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1.  Incidence and psychological-behavioral characteristics of refractory functional dyspepsia: A large, multi-center, prospective investigation from China 
AIM: To explore the incidence and psychological and behavioral characteristics of refractory functional dyspepsia (RFD) in China.
METHODS: The subjects of this study were 1341 new outpatients with functional dyspepsia (FD) who were diagnosed according to the Rome III criteria at four hospitals in Guangdong Province between June and September 2012, and 100 healthy volunteers. All subjects completed questionnaires and scales administered.
RESULTS: Three-hundred and twenty-seven of the 1341 patients with FD had RFD (24.4%). Patients with RFD had a longer disease duration and a more severe form of the disease than patients with non-refractory FD (NRFD). The prevalence of depression and anxiety symptoms was higher in patients with RFD than in patients with NRFD. The prevalence of unhealthy eating behaviors, lack of physical activity, and sleeping disorders was higher in patients with RFD than in patients with NRFD. Patients with RFD sought medical advice on more occasions and spent more money on treatment than patients with NRFD. Finally, patients with RFD had poorer quality of life than patients with NRFD.
CONCLUSION: RFD is not rare in clinical practice and should get attention by patients and doctors because of its long duration, severe symptoms, and associations with abnormal psychology and poor quality of life.
PMCID: PMC4323473
Refractory functional dyspepsia; Psychological-behavioral characteristics; Depression; Anxiety; Behavior; Quality of life
2.  Vulnerabilities of PTEN-p53-deficient prostate cancers to compound PARP/PI3K inhibition 
Cancer discovery  2014;4(8):896-904.
Prostate cancer (CaP) is the most prevalent cancer in males and treatment options are limited for advanced forms of the disease. Loss of the PTEN and p53 tumor suppressor genes is commonly observed in CaP, while their compound loss is often observed in advanced CaP. Here we show, that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the pro-survival signalling PI3K-AKT pathway limits the efficacy of a PARP-single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human CaP cell lines and in a Pten/p53 deficient mouse model of advanced CaP. Our findings therefore identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient CaP.
PMCID: PMC4125493  PMID: 24866151
PTEN; Prostate; PARP; PI3K; Senescence
3.  Effects of Different Types of Contraction in Abdominal Bracing on the Asymmetry of Left and Right Abdominal Muscles 
Journal of Physical Therapy Science  2014;26(12):1843-1845.
[Purpose] The purpose of this study was to investigate the effective strength levels of abdominal muscle contraction using the bracing contraction method. [Subjects] The experiment was conducted with 31 healthy male (M=15) and female (F=16) adults attending D University in Busan; all participants had less than obesity level BMI (BMI<30). [Methods] Bracing contraction was performed by the subjects in the hook-lying position at maximum and minimum pressure levels, five times each, using a Pressure Biofeedback Unit (PBU), and the mean measurement value was calculated. The maximum pressure level was set at 100% and the half maximum pressure level was set at 50%. Each subject’s left and right abdominal muscle thicknesses were then measured by ultrasound imaging in each state: at rest, 100% contraction, and 50% contraction. [Results] No significant differences were found between the left and right sides of the transversus abdominis (TrA) at rest, 50%, or 100% contraction. The external oblique abdominis (EO) and internal oblique abdominis (IO) showed no significant difference at rest or at the 50% contraction. However, a significant difference was noted at 100% contraction for the EO and IO. [Conclusion] Application of abdominal contraction using bracing can achieve symmetry in the left and right abdominal muscles at less than the maximum contractile strength. The occurrence of asymmetry in the left and right abdominal muscles at the maximum contractile strength suggests that the most suitable contractile strength in this exercise is less than the maximum contractile strength.
PMCID: PMC4273038  PMID: 25540478
Abdominal bracing; Symmetry; Ultrasound imaging
5.  Necrotizing fasciitis and streptococcal toxic shock syndrome secondary to varicella in a healthy child 
Korean Journal of Pediatrics  2014;57(12):538-541.
Varicella is usually considered to be a benign disease in healthy children; however, serious complications can occur such as necrotizing fasciitis and toxic shock syndrome. We describe a 38-month-old girl with necrotizing fasciitis and streptococcal toxic shock syndrome following varicella. She was previously healthy and vaccinated against varicella at 12 months of age. She had been diagnosed with varicella three days prior to presenting at our facility; she developed fever, vomiting, and painful swelling on her left flank. Her skin lesions worsened, she became lethargic, and had episodes of hypotension and coagulopathy. Necrotizing fasciitis on the left abdominal wall, buttocks, and left thigh was diagnosed by magnetic resonance imaging, and group A Streptococcus was isolated from a tissue culture. She was diagnosed as necrotizing fasciitis and streptococcal toxic shock syndrome, and successfully treated with repeated surgical debridement and fasciotomy, in addition to intensive antibiotics. Our experience suggests that necrotizing fasciitis in patients with varicella should be considered to be a rare complication even with widespread vaccine use. Early diagnosis and intensive treatment are required to prevent a fatal outcome.
PMCID: PMC4316598  PMID: 25653688
Chickenpox; Necrotizing fasciitis; Streptococcus pyogenes; Child
6.  Expression characteristics of FHIT, p53, BRCA2 and MLH1 in families with a history of oesophageal cancer in a region with a high incidence of oesophageal cancer 
Oncology Letters  2014;9(1):430-436.
The aim of the present study was to determine the changes to the expression levels of fragile histidine triad (FHIT), breast cancer type 2 susceptibility protein (BRCA2), MutL homolog 1 (MLH1) and tumour protein 53 (p53) exhibited by families with a history of oesophageal cancer in a region that has a high incidence of oesophageal cancer, and to determine the association of these changes with the cancer history of the families. Immunohistochemistry was used to detect the protein expression of FHIT, p53, BRCA2, and MLH1 in the excised specimens of cancer tissues from 74 oesophageal cancer patients (positive family history of oesophageal cancer [OCFH +], n=33; negative family history of oesophageal cancer [OCFH −], n=41) from a region with a high incidence of oesophageal cancer. The positive expression rates of FHIT (61%; 45/74), BRCA2 (50%; 37/74) and MLH1 (27%; 9/33) in the oesophageal cancer tissues were significantly lower than those in the healthy tissues adjacent to the cancer (97% [29/30], 87% [26/30] and 73% [25/41], respectively). A significant difference was identified between the positive expression rates (P<0.01). However, FHIT, p53, BRCA2 and MLH1 expression demonstrated no significant affect on clinicopathological changes, such as oesophageal cancerous tissue differentiation, the degree of infiltration and cancer cell metastasis. The FHIT, BRCA2 and MLH1 expression levels were identified to be significantly lower in the cancer tissues from OCFH + patients. This result indicates that the expression levels of FHIT, BRCA2, and MLH1 are important molecular indices of genetic susceptibility to oesophageal cancer.
PMCID: PMC4246613  PMID: 25436004
esophagus cancer; positive family history; fragile histidine triad; breast cancer type 2 susceptibility protein; mixed lymphocytic-histiocytic lymphoma; genetic predisposition
7.  Mechanical Modulation of Nascent Stem Cell Lineage Commitment in Tissue Engineering Scaffolds 
Biomaterials  2013;34(23):5766-5775.
Taking inspiration from tissue morphogenesis in utero, this study tests the concept of using tissue engineering scaffolds as delivery devices to modulate emergent structure-function relationships at early stages of tissue genesis. We report on the use of a combined computational fluid dynamics (CFD) modeling, advanced manufacturing methods, and experimental fluid mechanics (micro-piv and strain mapping) for the prospective design of tissue engineering scaffold geometries that deliver spatially resolved mechanical cues to cells seeded within. When subjected to a constant magnitude global flow regime, the local scaffold geometry dictates the magnitudes of mechanical stresses and strains experienced by a given cell, and in a spatially resolved fashion, similar to patterning during morphogenesis. In addition, early markers of mesenchymal stem cell lineage commitment relate significantly to the local mechanical environment of the cell. Finally, by plotting the range of stress-strain states for all data corresponding to nascent cell lineage commitment (95% CI), we begin to “map the mechanome”, defining stress-strain states most conducive to targeted cell fates. In sum, we provide a library of reference mechanical cues that can be delivered to cells seeded on tissue engineering scaffolds to guide target tissue phenotypes in a temporally and spatially resolved manner. Knowledge of these effects allows for prospective scaffold design optimization using virtual models prior to prototyping and clinical implementation. Finally, this approach enables the development of next generation scaffolds cum delivery devices for genesis of complex tissues with heterogenous properties, e.g., organs, joints or interface tissues such as growth plates.
PMCID: PMC4216563  PMID: 23660249
8.  Dependence Potential of Tramadol: Behavioral Pharmacology in Rodents 
Biomolecules & Therapeutics  2014;22(6):558-562.
Tramadol is an opioid analgesic agent that has been the subject of a series of case reports suggesting potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive in Korea. In this study, we examined the dependence potential and abuse liability of tramadol as well as its effect on the dopaminergic and serotonergic systems in rodents. In animal behavioral tests, tramadol did not show any positive effects on the experimental animals in climbing, jumping, and head twitch tests. However, in the conditioned place preference and self-administration tests, the experimental animals showed significant positive responses. Taken together, tramadol affected the neurological systems related to abuse liability and has the potential to lead psychological dependence.
PMCID: PMC4256037  PMID: 25489425
Tramadol; Dopamine system; Serotonin system; Drug dependence; Animal behavioral tests
9.  Transcription Factors Sp1 and Sp3 Regulate Expression of Human ABCG2 Gene and Chemoresistance Phenotype 
Molecules and Cells  2013;36(4):368-375.
ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electro-phoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by over-expression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.
PMCID: PMC3887993  PMID: 23996530
ABCG2; Sp1; Sp3; side population; transcription; chemoresistance
10.  Association between Serum Irisin Levels and Non-Alcoholic Fatty Liver Disease in Health Screen Examinees 
PLoS ONE  2014;9(10):e110680.
Irisin is a recently found myokine that aids obesity control and improves glucose homeostasis by acting on white adipose tissue cells and increases total energy consumption. The aim of this study was to evaluate serum irisin levels in patients with non-alcoholic fatty liver disease (NAFLD) and to compare these levels with those of normal controls. Among 595 health screen examinees who had visited our institute between January 2013 to March 2013, 355 patients (84 NAFLD patients and 271 normal controls) were enrolled depending on whether they gave written informed consents and their history of alcohol intake, blood tests, and abdominal ultrasonographic findings. Age; sex; laboratory test parameters; homeostasis model assessment-insulin resistance; and levels of leptin, adiponectin, and irisin were assessed. Serum irisin levels (ng/ml) were significantly higher in the NAFLD group than in normal controls (63.4±32.6 vs. 43.0±29.7, p<0.001) and higher in the mild fatty liver group than in the moderate-to-severe fatty liver group (68.3±38.2 vs. 56.6±21.2, p<0.001). Additionally, serum irisin levels were not different between the non-obese and obese groups (48.4±34.2 vs. 45.8±22.9, p = 0.492); however, the levels were significantly lowest in normal controls and highest in the mild fatty liver group in the non-obese (44.9±31.7 vs. 73.1±48.5 vs 59.7±18.0, p<0.001) and obese groups (35.0±17.0 vs. 62.9±21.2 vs. 54.6±23.3, p<0.001). Serum irisin levels were significantly higher in NAFLD patients, which is not consistent with the results of previously published studies. Therefore, more studies are needed to confirm the role of irisin in NAFLD.
PMCID: PMC4208808  PMID: 25343462
11.  Mdm2 and p53 Expression in Radiation-Induced Sarcomas of the Head and Neck: Comparison with De Novo Sarcomas 
Korean Journal of Pathology  2014;48(5):346-350.
The pathogenesis of radiation-induced sarcomas (RISs) is not well known. In RIS, TP53 mutations are frequent, but little is known about Mdm2-p53 interaction, which is a recent therapeutic target of sarcomas.
We studied the immunohistochemical expression of Mdm2 and p53 of 8 RISs. The intervals between radiation therapy and diagnosis of secondary sarcomas ranged from 3 to 17 years.
Mdm2 expression was more common in de novo sarcomas than RISs (75% vs 37.5%), and p53 expression was more common in RISs than in de novo cases (75% vs 37.5%). While half of the RISs were Mdm2(–)/p53(+), none of de novo cases showed such combination; while half of de novo sarcomas were Mdm2(+)/p53(–), which are a candidate group of Mdm2 inhibitors, only 1 RIS showed such a combination. Variable immunoprofiles observed in both groups did not correlate with tumor types, except that all of 2 myxofibrosarcomas were Mdm2(+)/p53(+).
In conclusion, we speculated that both radiation-induced and de novo sarcomagenesis are not due to a unique genetic mechanism. Mdm2-expression without p53 overexpression in 1 case of RIS decreases the future possibility of applying Mdm2 inhibitors on a subset of these difficult tumors.
PMCID: PMC4215959  PMID: 25366069
Cancer, radiation induced; Head and neck neoplasms; Sarcoma; Mdm2 protein, human; Tumor suppressor protein p53
12.  Solid Form of Epithelioid Hemangioma: A Case Report 
Korean Journal of Pathology  2014;48(5):394-397.
PMCID: PMC4215969  PMID: 25366079
13.  Calsyntenins Function as Synaptogenic Adhesion Molecules in Concert with Neurexins 
Cell reports  2014;6(6):1096-1109.
Multiple synaptic adhesion molecules govern synapse formation. Here, we propose calsyntenin-3/alcadein-β as a synapse organizer that specifically induces presynaptic differentiation in heterologous synapse-formation assays. Calsyntenin-3 (CST-3) was highly expressed during various postnatal periods of mouse brain development. The simultaneous knockdown of all three CSTs, but not CST-3 alone, decreased inhibitory, but not excitatory, synapse densities in cultured hippocampal neurons. Moreover, the knockdown of CSTs specifically reduced inhibitory synaptic transmission in vitro and in vivo. Remarkably, the loss of CSTs induced a concomitant decrease in neuron soma size in a non-cell-autonomous manner. Furthermore, α-neurexins (α-Nrxs) were affinity-purified as components of a CST-3 complex involved in CST-3-mediated presynaptic differentiation. However, CST-3 did not directly bind to Nrxs. Viewed together, these data suggest that the three CSTs redundantly regulate inhibitory synapse formation, inhibitory synapse function, and neuron development in concert with Nrxs.
PMCID: PMC4101519  PMID: 24613359
calsyntenin-3; neurexin; synapse function; synaptic adhesion
14.  High-Purity Prostate Circulating Tumor Cell Isolation by a Polymer Nanofiber-Embedded Microchip for Whole Exome Sequencing 
PMCID: PMC3875622  PMID: 23529932
Electrospun nanomaterials; microfluidics; circulating tumor cell; whole exome sequencing; prostate cancer
15.  GFAP Expression and Social Deficits in Transgenic Mice Overexpressing Human sAPPα 
Glia  2013;61(9):1556-1569.
Autisstic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPPα), the product of α-secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPPα protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPPα and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPPα were observed in brains of autistic patients compared with controls. Transgenic mice engineered to overexpress human sAPPα (TgsAPPα mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP), and altered Notch1 and IL-6 levels. Neural stem cells isolated from TgsAPPα mice, and those derived from wild-type mice treated with sAPPα, displayed suppressed β-tubulin III and elevated GFAP. These results suggest that elevations in the brain sAPPα are observed in subsets of individuals with autism and TgsAPPα mice display signs suggestive of gliosis and behavioral impairment.
PMCID: PMC3729742  PMID: 23840007
sAPPα; astrogliosis; autism; behavior; IL-6; Notch
16.  Time-Dependent Clinical Results of Rotating-Platform Total Knee Arthroplasty According to Mechanical Axis Deviation 
Knee Surgery & Related Research  2014;26(3):141-148.
We hypothesized that the low contact stress (LCS) posterior stabilization system in knees with ≤3° deviation of coronal alignment would provide more favorable clinical outcomes and survival rate over the course of time.
Materials and Methods
A retrospective study was performed on 253 consecutive cases of primary total knee arthroplasty (TKA). Patients were classified according to the degree of deviation of coronal alignment on the initial postoperative radiograph as Group 1 (≤3° deviation) and Group 2 (>3° deviation). The clinical assessments were performed using the Knee Society score and Hospital for Special Surgery systems and Western Ontario and McMaster Universities index.
The survival rate was 97.4% in Group 1 and 96.8% in Group 2. No statistically significant intergroup difference was observed in the clinical scores before surgery and since 1 year after surgery (p>0.05). However, a significant intergroup difference was noted between 6 months to 1 year after surgery (p<0.001). Less than 2 mm radiolucent lines were found more frequently in Group 2. Time-dependent improvement was noted within one year after TKA in both groups.
Most of the expected improvements were achieved at 6 months after surgery in Group 1 and at 1 year after surgery in Group 2. The present study suggests that the LCS system yields time-dependent improvement regardless of coronal alignment deviation.
PMCID: PMC4163571  PMID: 25229043
Knee; Arthroplasty; Treatment outcome
17.  DS-ARP: A New Detection Scheme for ARP Spoofing Attacks Based on Routing Trace for Ubiquitous Environments 
The Scientific World Journal  2014;2014:264654.
Despite the convenience, ubiquitous computing suffers from many threats and security risks. Security considerations in the ubiquitous network are required to create enriched and more secure ubiquitous environments. The address resolution protocol (ARP) is a protocol used to identify the IP address and the physical address of the associated network card. ARP is designed to work without problems in general environments. However, since it does not include security measures against malicious attacks, in its design, an attacker can impersonate another host using ARP spoofing or access important information. In this paper, we propose a new detection scheme for ARP spoofing attacks using a routing trace, which can be used to protect the internal network. Tracing routing can find the change of network movement path. The proposed scheme provides high constancy and compatibility because it does not alter the ARP protocol. In addition, it is simple and stable, as it does not use a complex algorithm or impose extra load on the computer system.
PMCID: PMC4163282  PMID: 25243205
18.  Esthetic rehabilitation of single anterior edentulous space using fiber-reinforced composite 
A fiber-reinforced composite (FRC) fixed prosthesis is an innovative alternative to a traditional metal restoration, as it is a conservative treatment method. This case report demonstrates a detailed procedure for restoring a missing anterior tooth with an FRC. A 44-year-old woman visited our department with an avulsed tooth that had fallen out on the previous day and was completely dry. This tooth was replanted, but it failed after one year. A semi-direct technique was used to fabricate a FRC fixed partial prosthesis for its replacement. The FRC framework and the pontic were fabricated using a duplicated cast model and nanofilled composite resin. Later on, interproximal contact, tooth shape, and shade were adjusted at chairside. This technique not only enables the clinician to replace a missing tooth immediately after extraction for minimizing esthetic problems, but it also decreases both tooth reduction and cost.
PMCID: PMC4125587  PMID: 25110647
Avulsion; Fiber-reinforced composite; Immediate restoration; Single anterior tooth replacement
19.  Cancer Cell Growth Inhibitory Effect of Bee Venom via Increase of Death Receptor 3 Expression and Inactivation of NF-kappa B in NSCLC Cells 
Toxins  2014;6(8):2210-2228.
Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB) activity assay. BV (1–5 μg/mL) inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax) was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF)-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.
PMCID: PMC4147578  PMID: 25068924
bee venom; apoptosis; death receptors; NF-κB
20.  NOTCH1 signaling contributes to cell growth, anti-apoptosis and metastasis in salivary adenoid cystic carcinoma 
Oncotarget  2014;5(16):6885-6895.
Background: Numerous studies have reported both the tumor-suppressive and oncogenic roles of the Notch pathway, indicating that Notch activity regulates tumor biology in a complex, context-dependent manner. The aim of the present study was to identify the role of NOTCH1 in the cell growth and metastasis of SACC.
Methods: We analyzed the expression of NOTCH1 in clinical SACC samples using immunohistochemical staining. We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion. NOTCH1 target genes were validated by real-time PCR.
Results: Our results showed that NOTCH1 was upregulated in SACC tissues when compared with normal tissues, and this upregulation was further enhanced in SACC tissues with metastasis and recurrence when compared with SACC tissues without metastasis. Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.
Conclusions:The results of this study suggest that NOTCH1 plays a key role in the cell growth, anti-apoptosis, and metastasis of SACC. NOTCH1 inhibitors might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.
PMCID: PMC4196170  PMID: 25149541
NOTCH1; salivary adenoid cystic carcinoma; proliferation; apoptosis; metastasis
21.  microRNA-antagonism regulates breast cancer stemness and metastasis via TET family dependent chromatin remodeling 
Cell  2013;154(2):311-324.
Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing anti-metastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytocine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness towards metastasis.
PMCID: PMC3767157  PMID: 23830207
22.  Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches 
Biomolecules & Therapeutics  2014;22(4):363-369.
Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as “Spice” and “Smoke”. Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Δ9-tetrahydrocannabinol (Δ9-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Δ9-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.
PMCID: PMC4131522  PMID: 25143817
Synthetic cannabinoid; Δ9-Tetrahydrocannabinol (Δ9-THC); Psychological dependence; CB1 receptor; Binding affinity
23.  Mapping biological entities using the longest approximately common prefix method 
BMC Bioinformatics  2014;15:187.
The significant growth in the volume of electronic biomedical data in recent decades has pointed to the need for approximate string matching algorithms that can expedite tasks such as named entity recognition, duplicate detection, terminology integration, and spelling correction. The task of source integration in the Unified Medical Language System (UMLS) requires considerable expert effort despite the presence of various computational tools. This problem warrants the search for a new method for approximate string matching and its UMLS-based evaluation.
This paper introduces the Longest Approximately Common Prefix (LACP) method as an algorithm for approximate string matching that runs in linear time. We compare the LACP method for performance, precision and speed to nine other well-known string matching algorithms. As test data, we use two multiple-source samples from the Unified Medical Language System (UMLS) and two SNOMED Clinical Terms-based samples. In addition, we present a spell checker based on the LACP method.
The Longest Approximately Common Prefix method completes its string similarity evaluations in less time than all nine string similarity methods used for comparison. The Longest Approximately Common Prefix outperforms these nine approximate string matching methods in its Maximum F1 measure when evaluated on three out of the four datasets, and in its average precision on two of the four datasets.
PMCID: PMC4086698  PMID: 24928653
24.  Heteroatom-doped highly porous carbon from human urine 
Scientific Reports  2014;4:5221.
Human urine, otherwise potentially polluting waste, is an universal unused resource in organic form disposed by the human body. We present for the first time “proof of concept” of a convenient, perhaps economically beneficial, and innovative template-free route to synthesize highly porous carbon containing heteroatoms such as N, S, Si, and P from human urine waste as a single precursor for carbon and multiple heteroatoms. High porosity is created through removal of inherently-present salt particles in as-prepared “Urine Carbon” (URC), and multiple heteroatoms are naturally doped into the carbon, making it unnecessary to employ troublesome expensive pore-generating templates as well as extra costly heteroatom-containing organic precursors. Additionally, isolation of rock salts is an extra bonus of present work. The technique is simple, but successful, offering naturally doped conductive hierarchical porous URC, which leads to superior electrocatalytic ORR activity comparable to state of the art Pt/C catalyst along with much improved durability and methanol tolerance, demonstrating that the URC can be a promising alternative to costly Pt-based electrocatalyst for ORR. The ORR activity can be addressed in terms of heteroatom doping, surface properties and electrical conductivity of the carbon framework.
PMCID: PMC4049026  PMID: 24909133
25.  Activator- and repressor-type MYB transcription factors are involved in chilling injury induced flesh lignification in loquat via their interactions with the phenylpropanoid pathway 
Journal of Experimental Botany  2014;65(15):4349-4359.
Two novel MYB transcription factors are involved in lignin biosynthesis and flesh lignification in loquat fruit, which are manipulated by temperature condition and treatments.
Lignin biosynthesis and its transcriptional regulatory networks have been studied in model plants and woody trees. However, lignification also occurs in some fleshy fruit and has rarely been considered in this way. Loquat (Eriobotrya japonica) is one such convenient tissue for exploring the transcription factors involved in regulating fruit flesh lignification. Firmness and lignin content of ‘Luoyangqing’ loquat were fund to increase during low-temperature storage as a typical symptom of chilling injury, while heat treatment (HT) and low-temperature conditioning (LTC) effectively alleviated them. Two novel EjMYB genes, EjMYB1 and EjMYB2, were isolated and were found to be localized in the nucleus. These genes responded differently to low temperature, with EjMYB1 induced and EjMYB2 inhibited at 0 °C. They also showed different temperature responses under HT and LTC conditions, and may be responsible for different regulation of flesh lignification at the transcriptional level. Transactivation assays indicated that EjMYB1 and EjMYB2 are a transcriptional activator and repressor, respectively. EjMYB1 activated promoters of both Arabidopsis and loquat lignin biosynthesis genes, while EjMYB2 countered the inductive effects of EjMYB1. This finding was also supported by transient overexpression in tobacco. Regulation of lignification by EjMYB1 and EjMYB2 is likely to be achieved via their competitive interaction with AC elements in the promoter region of lignin biosynthesis genes such as Ej4CL1.
PMCID: PMC4112638  PMID: 24860186
Chilling injury; flesh lignification; heat treatment; Loquat; low-temperature condition; MYB; transcriptional regulation.

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