[Show abstract][Hide abstract] ABSTRACT: Glioblastoma (GBM) is the most aggressive and most lethal brain tumor. As current standard therapy consisting of surgery and chemo-irradiation provides limited benefit for GBM patients, novel therapeutic options are urgently required. Forkhead box M1 (FoxM1) transcription factor is an oncogenic regulator that promotes the proliferation, survival, and treatment resistance of various human cancers. The roles of FoxM1 in GBM remain incompletely understood, due in part to pleotropic nature of the FoxM1 pathway. Here, we show the roles of FoxM1 in GBM stem cell maintenance and radioresistance. ShRNA-mediated FoxM1 inhibition significantly impeded clonogenic growth and survival of patient-derived primary GBM cells with marked downregulation of Sox2, a master regulator of stem cell phenotype. Ectopic expression of Sox2 partially rescued FoxM1 inhibition-mediated effects. Conversely, FoxM1 overexpression upregulated Sox2 expression and promoted clonogenic growth of GBM cells. These data, with a direct binding of FoxM1 in the Sox2 promoter region in GBM cells, suggest that FoxM1 regulates stemness of primary GBM cells via Sox2. We also found significant increases in FoxM1 and Sox2 expression in GBM cells after irradiation both in vitro and in vivo orthotopic tumor models. Notably, genetic or a small-molecule FoxM1 inhibitor-mediated FoxM1 targeting significantly sensitized GBM cells to irradiation, accompanying with Sox2 downregulation. Finally, FoxM1 inhibition combined with irradiation in a patient GBM-derived orthotopic model significantly impeded tumor growth and prolonged the survival of tumor bearing mice. Taken together, these results indicate that the FoxM1-Sox2 signaling axis promotes clonogenic growth and radiation resistance of GBM, and suggest that FoxM1 targeting combined with irradiation is a potentially effective therapeutic approach for GBM.
PLoS ONE 10/2015; 10(10):e0137703. DOI:10.1371/journal.pone.0137703 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen.
Cancer cell 09/2015; 28(3):318-28. DOI:10.1016/j.ccell.2015.07.013 · 23.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma multiforme (GBM) possesses florid angiogenesis. However, the anti-angiogenic agent, Bevacizumab, did not improve overall survival of GBM patients. For more durable anti-angiogenic treatment, we interrogated resistant mechanisms of GBM against Bevacizumab. Serial orthotopic transplantation of in vivo Bevacizumab-treated GBM cells provoked complete refractoriness to the anti-angiogenic treatment. These tumors were also highly enriched with malignant phenotypes such as invasiveness, epithelial to mesenchymal transition, and stem-like features. Through transcriptome analysis, we identified that Talin1 (TLN1) significantly increased in the refractory GBMs. Inhibition of TLN1 not only attenuated malignant characteristics of GBM cells but also reversed the resistance to the Bevacizumab treatment. These data implicate TLN1 as a novel therapeutic target for GBM to overcome resistance to anti-angiogenic therapies.
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/β-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen.
[Show abstract][Hide abstract] ABSTRACT: A copper-catalyzed direct ring-opening double N-arylation of benzoxazoles with aryl iodides has been developed. The present system exhibits high selectivity despite competition from C-arylation. The selectivity between ring-opening N-arylation and C-arylation was controlled by the choice of reaction vessel. The nitrile bound bis(triphenylphosphine)copper cyanide was identified as the active catalytic species for both reactions, and when combined with a nitrile-containing solvent, enhanced the reaction efficiency.
The Journal of Organic Chemistry 03/2015; 80(7). DOI:10.1021/acs.joc.5b00019 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A chemosensor for selective detection of zinc has been prepared by the simple one-step reaction of pyrrole-2-carboxaldehyde and amino indanol. Whereas other metal ions except Zn2+ have no effect on the fluorescence of it, Zn2+ enhanced the fluorescence at 400 nm by the complexation of the sensor molecule and Zn2+ ion. The chemosensor has high selectivity and sensitivity toward Zn2+ ion with high binding constant (3 x 10(6) M-1) and low detection limit (1.0 x 10(-6) mol/L). H-1 NMR spectroscopy and Job's plot suggest that they formed 1:1 complex.
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.
PLoS ONE 08/2014; 9(8):e103327. DOI:10.1371/journal.pone.0103327 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma multiforme (GBM), the most common and aggressive malignant brain tumor, almost always recurs despite aggressive treatments combining surgery, radiation, and chemotherapy. Thus, understanding how individual tumors evolve in response to the standard treatments is essential for improved patient care.
[Show abstract][Hide abstract] ABSTRACT: Hardening phenomenon of human skin after repeated exposure to the irritants is well-known, but the precise mechanism remains elusive.
To modify the previous experimental model of hardening phenomenon by repeated applications of two different concentrations of sodium lauryl sulfate (SLS) solutions to Korean healthy volunteers and to investigate the quantitative changes of ceramides in stratum corneum before and after chronic repeated irritation.
Eight hundred microliters of distilled water containing 0.1% and 2% SLS was applied for 10 minutes on the forearm of 41 healthy volunteers for 3 weeks. After an intervening 3-week rest, 24-hour patch tests with 1% SLS were conducted on previously irritated sites. Transepidermal water loss (TEWL), erythema index and quantity of ceramide were measured in the stratum corneum before and after irritation.
TEWL values on the sites preirritated with 2% SLS were lower than those with 0.1% SLS. Hardening phenomenon occurred in 24 volunteers at day 44. The changes in ceramide levels were not significantly higher in the hardened skin than in the non-hardened skin.
Repetitive stimulation with a higher concentration of SLS can more easily trigger skin hardening.
Annals of Dermatology 02/2014; 26(1):35-42. DOI:10.5021/ad.2014.26.1.35 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Due to innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor Progression Locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of mitogen activated protein kinase (MAPK) pathways. Herein we aim to explore the relevance of Tpl2 in tumor growth and metastasis of RCC. Inspection of The Cancer Genome Atlas database indicated that Tpl2 overexpression was significantly related to presence of metastases and worse outcomes of clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and Chemokine Receptor type 4 (CXCR4) showed positive correlation. Depletion of Tpl2 activity with short hairpin (sh) RNAs or a Tpl2 kinase inhibitor in human ccRCC cells including Caki-1 remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Consistent with the in vitro data, orthotopic xenograft growth and lung metastasis of Caki-1 cells were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown in Caki-1 cells reduced chemokine (C-X-C motif) ligand 12 (CXCL12) directed chemotaxis/chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4 mediated metastasis. Taken together, these data suggest that Tpl2 can be a novel potential therapeutic target linked to the disease progression of ccRCC.
Molecular Cancer Research 08/2013; DOI:10.1158/1541-7786.MCR-13-0101-T · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic idiopathic urticaria (CIU) is considered a complex and multifactorial disease. Excessive histamine intake may induce an attack of urticaria. The main enzyme for histamine metabolism is diamine oxidase (DAO).
Plasma histamine concentrations and DAO activities were evaluated to determine whether there are abnormalities in the histamine metabolism of CIU patients.
Seventy-five CIU patients and twenty-five healthy control subjects were included in the study. Blood was taken from all subjects to measure plasma levels of the histamine and DAO.
Mean plasma histamine levels were significantly higher in CIU patients (11.59±10.98 nM) than in the control subjects (8.75±2.55 nM) (p=0.04). Mean DAO activities were lower in patients of CIU (80.86±26.81 histamine degrading unit [HDU]/ml) than in the controls (81.60±9.67 HDU/ml), but without significant difference. In 15 CIU patients with gastrointestinal symptoms, the mean histamine concentration was higher (12.43±7.97 nM) and DAO activity was lower (77.93±27.53 HDU/ml) than in the remaining 60 CIU patients without gastrointestinal symptoms (11.38±11.67 nM and 81.58±26.82 HDU/ml), without significant difference. The relationship between DAO activity and plasma histamine concentrations showed a significant negative linear value (p=0.001). There were no significant relationships between plasma histamine concentrations and symptom severity score.
In CIU patients, a high plasma histamine concentration may not be explained by DAO activity. CIU patients with gastrointestinal (GI) symptoms showed no significantly lower DAO activity. Larger group studies are required to elucidate the relationship between plasma histamine concentrations and DAO activity, especially of CIU patients with GI symptomsto understand the difference in CIU patients with and without GI symptoms.
Annals of Dermatology 05/2013; 25(2):189-195. DOI:10.5021/ad.2013.25.2.189 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is well known that atopic dermatitis (AD) is related to food hypersensitivity, although its prevalence varies among several studies according to age group, severity, country, survey time, and test method.
To examine the prevalence and status of food hypersensitivity among childhood AD patients in Korea.
A total of 95 patients were enrolled in the study. The history of food hypersensitivity was collected by interviews. The severity of AD was evaluated by eczema area and severity index (EASI). We took blood samples to measure serum total and food-specific immunoglobulin E (IgE) levels. Based on the histories and serum IgE levels, open oral food challenge (OFC) testing was performed to confirm food hypersensitivity.
Forty-two (44.2%) of the 95 AD patients had histories of food hypersensitivity. They reported that the most common suspicious foods were egg (n=13, 13.7%), pork (n=9, 9.5%) and cow milk (n=8, 8.4%). The mean EASI score was 16.05±9.76. Thirty-nine (41.1%) of the 95 patients showed elevated serum food-specific IgE levels. The specific IgE levels were elevated for egg (n=17, 17.9%), milk (n=12, 12.6%), peanut (n=10, 10.5%) and wheat (n=8, 8.4%). Fifty-one (53.8%) of 95 patients underwent open OFC, and only 7 (13.7%) of these patients showed positive reactions.
The overall prevalence of food hypersensitivity in patients with childhood AD in Korea was 8.3% (7/84). The most common foods causing food hypersensitivity were egg and milk. Among the foods causing hypersensitivity, AD patients in Korea often underestimated peanut, while they overestimated pork.
Annals of Dermatology 05/2013; 25(2):196-202. DOI:10.5021/ad.2013.25.2.196 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fractional technology overcomes the problems of ablative lasers, such as inaccurate depth control and damage to the epidermis. Minimally invasive fractional radiofrequency microneedle devices allow for more-selective heating of the dermis.
To evaluate the clinical efficacy of fractional radiofrequency microneedle (ERM) treatment in acne scars and large facial pores.
Thirty patients with acne scars and large facial pores were enrolled. Bipolar radiofrequency energy was delivered to the skin through the electrodes of the FRM device. Skin lesions were evaluated according to grade of acne scars, Investigator Global Assessment of large pores, skin surface roughness, transepidermal water loss (TEWL), dermal density, microscopic and composite image, sebum measurement, and questionnaires regarding patient satisfaction.
The grade of acne scars and Investigator Global Assessment of large pores improved in more than 70% of all patients. Skin surface roughness, dermal density, and microscopic and composite images also improved, whereas TEWL and sebum measurement did not change.
Clinical improvement from FRM treatment appeared to be related to dermal matrix regeneration. FRM treatment may be effective in improving acne scars and facial pores.
[Show abstract][Hide abstract] ABSTRACT: People with sensitive skin (SS) are those who state their skin is more sensitive than that of average persons. The stratum corneum is responsible for maintaining skin barrier function. Ceramides, major constituents of stratum corneum lipids, have been shown to predominantly contribute to the role. It has been suggested that barrier function in SS is decreased. However, we could find very few reports about stratum corneum ceramides in SS. This study was done to find out differences in stratum corneum ceramides between SS and non-SS groups. Fifty individuals (20 with SS and 30 with non-SS) were recruited. Lactic acid sting test (LAST) was performed on the left cheek. On six sites including the right cheek, arm, thigh, leg, back and palm, transepidermal water loss (TEWL) and erythema index (EI) were measured. On the above six sites, stratum corneum sheets were obtained by stripping with cyanoacrylate resin and stratum corneum lipids were extracted, then, analyzed by high-performance liquid chromatography electrospray ionization mass spectrometry. LAST scores were higher in the SS group, but not statistically significant. There were no differences in TEWL and EI values between the two groups. The mean value of the quantity of stratum corneum ceramides on the face was significantly lower in the SS group. On other sites, mean values were also lower in the SS group, but not statistically significant. The quantity of ceramides was significantly decreased in the face of the SS group compared to that of the non-SS group. These results suggest that the decrease in stratum corneum ceramides on facial skin could be related to SS development.
The Journal of Dermatology 03/2012; 39(3):295-300. DOI:10.1111/j.1346-8138.2011.01406.x · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although much research has been conducted into the origin of syringoma, the histogenesis and differentiation of it remains controversial. The published studies examined various antibodies, and our study is an additional immunohistochemical work-up.
We attempted to identify the cell that acts as the precise origin of a syringoma, based on a comparative analysis of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), and cytokeratin (CK) 5 through immunohistochemical staining in the solid strand of basophilic epithelial cells of syringoma.
A total of 31 patients with biopsy-confirmed syringoma were included in this study. Each sample was analyzed with antibodies to CEA, EMA, and CK5. These markers were indicating each part of the normal sweat gland structure: CEA stains the luminal surface of sweat ductal structures; EMA stains the peripheral cells of normal dermal ducts and the intraepidermal duct; CK5 stains the outer cells of the dermal duct and lower intraepidermal duct but does not stain the intraepidermal duct located in the upper epidermis.
We were able to confirm that the solid strands stained for EMA and CK5, as did the outer cells of the ductal structure. However, the solid strands did not stain with CEA.
The results indicated that solid strands observed in syringomas originate from the outer cells of the two layers of cells that compose the lower epidermal duct or the transitional portion between the intraepidermal duct and dermal duct in the normal eccrine or apocrine structure. Thus, we surmise that a syringoma is developed by the proliferation of these cells.
International journal of dermatology 11/2011; 51(7):817-22. DOI:10.1111/j.1365-4632.2011.05069.x · 1.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A cutaneous metaplastic synovial cyst (CMSC) is a cyst lined with metaplastic synovial tissue, which includes the formation of an intracystic villous structure resembling hyperplastic synovial villi. Clinically, the lesion is a tender, subcutaneous nodule that usually occurs at the site of previous surgical trauma and is frequently misdiagnosed as a suture granuloma. The actual cause remains unclear; however, trauma is presumed to be a precipitating factor, as most reported cases have demonstrated a history of antecedent cutaneous injury. Here, we present a case of CMSC in a 51-year-old woman who presented with a cystic mass localized in the left sole. She had no history of previous trauma or surgical procedures performed in the area. Although the case explained in this report is a spontaneous case of CMSC that occurred without a history of trauma, it is believed to have been caused by constant and chronic pressure since CMSC occurred in the first metatarsal head area, a part of the sole where heavy pressure is consistently applied.
[Show abstract][Hide abstract] ABSTRACT: Benign cephalic histiocytosis (BCH) is a rare non-Langerhans cell histiocytosis of unknown etiology. Clinically, lesions are characterized by small, red-to-yellow papules distributed mainly on the head, face, neck, and shoulders of infants and children. Histopathological specimens show massive histiocytic infiltration of the superficial dermis. Immunohistochemically, they are positive for CD68, but negative for CD1a and S-100. Two cases have been reported so far in the relevant work published in Korean literature. Herein, we report on an additional case of BCH.