Biopsy confirmed the diagnosis of adenocarcinoma. Later, cerebrospinal fluid cytology exam also confirmed leptomeningeal seeding. It is rare for leptomeningeal carcinomatosis patients to present with chest wall pain. Therefore, a high index of suspicion is mandatory for accurate and prompt diagnosis.
PMCID: PMC4280386  PMID: 25566489
Meningeal carcinomatosis; Neoplasm metastasis; Chest pain; Lung cancer; Leptomeningeal metastasis
11.  Association between Vestibular Function and Hearing Outcome in Idiopathic Sudden Sensorineural Hearing Loss 
Korean Journal of Audiology  2014;18(3):131-136.
Background and Objectives
To investigate whether different vestibular function tests such as cervical vestibular evoked myogenic potential (cVEMP) and caloric test were correlated with severity, pattern and prognosis in idiopathic sudden sensorineural hearing loss (ISSNHL).
Subjects and Methods
Ninety-two patients with unilateral ISSNHL were subjected to complete audiovestibular evaluation. cVEMP and caloric test results were compared with patients' initial and final audiogram. We classified patients in 4 groups as cochlear nerve (C) type, cochlear and superior vestibular nerve (C+S) type, cochlear and inferior vestibular nerve (C+I) type and cochlear, superior vestibular nerve, inferior vestibular nerve (C+S+I) type, for evaluation of the results. cVEMP and caloric tests were compared among the groups.
Abnormal caloric test results and abnormal cVEMP results were found in 50% and 31.6% patients, respectively. Multivariate analysis showed that abnormal caloric result (canal paresis) is a significant negative prognostic factor.
Initial vestibular function test can be valuable in predicting the final outcome in patients with ISSNHL.
PMCID: PMC4280755  PMID: 25558407
Sudden sensorineural hearing loss; Vestibular function; Hearing outcome
12.  Proangiogenic TIE2+/CD31+ Macrophages Are the Predominant Population of Tumor-Associated Macrophages Infiltrating Metastatic Lymph Nodes 
Molecules and Cells  2013;36(5):432-438.
Tumor-associated macrophages (TAMs) accumulate in various cancers and promote tumor angiogenesis and metastasis, and thus may be ideal targets for the clinical diagnosis of tumor metastasis with high specificity. However, there are few specific markers to distinguish between TAMs and normal or inflammatory macrophages. Here, we show that TAMs localize in green fluorescent protein-labeled tumors of metastatic lymph nodes (MLNs) from B16F1 melanoma cells but not in necrotic tumor regions, suggesting that TAMs may promote the growth of tumor cells and the progression of tumor metastasis. Furthermore, we isolated pure populations of TAMs from MLNs and characterized their gene expression signatures compared to peritoneal macrophages (PMs), and found that TAMs significantly overexpress immunosuppressive cytokines such as IL-4, IL-10, and TGF-β as well as proangiogenic factors such as VEGF, TIE2, and CD31. Notably, immunological analysis revealed that TIE2+/CD31+ macrophages constitute the predominant population of TAMs that infiltrate MLNs, distinct from tissue or inflammatory macrophages. Importantly, these TIE2+/CD31+ macrophages also heavily infiltrated MLNs from human breast cancer biopsies but not reactive hyperplastic LNs. Thus, TIE2+/CD31+ macrophages may be a unique histopathological biomarker for detecting metastasis in clinical diagnosis, and a novel and promising target for TAM-specific cancer therapy.
PMCID: PMC3887941  PMID: 24158612
breast cancer; melanoma; metastasis; proangiogenic macrophages; tumor-associated macrophages
13.  Gal-geun-dang-gwi-tang improves diabetic vascular complication in apolipoprotein E KO mice fed a western diet 
Gal-geun-dang-gwi-tang (GGDGT), an herbal medicine, is used to treat hypertension, stroke, and other inflammatory disorders in the clinical setting. Recently, GGDGT was recognized by the Korea Institute of Oriental Medicine. This study aimed to evaluate the effects of GGDGT in a diabetic atherosclerosis model using apolipoprotein E knockout (ApoE-/-) mice fed a Western diet.
The mice were divided into four groups: control group, C57BL6J mice receiving a regular diet (RD); ApoE-/- group, ApoE-/- mice receiving a Western diet (WD); rosiglitazone group, ApoE-/- mice receiving rosiglitazone (WD + 10 mg · kg-1 · day-1); GGDGT group, ApoE-/- mice receiving GGDGT (WD + 200 mg · kg-1 · day-1).
Treatment with GGDGT significantly improved glucose tolerance and plasma lipid levels. In addition, GGDGT ameliorated acetylcholine-induced vascular relaxation of the aortic rings. Immunohistochemical staining showed that GGDGT suppressed intercellular adhesion molecule (ICAM)-1 expression; however, expression of endothelial nitric oxide synthase (eNOS) and insulin receptor substrate (IRS)-1 were restored in the thoracic aorta and skeletal muscle, respectively.
These findings suggest that GGDGT attenuates endothelial dysfunction via improvement of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway and improves insulin sensitivity in diabetic atherosclerosis.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6882-14-453) contains supplementary material, which is available to authorized users.
PMCID: PMC4247676  PMID: 25416139
Gal-geun-dang-gwi-tang; Diabetes; Atherosclerosis; Insulin resistance; eNOS
14.  Optimal Dosage of Methylprednisolone for the Treatment of Sudden Hearing Loss in Geriatric Patients: A Propensity Score-Matched Analysis 
PLoS ONE  2014;9(11):e111479.
We aimed to compare the treatment outcomes and the occurrence rates of adverse events associated with different steroid regimens in geriatric patients (aged 65 years or older) with unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). After thorough medical chart reviews of 109 patients with ISSNHL between May 2006 and December 2013, we performed a propensity score-matched analysis using previously known prognostic factors, steroid regimens, and other cointerventions. Patients were divided based on their steroid regimens into group I (which initially received 48 mg of methylprednisolone daily with a subsequently tapered dose) and group II (which initially received 24 mg of methylprednisolone daily with a subsequently tapered dose). We compared final hearing and the occurrence of adverse events between the two groups. As a result, 20 pairs of propensity score-matched patients (n = 40) were enrolled. Group I patients showed better final hearing levels compared with group II patients (42.00±22.35 dB and 57.38±26.40 dB, respectively), although this difference was marginally significant (p = 0.058). Based on the comparative analysis of each of the frequencies in the final audiograms, lower hearing thresholds at 2 KHz were observed in group I (p = 0.049). There was no significant difference in the occurrence of adverse effects between the two groups (p>0.05). In conclusion, conventional steroid regimens produced adverse event occurrence rates that were similar to those of low-dose treatment but may also have produced superior hearing recovery. The use of steroid dose reduction in geriatric patients with ISSNHL is not preferable to conventional steroid regimens.
PMCID: PMC4226486  PMID: 25383617
15.  Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients 
Nature Communications  2014;5:5317.
Here, we demonstrate that electroporation-enhanced immunization with a rationally designed HPV DNA vaccine (GX-188E), preferentially targeting HPV antigens to dendritic cells, elicits a significant E6/E7-specific IFN-γ-producing T-cell response in all nine cervical intraepithelial neoplasia 3 (CIN3) patients. Importantly, eight out of nine patients exhibit an enhanced polyfunctional HPV-specific CD8 T-cell response as shown by an increase in cytolytic activity, proliferative capacity and secretion of effector molecules. Notably, seven out of nine patients display complete regression of their lesions and viral clearance within 36 weeks of follow up. GX-188E administration does not elicit serious vaccine-associated adverse events at all administered doses. These findings indicate that the magnitude of systemic polyfunctional CD8 T-cell response is the main contributing factor for histological, cytological and virological responses, providing valuable insights into the design of therapeutic vaccines for effectively treating persistent infections and cancers in humans.
While several human papilloma virus (HPV) vaccines exist, a highly effective vaccine that mediates regression of HPV-induced tumours is lacking. Here the authors show that a therapeutic DNA vaccine-induced HPV-specific polyfunctional CD8 T cell in 7 out of 9 patients who all exhibited complete regression of lesions and viral clearance.
PMCID: PMC4220493  PMID: 25354725
16.  Relationship Between Indoor Air Pollutant Levels and Residential Environment in Children With Atopic Dermatitis 
This study was aimed to investigate the relationship between indoor air pollutant levels and residential environment in children with atopic dermatitis (AD) living in Seoul.
A total of 150 children with AD were included. Residential environment was assessed by questionnaires which were completed by their parents. To evaluate the level of exposure to the indoor air pollutants, concentrations of the indoor air pollutants including particulate matter with diameter less than 10 µm (PM10), formaldehyde, carbon dioxide (CO2), carbon monoxide (CO), nitrogen dioxide (NO2), Total Volatile Organic Compound (TVOC), benzene, toluene, ethyl-benzene, xylene, styrene, bacterial aerosols, and airborne fungi were measured.
A significant difference was exhibited in the levels of PM10 in case of visible fungus on the walls (P=0.047). There was relationship between the construction year of the house, moving to a newly constructed building within 1 year and formaldehyde level. With the use of artificial air freshener, the differences were found in the concentrations of TVOC (P=0.003), benzene (P=0.015), toluene (P=0.012) and ethyl-benzene (P=0.027). The concentration of xylene was significantly high when oil was used as heating fuel (P=0.015). Styrene exhibited differences depending on building type and its concentrations were significantly high in a residential and commercial complex building (P=0.005). The indoor concentration of bacterial aerosols was significantly low with the use of air cleaner (P=0.045). High NO2, benzene concentrations were present in case of almost no ventilation (P=0.028 and P=0.028, respectively).
Individual residential environments are closely related with the levels of the indoor air pollutants. To alleviate AD symptoms, simple questions about residential environments such as visible fungus on the walls and the use of artificial air freshener are helpful to assess the possibility of increased indoor air pollutant levels when direct measurement is not available.
PMCID: PMC4214972  PMID: 25374751
Atopic dermatitis; environment; childhood; air pollution; pollutant
17.  Lichen Secondary Metabolites in Flavocetraria cucullata Exhibit Anti-Cancer Effects on Human Cancer Cells through the Induction of Apoptosis and Suppression of Tumorigenic Potentials 
PLoS ONE  2014;9(10):e111575.
Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.
PMCID: PMC4216107  PMID: 25360754
18.  Effects of a Rivastigmine Patch on Self-Care Activities in Patients with Alzheimer's Disease plus Cerebrovascular Disease 
In dementia patients, a deficit in activities of daily living (ADL) is one of the main problems. Our objective was to assess ADL using the Korean Modified Barthel Index (K-MBI) in patients with Alzheimer's disease (AD) plus cerebrovascular disease (CVD) treated with a rivastigmine patch for 24 weeks in an open-label, observational study.
29 patients were enrolled who met the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ ANDRA) criteria and had a score of 10-26 on the Korean version of the Mini-Mental State Examination (K-MMSE). After the rivastigmine patch had been applied for 24 weeks, changes in self-care activities were assessed using the K-MBI.
The average age of the patients was 62.8 years, and they had an average K-MMSE score of 16.2. Patients showed a mean improvement of 21.9 points, as compared with the baseline K-MBI score of 30.3 (p < 0.05). Significantly better outcomes were seen in secondary outcome variables, for example the K-MMSE and backward digit span. The most frequent adverse events were skin problems, such as itching sensation (10%).
In this multicenter, open-label, observational study, the rivastigmine patch was associated with improvements in ADL in patients with AD plus CVD.
PMCID: PMC4255993  PMID: 25493089
Alzheimer's disease with cerebrovascular disease; Rivastigmine patch; Activities of daily living
19.  Combating Resistance to Anti-IGFR Antibody by Targeting the Integrin β3-Src Pathway 
Several phase II/III trials of anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined.
IGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non–small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line– or patient-derived xenograft tumors in athymic nude mice (n = 6–9 per group). Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were determined by Western or ligand blotting, immunoprecipitation, immunofluorescence, and cell adhesion analyses and enzyme-linked immunosorbent assay. Data were analyzed by the two-sided Student t test or one-way analysis of variance.
Integrin β3–Src signaling cascade was activated by IGF-1 in HNSCC and NSCLC cells, when IGF-1 binding to IGF-1R was hampered by cixutumumab, resulting in Akt activation and cixutumumab resistance. Targeting integrin β3 or Src enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines and patient-derived tumors in vitro and in vivo. Mean tumor volume of mice cotreated with cixutumumab and integrin β3 siRNA was 133.7mm3 (95% confidence interval [CI] = 57.6 to 209.8mm3) compared with those treated with cixutumumab (1472.5mm3; 95% CI = 1150.7 to 1794.3mm3; P < .001) or integrin β3 siRNA (903.2mm3; 95% CI = 636.1 to 1170.3mm3; P < .001) alone.
Increased Src activation through integrin ανβ3 confers considerable resistance against anti–IGF-1R mAb-based therapies in HNSCC and NSCLC cells. Dual targeting of the IGF-1R pathway and collateral integrin β3–Src signaling module may override this resistance.
PMCID: PMC3797025  PMID: 24092920
20.  Proteome profiling of lipopolysaccharide induced L6 rat skeletal muscle cells response to flavonoids from Scutellaria baicalensis Georgi 
Scutellaria baicalensis Georgi is a commonly used medicinal herb in several Asian countries like Korea, China and Japan for thousands of years. It has been reported to have various medicinal properties such as anti-microbial, anti-inflammatory and anti-cancer effects. However, the anti-inflammatory mechanism of S. baicalensis G at proteome level has not yet been reported. Hence, we performed a proteome analysis to study differentially expressed proteins and its anti-inflammatory role in lipopolysaccharide (LPS) stimulated L6 skeletal muscle cells response to flavonoids isolated from S. baicalensis G.
For that, 150 μg of proteins from the L6 cells of the control (Vehicle only), LPS treated and flavonoid treated groups were separated using 18 cm, pH 4–7 IPG strips in the first dimension and resolved by 12% linear gradient SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The silver stained gels were analyzed by using progenesis SameSpots software and twenty six differentially expressed protein spots (≥2 fold, p < 0.05) were selected for matrix assisted laser desorption ionization- time of flight mass spectroscopy/mass spectrometry (MALDI-TOF/MS) analysis. Also, the expression of COX-2, iNOS and Annexin A2 proteins were analyzed by western blot.
Totally, 12 differentially expressed proteins were successfully identified by MALDI-TOF/MS and database searching, that’s involved in inflammatory responses such vimentin, T-box transcription factor TBX3, annexin A1, annexin A2 and annexin A5. In addition, flavonoids inhibited the expression of COX-2, iNOS and Annexin A2 proteins in LPS-stimulated L6 skeletal muscle cells.
The findings revealed that the flavonoids from S. baicalensis G. directly protect the LPS stimulated inflammation process in L6 cells and, would be helpful to study further the muscle cell inflammatory mechanism. This is the first proteome study provide the anti-inflammatory mechanism of flavonoids from S. baicalensis G. in LPS stimulated L6 skeletal muscle cells.
PMCID: PMC4195865  PMID: 25287937
Flavonoids; Scutellaria baicalensis G; L6 skeletal muscle cells; Lipopolysaccharide (LPS); Two dimensional gel electrophoresis; Matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/MS)
21.  Changes in suprarenal and infrarenal aortic angles after endovascular aneurysm repair 
We investigated whether suprarenal and infrarenal aortic angles change after the endovascular aneurysm repair (EVAR) procedure and during follow-up, and investigated the correlation between infrarenal aortic angle after EVAR and type Ia endoleaks.
Data collected on 70 EVAR procedures for a fusiform infrarenal aortic aneurysm performed between May 2006 and December 2012 were supplemented with a retrospective review of charts and radiographs.
The greater the preoperative infrarenal aortic angle, the greater the suprarenal aortic angle (r = 0.72, P < 0.001). The infrarenal aortic angle decreased after the EVAR procedure and continued to decrease slowly thereafter (all P < 0.001). Suprarenal aortic angle decreased immediately after the EVAR procedure and continued to decrease during the first month (P < 0.001). No differences in angulation were observed based on stent graft type. Type Ia endoleaks occurred with significantly greater incidence in patients with a larger post EVAR infrarenal angle (P = 0.037).
The infrarenal aortic angle decreased significantly immediately after the EVAR procedure and continued to decrease slowly thereafter. Suprarenal aortic angle decreased immediately after the EVAR procedure and continued to decrease during the first month. We found a correlation between infrarenal and suprarenal aortic angle. Type Ia endoleaks occurred with greater incidence in patients with a larger infrarenal angle immediately after EVAR.
PMCID: PMC4196438  PMID: 25317415
Aortic aneurysm; Endovascular procedures; Endoleak
22.  Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study 
To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain.
Materials and Methods
One hundred twenty cancer patients with pain (numeric rating scale [NRS] ≥ 4) and sleep disturbance (NRS ≥ 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator’s discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated.
A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea.
HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.
PMCID: PMC4206066  PMID: 25043822
Cancer pain; Sleep disturbance; Hydromorphone-OROS (HM-OROS)
23.  Ultra-Low-Dose Chest CT in Patients with Neutropenic Fever and Hematologic Malignancy: Image Quality and Its Diagnostic Performance 
The aim of this study was to evaluate the image quality of ultra-low-dose computed tomography (ULDCT) and its diagnostic performance in making a specific diagnosis of pneumonia in febrile neutropenic patients with hematological malignancy.
Materials and Methods
ULDCT was performed prospectively in 207 febrile neutropenic patients with hematological malignancy. Three observers independently recorded the presence of lung parenchymal abnormality, and also indicated the cause of the lung parenchymal abnormality between infectious and noninfectious causes. If infectious pneumonia was considered the cause of lung abnormalities, they noted the two most appropriate diagnoses among four infectious conditions, including fungal, bacterial, viral, and Pneumocystis pneumonia. Sensitivity for correct diagnoses and receiver operating characteristic (ROC) curve analysis for evaluation of diagnostic accuracy were calculated. Interobserver agreements were determined using intraclass correlation coefficient.
Of 207 patients, 139 (67%) had pneumonia, 12 had noninfectious lung disease, and 56 had no remarkable chest computed tomography (CT) (20 with extrathoracic fever focus and 36 with no specific disease). Mean radiation expose dose of ULDCT was 0.60±0.15 mSv. Each observer regarded low-dose CT scans as unacceptable in only four (1.9%), one (0.5%), and three (1.5%) cases of ULDCTs. Sensitivity and area under the ROC curve in making a specific pneumonia diagnosis were 63.0%, 0.65 for reader 1; 63.0%, 0.61 for reader 2; and 65.0%, 0.62 for reader 3; respectively
ULDCT, with a sub-mSv radiation dose and acceptable image quality, provides ready and reasonably acceptable diagnostic information for pulmonary infection in febrile neutropenic patients with hematologic malignancy
PMCID: PMC4206072  PMID: 25308150
Hematologic neoplasms; Febrile neutropenia; Pulmonary infection; Ultra-low-dose CT
24.  Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw 
To identify post-treatment prognostic factors for medication-related osteonecrosis of the jaw (MRONJ).
Materials and Methods
We evaluated 54 MRONJ patients who visited the Department of Dentistry, Ajou University Hospital, from May 2007 to March 2014. Twenty-one patients were surgically managed with debridement or sequestrectomy and 33 patients were conservatively managed using antibiotics. Correlations of age, sex, stage, bisphosphonate duration and type, and drug holiday with the prognosis of MRONJ were investigated. Correlations were verified by logistic regression analysis and t-tests with a significance level of 0.05.
Clinical outcomes were evaluated on the basis of both clinical and radiographic findings. Twelve out of 21 surgically managed patients showed a favorable prognosis and nine patients relapsed. Thirty-one of the 33 conservatively managed patients showed no specific change in prognosis, and two patients worsened. Statistical analyses of the conservative management group did not reveal any correlation of the above factors with the prognosis of conservative management. Drug holiday was the only prognostic factor in the surgical management group (P=0.031 in logistic regression analysis, P=0.004 in t-test).
Drug holiday is a prognostic factor in the surgical management of MRONJ. Because the drug holiday in the patients of the poor prognosis group occurred 1.5 to 4 months prior to surgical management, we recommend a drug holiday more than 4 months before surgery.
PMCID: PMC4217272  PMID: 25368832
Medication-related osteonecrosis of the jaw; Bisphosphonate; Prognosis; Drug holiday
25.  Structure-Based Discovery of Natural Product-Like TNF-α Inhibitors 
Two natural product-like inhibitors of TNF-α have been identified using structure-based virtual screening. These compounds represent only the third and fourth examples of direct target of TNF-α by a small molecule and display comparable potency to the strongest TNF-α inhibitor reported to date.
PMCID: PMC4162403  PMID: 20235259
inhibitors; tumor necrosis factor; virtual screening; natural products; drug discovery

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