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1.  Developing Korean Academy of Medical Sciences Guideline for Rating the Impairment in Mental and Behavioral Disorders; A Comparative Study of KNPA's New Guidelines and AMA's 6th Guides 
Journal of Korean Medical Science  2009;24(Suppl 2):S338-S342.
Quantifying and rating the impairments due to mental and behavior disorders are difficult for their own characteristics. Korean Academy of Medical Sciences (KAMS) is developing guidelines of rating impairment in mental and behavioral disorders based on Korean Neuropsychiatric Association (KNPA)'s new guidelines. We compared the new KNPA's guidelines and the American Medical Association (AMA)'s 6th Guides in assessing impairment due to mental and behavioral disorders to develop new guidelines of KAMS. Two guidelines are different in diagnosing system, applicable disorders, qualification of assessors, application of scales, contents of assessment and rate of impairment of the whole person. Both AMA's and the proposed guidelines have individual merits and characteristics. There is a limitation in using the 6th AMA's Guides in Korean situation. However to improve objectivity in Korean assessment of psychiatric impairment, the new AMA's Guides can serve as a good reference.
doi:10.3346/jkms.2009.24.S2.S338
PMCID: PMC2690069  PMID: 19503692
Disability Evaluation; Mental Disorders; Behavioral Symptoms
2.  The Assessment of Tumor Response by Measuring the Single Largest Lesion per Organ in Metastatic Tumors: A Pooled Analysis of Previously Reported Data 
Journal of Cancer  2015;6(2):169-176.
Background: The RECIST 1.1 adopted a total of five target lesions to be measured, with a maximum of two lesions per organ. To the best of our knowledge, the criterion of two target lesions per organ in the RECIST 1.1 is arbitrary and has not been supported by any objective evidence. Recently, we reported that the modified RECIST 1.1 (measuring the single largest lesion in each organ) showed a high level of concordance with the original RECIST 1.1 in patients with advanced or metastatic non-small cell lung cancer (NSCLC), gastric cancer (GC), and colorectal cancer (CRC). However, each study had a major limitation of a small number of patients.
Methods: We conducted a pooled analysis using the data from the three individual studies to improve statistical power. Tumor responses were compared according to the RECIST 1.1 and modified RECIST 1.1 (mRECIST 1.1).
Results: A total of 153 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included in this pooled study: 64 with NSCLC, 51 with GC, and 38 with CRC. Regardless of primary sites, the number of target lesions according to the mRECIST 1.1 was significantly lower than that according to the RECIST 1.1 (P<0.001). The assessment of tumor responses showed a high concordance between the two criteria (k = 0.908). Only eight patients (5.2%) showed disagreement in the tumor response assessment between the two criteria. The overall response rates of chemotherapy were not significantly different between the two criteria (33.3% versus 33.3%, P=1.0).
Conclusions: The modified RECIST 1.1 was comparable to the original RECIST 1.1 in the tumor response assessment of patients with advanced or metastatic NSCLC, GC, and CRC. Our results suggest that it may be possible to measure the single largest lesion per organ for assessing tumor response in clinical practice.
doi:10.7150/jca.10912
PMCID: PMC4280400  PMID: 25561982
RECIST 1.1; modified RECIST 1.1; Target lesion; Tumor response; Single-lesion measurement
3.  A Phase I/II Trial to Evaluate the Technical Feasibility of Partial Breast Irradiation with Three-Dimensional Conformal Radiation Therapy in Korean Women with Stage I Breast Carcinoma: An Initial Report of the Korean Radiation Therapy Oncology Group (KROG) Study 0804 
Purpose
This prospective study was designed to verify the technical feasibility of partial breast irradiation in breast cancer patients with small breasts, which are commonly encountered in Korean women.
Materials and Methods
A total of 40 Gy, administered in 10 fractions on consecutive days (one fraction per day), was prescribed to the isocenters of the fields using three-dimensional conformal radiotherapy (3-DCRT). For all patients, treatment planning and dose parameters strictly adhered to the constraints set forth in the Radiation Therapy Oncology Group (RTOG) 0319 protocol. This study was designed such that if fewer than five of the first 42 evaluable patients received unacceptable scores, the treatment would be considered reproducible.
Results
Ten treatment plans (23.8%) were determined to have major variations. There was no major variation in planning target volume (PTV) coverage. The ipsilateral and contralateral breast dose limitations were not met in four (9.5%) and four cases (9.5%), respectively. Major variations in ipsilateral and contralateral lung dose limitations were observed in two cases (4.8%). Major variations in the heart and thyroid dose limitations were observed in one (2.4%) and one case (2.4%), respectively. In multivariate analysis, a ratio of PTV to ipsilateral breast volume (PTV/IB) > 0.16 was the only significant factor that statistically affected major variations.
Conclusion
We concluded that partial breast irradiation using 3-DCRT could not be reproduced in Korean breast cancer patients, particularly small-volumed breast surrogated as PTV/IB > 0.16. The dominant cause was the major variation in surrounding normal breast tissues.
doi:10.4143/crt.2013.202
PMCID: PMC4296846  PMID: 25143050
Breast neoplasms; Partial breast irradiation; Conformal radiotherapy
4.  Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer 
BMC Cancer  2014;14(1):959.
Background
Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.
Methods
Tissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.
Results
Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.
Conclusion
We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.
doi:10.1186/1471-2407-14-959
PMCID: PMC4301952  PMID: 25510449
Breast cancer; Molecular subtype; Immunohistochemistry; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase
5.  Calcifying tissue regeneration via biomimetic materials chemistry 
Journal of the Royal Society Interface  2014;11(101):20140537.
Materials chemistry is making a fundamental impact in regenerative sciences providing many platforms for tissue development. However, there is a surprising paucity of replacements that accurately mimic the structure and function of the structural fabric of tissues or promote faithful tissue reconstruction. Methodologies in biomimetic materials chemistry have shown promise in replicating morphologies, architectures and functional building blocks of acellular mineralized tissues dentine, enamel and bone or that can be used to fully regenerate them with integrated cell populations. Biomimetic materials chemistry encompasses the two processes of crystal formation and mineralization of crystals into inorganic formations on organic templates. This review will revisit the successes of biomimetics materials chemistry in regenerative medicine, including coccolithophore simulants able to promote in vivo bone formation. In-depth knowledge of biomineralization throughout evolution informs the biomimetic materials chemist of the most effective techniques for regenerative framework construction exemplified via exploitation of liquid crystals (LCs) and complex self-organizing media. Therefore, a new innovative direction would be to create chemical environments that perform reaction–diffusion exchanges as the basis for building complex biomimetic inorganic structures. This has evolved widely in biology, as have LCs, serving as self-organizing templates in pattern formation of structural biomaterials. For instance, a study is highlighted in which artificially fabricated chiral LCs, made from bacteriophages are transformed into a faithful copy of enamel. While chemical-based strategies are highly promising at creating new biomimetic structures there are limits to the degree of complexity that can be generated. Thus, there may be good reason to implement living or artificial cells in ‘morphosynthesis’ of complex inorganic constructs. In the future, cellular construction is probably key to instruct building of ultimate biomimetic hierarchies with a totality of functions.
doi:10.1098/rsif.2014.0537
PMCID: PMC4223895  PMID: 25320063
biomineralization; regenerative medicine; bioinorganic materials chemistry
6.  Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3-K, MKK4 and MKK7 in human melanoma 
Cancer prevention research (Philadelphia, Pa.)  2013;6(12):10.1158/1940-6207.CAPR-13-0134.
Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin (Gc), a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of Gc causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than Gc in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell cycle progression at the G1 phase and inhibited the expression of G1-phase regulatory proteins, including cyclin D1 and cyclin E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK3β and JNK1/2. IAA also bound to phosphatidylinositol 3-kinase (PI3-K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3-K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biological actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.
doi:10.1158/1940-6207.CAPR-13-0134
PMCID: PMC3855899  PMID: 24104352
Isoangustone A; PI3K; MKK4; MKK7; melanoma
7.  The Factors Affecting Pain Pattern after Arthroscopic Rotator Cuff Repair 
Clinics in Orthopedic Surgery  2014;6(4):392-400.
Background
We evaluated the factors that affect pain pattern after arthroscopic rotator cuff repair.
Methods
From June 2009 to October 2010, 210 patients underwent arthroscopic rotator cuff repair operations. Of them, 84 patients were enrolled as subjects of the present study. The evaluation of postoperative pain was conducted by visual analog scale (VAS) scores during postoperative outpatient interviews at 6 weeks, 3 months, 6 months, and 12 months. The factors that were thought to affect postoperative pain were evaluated by dividing into three categories: preoperative, operative, and postoperative.
Results
Pain after arthroscopic rotator cuff repair surgery showed a strictly decreasing pain pattern. In single analysis and multiple regression tests for factors influencing the strictly decreasing pain pattern, initial VAS and pain onset were shown to be statistically significant factors (p = 0.012, 0.012, 0.044 and 0.028, respectively). With regard to the factors influencing lower than average intensity pain pattern for each period, the stiffness of internal rotation at 3 months postoperatively was shown to be a statistically significant factor in single and multiple regression tests (p = 0.017 and p = 0.004, respectively).
Conclusions
High initial VAS scores and the acute onset of pain affected the strictly decreasing postoperative pain pattern. Additionally, stiffness of internal rotation at postoperative 3 months affected the higher than average intensity pain pattern for each period after arthroscopic rotator cuff repair.
doi:10.4055/cios.2014.6.4.392
PMCID: PMC4233217  PMID: 25436062
Arthroscopy; Rotator cuff repair; Stiffness; Postoperative pain; Visual analog scale
8.  Temporal and Spatial Expression Patterns of miR-302 and miR-367 During Early Embryonic Chick Development 
The microRNAs (miRNAs) are small, non-coding RNAs that modulate protein expression by interfering with target mRNA translation or stability. miRNAs play crucial roles in various functions such as cellular, developmental, and physiological processes. The spatial expression patterns of miRNAs are very essential for identifying their functions. The expressions of miR-302 and miR-367 are critical in maintaining stemness of pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) but their functions in early development are not fully elucidated. So, we used Locked Nucleic Acid (LNA) probes to perform in situ hybridization and confirmed the temporal and spatial distribution patterns during early chick development. As a result, we found that miR-302 and miR-367 were expressed in various tissues such as primitive steak, neural ectoderm, neural plate, neural fold, neural tube, notochord, and oral cavity. Specially, we confirmed that miR-302 and miR-367 were strongly expressed in neural folds in HH8 to HH10. miR-302 was expressed on dorsal part of the neural tube but miR-367 was expressed on lateral and ventral parts of the neural tube. And also we performed quantitative stem-loop real-time PCR to analyze global expression level of miR-302 and miR-367. miR-302 and miR-367 expression was sustained before Hamburger and Hamilton stage (HH) 14. Thus, the temporal and spatial expression patterns of miR-302 and miR-367 may provide us information of the role of these miRNAs on tissue formation during early chick development.
doi:10.15283/ijsc.2014.7.2.162
PMCID: PMC4249900  PMID: 25473455
Early chick development; miRNAs; LNA; In situ hybridization
9.  Berteroin Present in Cruciferous Vegetables Exerts Potent Anti-Inflammatory Properties in Murine Macrophages and Mouse Skin 
Berteroin (5-methylthiopentyl isothiocyanate) is a sulforaphane analog present in cruciferous vegetables, including Chinese cabbage, rucola salad leaves, and mustard oil. We examined whether berteroin exerts anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin inflammation models. Berteroin decreased LPS-induced release of inflammatory mediators and pro-inflammatory cytokines in Raw 264.7 macrophages. Berteroin inhibited LPS-induced degradation of inhibitor of κBα (IκBα) and nuclear factor-κB p65 translocation to the nucleus and DNA binding activity. Furthermore, berteroin suppressed degradation of IL-1 receptor-associated kinase and phosphorylation of transforming growth factor β activated kinase-1. Berteroin also inhibited LPS-induced phosphorylation of p38 MAPK, ERK1/2, and AKT. In the mouse ear, berteroin effectively suppressed TPA-induced edema formation and down-regulated iNOS and COX-2 expression as well as phosphorylation of AKT and ERK1/2. These results demonstrate that berteroin exhibits potent anti-inflammatory properties and suggest that berteroin can be developed as a skin anti-inflammatory agent.
doi:10.3390/ijms151120686
PMCID: PMC4264190  PMID: 25393510
inflammation; berteroin; iNOS; COX-2
10.  The Effectiveness of Cross-Tapering Switching to Ziprasidone in Patients with Schizophrenia or Schizoaffective Disorder 
Psychiatry Investigation  2014;11(4):459-466.
Objective
Switching antipsychotics is one useful therapeutic option when the treatment of schizophrenia encounters suboptimal efficacy and intolerability issues. This study aimed to investigate the efficacy and tolerability of cross-tapering switching to ziprasidone from other antipsychotics.
Methods
A total of 67 patients with schizophrenia or schizoaffective disorder were recruited in this 12-week, multicenter, non-comparative, open-label trial. Prior antipsychotics were allowed to be maintained for up to 4 weeks during the titration of ziprasidone. Efficacy was primarily measured using the 18-item Brief Psychotic Rating Scale (BPRS) at baseline, 4 weeks, 8 weeks, and 12 weeks. Efficacy was secondarily measured by the Clinical Global Impression-Severity (CGI-S) scale and the Global Assessment of Functioning (GAF) scale at each visit. Regarding the metabolic effects of switching to ziprasidone, weight, body mass index (BMI), waist-to-hip ratio (WHR), and lipid profile-including triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol levels-were measured at each follow-up visit.
Results
The BPRS scores were significantly improved at 12 weeks after switching to ziprasidone (F=5.96, df=2.11, p=0.003), whereas the CGI-S and GAF scores were not significantly changed. BMIs, WHRs, and TG levels were significantly decreased, with no significant changes in other lipid profiles.
Conclusion
Cross-tapering switching to ziprasidone is effective for patients with schizophrenia spectrum disorders. Beyond the efficacy of the procedure, favorable metabolic profiles show that switching to ziprasidone may be helpful for maintenance therapy over an extended period.
doi:10.4306/pi.2014.11.4.459
PMCID: PMC4225211  PMID: 25395978
Ziprasidone; Schizophrenia; Switching; Pharmacotherapy; Triglyceride
11.  Adult Multisystem Langerhans Cell Histiocytosis Presenting with Central Diabetes Insipidus Successfully Treated with Chemotherapy 
Endocrinology and Metabolism  2014;29(3):394-399.
We report the rare case of an adult who was diagnosed with recurrent multisystem Langerhans cell histiocytosis (LCH) involving the pituitary stalk and lung who present with central diabetes insipidus and was successfully treated with systemic steroids and chemotherapy. A 49-year-old man visited our hospital due to symptoms of polydipsia and polyuria that started 1 month prior. Two years prior to presentation, he underwent excision of right 6th and 7th rib lesions for the osteolytic lesion and chest pain, which were later confirmed to be LCH on pathology. After admission, the water deprivation test was done and the result indicated that he had central diabetes insipidus. Sella magnetic resonance imaging showed a mass on the pituitary stalk with loss of normal bright spot at the posterior lobe of the pituitary. Multiple patchy infiltrations were detected in both lung fields by computed tomography (CT). He was diagnosed with recurrent LCH and was subsequently treated with inhaled desmopressin, systemic steroids, vinblastine, and mercaptopurine. The pituitary mass disappeared after two months and both lungs were clear on chest CT after 11 months. Although clinical remission in multisystem LCH in adults is reportedly rare, our case of adult-onset multisystem LCH was treated successfully with systemic chemotherapy using prednisolone, vinblastine, and 6-mercaptopurine, which was well tolerated.
doi:10.3803/EnM.2014.29.3.394
PMCID: PMC4192804  PMID: 25309800
Histiocytosis, Langerhans-cell; Drug therapy; Diabetes insipidus
12.  Validation of Risk Assessment Models for Predicting the Incidence of Breast Cancer in Korean Women 
Journal of Breast Cancer  2014;17(3):226-235.
Purpose
The Gail model is one of the most widely used tools to assess the risk of breast cancer. However, it is known to overestimate breast cancer risk for Asian women. Here, we validate the Gail model and the Korean model using Korean data, and subsequently update and revalidate the Korean model using recent data.
Methods
We validated the modified Gail model (model 2), Asian American Gail model, and a previous Korean model using screening patient data collected between January 1999 and July 2004. The occurrence of breast cancer was confirmed by matching the resident registration number with data from the Korean Breast Cancer Registration Program. The expected-to-observed (E/O) ratio was used to validate the reliability of the program, and receiver operating characteristics curve analysis was used to evaluate the program's discriminatory power. There has been a rapid increase in the incidence of breast cancer in Korea, and we updated and revalidated the Korean model using incidence and mortality rate data from recent years.
Results
Among 40,229 patients who were included in the validation, 161 patients were confirmed to have developed breast cancer within 5 years of screening. The E/O ratios and 95% confidence intervals (CI) were 2.46 (2.10-2.87) for the modified Gail model and 1.29 (1.11-1.51) for the Asian American Gail model. The E/O ratio and 95% CI for the Korean model was 0.50 (0.43-0.59). For the updated Korean model, the E/O ratio and 95% CI were 0.85 (0.73-1.00). In the discriminatory power, the area under curve and 95% CI of the modified Gail model, Asian American Gail model, Korean model and updated Korean model were 0.547 (0.500-0.594), 0.543 (0.495-0.590), 0.509 (0.463-0.556), and 0.558 (0.511-0.605), respectively.
Conclusion
The updated Korean model shows a better performance than the other three models. It is hoped that this study can provide the basis for a clinical risk assessment program and a future prospective study of breast cancer prevention.
doi:10.4048/jbc.2014.17.3.226
PMCID: PMC4197352  PMID: 25320620
Breast neoplasms; Risk assessment; Validation studies
13.  First Report of Stemonitis splendens Rostaf Causing Bark Decay of Oak Logs Used for Shiitake Cultivation in Korea 
Mycobiology  2014;42(3):279-281.
Severe bark decay disease was observed on oak logs at a shiitake cultivation farm in Geochang-gun, Gyeongnam province. The symptoms observed were fruiting bodies that had developed on the top and side surface of oak logs. As a result, the bark came off easily exposing the sapwood. Slime mold specimens collected from oak logs showed developing fruiting bodies comprising of stalks, hypothallus, capillitium, and columella, and the causal agent of bark decay disease was identified as Stemonitis splendens on the basis of morphological characteristics. To our knowledge, this is the first report of Stemonitis splendens causing bark decay of oak logs used for shiitake mushroom cultivation in Korea.
doi:10.5941/MYCO.2014.42.3.279
PMCID: PMC4206795  PMID: 25346606
Bark decay; Lentinula edodes; Oak log; Stemonitis splendens Rostaf
14.  Kaempferol Downregulates Insulin-like Growth Factor-I Receptor and ErbB3 Signaling in HT-29 Human Colon Cancer Cells 
Journal of Cancer Prevention  2014;19(3):161-169.
Background:
Novel dietary agents for colon cancer prevention and therapy are desired. Kaempferol, a flavonol, has been reported to possess anticancer activity. However, little is known about the molecular mechanisms of the anticancer effects of kaempferol. The aim of this study was to determine the inhibitory effect of kaempferol on growth factor-induced proliferation and to elucidate its underlying mechanisms in the HT-29 human colon cancer cell line.
Methods:
To assess the effects of kaempferol and/or growth factors [insulin-like growth factor (IGF)-I and heregulin (HRG)-β], cells were cultured with or without 60 μmol/L kaempferol and/or 10 nmol/L IGF-I or 20 μg/L HRG-β. Cell proliferation, DNA synthesis, and apoptosis were determined by a cell viability assay, a [3H]thymidine incorporation assay, and Annexin-V staining, respectively. Western blotting, immunoprecipitation, and an in vitro kinase assay were conducted to evaluate expression and activation of various signaling molecules involved in the IGF-I receptor (IGF-IR) and ErbB3 signaling pathways.
Results:
IGF-I and HRG-β stimulated HT-29 cell growth but did not abrogate kaempferol-induced growth inhibition and apoptosis. Kaempferol reduced IGF-II secretion, HRG expression and phosphorylation of Akt and extracellular signal-regulated kinase (ERK)-1/2. Kaempferol reduced IGF-I- and HRG-β-induced phosphorylation of the IGF-IR and ErbB3, their association with p85, and phosphatidylinositol 3-kinase (PI3K) activity. Additionally, kaempferol inhibited IGF-I- and HRG-β-induced phosphorylation of Akt and ERK-1/2.
Conclusions:
The results demonstrate that kaempferol downregulates activation of PI3K/Akt and ERK-1/2 pathways by inhibiting IGF-IR and ErbB3 signaling in HT-29 cells. We suggest that kaempferol could be a useful chemopreventive agent against colon cancer.
doi:10.15430/JCP.2014.19.2.161
PMCID: PMC4189510  PMID: 25337585
Kaempferol; Insulin-like growth factor-I receptor; ErbB3; HT-29 human colon cancer
15.  Expression of p75NGFR, a Proliferative and Basal Cell Marker, in the Buccal Mucosa Epithelium during Re-epithelialization 
Acta Histochemica et Cytochemica  2014;47(4):145-153.
We investigated the expression of p75NGFR, a proliferative and basal cell marker, in the mouse buccal mucosa epithelium during wound healing in order to elucidate the role of epithelial stem cells. Epithelial defects were generated in the epithelium of the buccal mucosa of 6-week-old mice using CO2 laser irradiation. BrdU was immediately administered to mice following laser irradiation. They were then sacrificed after 1, 3, 7, and 14 days. Paraffin sections were prepared and the irradiated areas were analyzed using immunohistochemistry with anti-p75NGFR, BrdU, PCNA, and CK14 antibodies. During re-epithelialization, PCNA (–)/p75NGFR (+) cells extended to the wound, which then closed, whereas PCNA (+)/p75NGFR (+) cells were not observed at the edge of the wound. In addition, p75NGFR (–)/CK14 (+), which reflected the presence of post-mitotic differentiating cells, was observed in the supra-basal layers of the extended epithelium. BrdU (+)/p75NGFR (+), which reflected the presence of epithelial stem cells, was detected sparsely in buccal basal epithelial cells after healing, and disappeared after 7 days. These results suggest that p75NGFR (+) keratinocytes are localized in the basal layer, which contains oral epithelial stem cells, and retain the ability to proliferate in order to regenerate the buccal mucosal epithelium.
doi:10.1267/ahc.14011
PMCID: PMC4164702  PMID: 25392568
p75; buccal mucosa; wound healing; proliferation; stem cells
16.  Ideal number of target lesions per organ to measure in metastatic colorectal cancer 
Oncology Letters  2014;8(4):1896-1900.
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guideline states that the two largest lesions per organ should be measured as target lesions for assessment of the tumor response. This criterion is considered to be arbitrary and, to the best of our knowledge, has not been supported by any objective evidence. The present study hypothesized that measuring the single largest lesion in each organ into which the cancer had metastasized (termed the modified RECIST; mRECIST 1.1) may yield the same response classification as measuring the two target lesions per organ (as per the RECIST 1.1 guideline). The medical records of patients with metastatic colorectal cancer (CRC), who received first-line chemotherapy between January 2004 and June 2013 were reviewed. The tumor responses of the patients were compared according to the two criteria using computed tomography. A total of 38 patients were included in the present study, all of whom had at least two target lesions in any one organ according to the RECIST 1.1 guidelines. When adopting the mRECIST 1.1, rather than the RECIST 1.1, 18 patients (47.4%) demonstrated an increase in the rate of change of the sum of the tumor measurements. The overall response rates of chemotherapy were 39.4% and 34.2% according to the RECIST 1.1 and the mRECIST 1.1, respectively, and the difference between the two criteria was not identified to be significantly different (P=0.226). The tumor response showed near perfect agreement between the RECIST 1.1 and mRECIST 1.1 criteria (κ=0.905). Only two patients (5.3%) showed a disagreement with regard to the tumor responses between the two criteria. Therefore, it was identified that the mRECIST 1.1 showed a high level of concordance with the original RECIST 1.1 guidelines in the tumor response assessment of metastatic CRC patients to chemotherapy. The present results indicate that the mRECIST 1.1, with a decreased number of target lesions to be measured, may be more convenient in clinical practice for the assessment of tumor response.
doi:10.3892/ol.2014.2409
PMCID: PMC4156276  PMID: 25202433
target lesion; Response Evaluation Criteria in Solid Tumors 1.1; tumor response; colorectal cancer
17.  Two Concurrent Facial Epidermal Nevi without Systemic Abnormalities: Nevus Sebaceus and Nevus Comedonicus 
Annals of Dermatology  2014;26(4):501-504.
Epidermal nevi (EN) are hamartomatous lesions derived from epidermal components originating from pluripotent cell mutations. They have been categorized according to their predominant component. The existence of >2 types of EN concurrently within a single area or within contiguous areas has been rarely reported. This report describes the case of simultaneous presence of a yellowish plaque on the left medial canthus and an aggregation of closed comedo-like papules on the right side of the cheek of a 15-year-old girl.
doi:10.5021/ad.2014.26.4.501
PMCID: PMC4135107  PMID: 25143681
Epidermal nevus; Nevus comedonicus; Nevus sebaceus
18.  Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling 
BMC Pulmonary Medicine  2014;14:122.
Background
Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways.
Methods
Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1–20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis.
Results
When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.
Conclusions
Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
doi:10.1186/1471-2466-14-122
PMCID: PMC4118077  PMID: 25069610
Asthma; Airway apoptosis; Astragalin; Eotaxin-1; Oxidative stress
19.  Distinctive Genetic Activity Pattern of the Human Dental Pulp between Deciduous and Permanent Teeth 
PLoS ONE  2014;9(7):e102893.
Human deciduous and permanent teeth exhibit different developmental processes, morphologies, histological characteristics and life cycles. In addition, their pulp tissues react differently to external stimuli, such as the pulp sensitivity test, dental trauma and pulp therapy materials. These suggest differences in gene expression and regulation, and in this study we compared gene-expression profiles of the human dental pulp from deciduous and permanent teeth. Pulp tissues from permanent premolars and deciduous molars aged 11–14 years were extirpated and mRNA was isolated for cDNA microarray analysis, and quantitative real-time PCR (qPCR). Other teeth were used for immunohistochemical analysis (IHC). Microarray analysis identified 263 genes with a twofold or greater difference in expression level between the two types of pulp tissue, 43 and 220 of which were more abundant in deciduous and permanent pulp tissues, respectively. qPCR analysis was conducted for eight randomly selected genes, and the findings were consistent with the cDNA microarray results. IHC confirmed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was broadly expressed in deciduous dental pulp tissue, but minimally expressed in permanent dental pulp tissue. Immunohistochemical analysis showed that calbindin 1 (CALB1), leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), and gamma-aminobutyric acid A receptor beta 1 (GABRB1) were abundantly expressed in permanent predentin/odontoblasts, but only minimally expressed in deciduous dental pulp tissue. These results show that deciduous and permanent pulp tissues have different characteristics and gene expression, suggesting that they may have different functions and responses to therapies focused on pulp or dentin regeneration.
doi:10.1371/journal.pone.0102893
PMCID: PMC4105481  PMID: 25047033
20.  Carnosic Acid Inhibits the Epithelial-Mesenchymal Transition in B16F10 Melanoma Cells: A Possible Mechanism for the Inhibition of Cell Migration 
Carnosic acid is a natural benzenediol abietane diterpene found in rosemary and exhibits anti-inflammatory, antioxidant, and anti-carcinogenic activities. In this study, we evaluated the effects of carnosic acid on the metastatic characteristics of B16F10 melanoma cells. When B16F10 cells were cultured in an in vitro Transwell system, carnosic acid inhibited cell migration in a dose-dependent manner. Carnosic acid suppressed the adhesion of B16F10 cells, as well as the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, urokinase plasminogen activator (uPA), and vascular cell adhesion molecule (VCAM)-1. Interestingly, secretion of TIMP-2 increased significantly in B16F10 cells treated with 10 μmol/L carnosic acid. Additionally, carnosic acid suppressed the mesenchymal markers snail, slug, vimentin, and N-cadherin and induced epithelial marker E-cadherin. Furthermore, carnosic acid suppressed phosphorylation of Src, FAK, and AKT. These results indicate that inhibition of the epithelial-mesenchymal transition may be important for the carnosic acid-induced inhibition of B16F10 cell migration.
doi:10.3390/ijms150712698
PMCID: PMC4139869  PMID: 25036034
carnosic acid; melanoma; migration; epithelial-mesenchymal transition
21.  Cell Transfection with a β-Cyclodextrin-PEI-Propane-1,2,3-Triol Nanopolymer 
PLoS ONE  2014;9(6):e100258.
Successful gene therapy necessitates safe and efficient gene transfer. This article describes the use of a cationic polymer, which was synthesized by cross-linking low molecular weight branched poly(ethylenimine) (PEI) with both β-cyclodextrin and propane-1,2,3-triol, for efficient and safe non-viral gene delivery. Experimentation demonstrated that the polymer had a pH buffering capacity and DNA condensing ability comparable to those of PEI 25 kDa. In B16-F0 cells, the polymer increased the transfection efficiency of naked DNA by 700-fold and yielded better transfection efficiencies than Fugene HD (threefold higher) and PEI 25 kDa (fivefold higher). The high transfection efficiency of the polymer was not affected by the presence of serum during transfection. In addition to B16-F0 cells, the polymer enabled efficient transfection of HepG2 and U87 cells with low cytotoxicity. Our results indicated that our polymer is a safe and efficient transfection reagent that warrants further development for in vitro, in vivo and clinical applications.
doi:10.1371/journal.pone.0100258
PMCID: PMC4067318  PMID: 24956480
22.  Anti-carcinogenic effects of non-polar components containing licochalcone A in roasted licorice root 
Nutrition Research and Practice  2014;8(3):257-266.
BACKGROUND/OBJECTIVE
Licorice has been shown to possess cancer chemopreventive effects. However, glycyrrhizin, a major component in licorice, was found to interfere with steroid metabolism and cause edema and hypertension. The roasting process of licorice modifies the chemical composition and converts glycyrrhizin to glycyrrhetinic acid. The purpose of this study was to examine the anti-carcinogenic effects of the ethanol extract of roasted licorice (EERL) and to identify the active compound in EERL.
MATERIALS/METHODS
Ethanol and aqueous extracts of roasted and un-roasted licorice were prepared. The active fraction was separated from the methylene chloride (MC)-soluble fraction of EERL and the structure of the purified compound was determined by nuclear magnetic resonance spectroscopy. The anti-carcinogenic effects of licorice extracts and licochalcone A was evaluated using a MTT assay, Western blot, flow cytometry, and two-stage skin carcinogenesis model.
RESULTS
EERL was determined to be more potent and efficacious than the ethanol extract of un-roasted licorice in inhibiting the growth of DU145 and MLL prostate cancer cells, as well as HT-29 colon cancer cells. The aqueous extracts of un-roasted and roasted licorice showed minimal effects on cell growth. EERL potently inhibited growth of MCF-7 and MDA-MB-231 breast, B16-F10 melanoma, and A375 and A2058 skin cancer cells, whereas EERL slightly stimulated the growth of normal IEC-6 intestinal epithelial cells and CCD118SK fibroblasts. The MC-soluble fraction was more efficacious than EERL in inhibiting DU145 cell growth. Licochalcone A was isolated from the MC fraction and identified as the active compound of EERL. Both EERL and licochalcone A induced apoptosis of DU145 cells. EERL potently inhibited chemically-induced skin papilloma formation in mice.
CONCLUSIONS
Non-polar compounds in EERL exert potent anti-carcinogenic effects, and that roasted rather than un-roasted licorice should be favored as a cancer preventive agent, whether being used as an additive to food or medicine preparations.
doi:10.4162/nrp.2014.8.3.257
PMCID: PMC4058558
Roasted licorice roots; apoptosis; licochalcone A; cancer
23.  Arnold-Chiari Malformation Type III With Meningoencephalocele: A Case Report 
Annals of Rehabilitation Medicine  2014;38(3):401-404.
Arnold-Chiari malformation type III (CM III) is an extremely rare anomaly with poor prognosis. An encephalocele with brain anomalies as seen in CM II, and herniation of posterior fossa contents like the cerebellum are found in CM III. The female infant was a twin, born at 33 weeks, weighing 1.7 kg with a huge hydrocele on the craniocervical junction. After operations were performed, she was referred to the department of rehabilitation medicine for poor motor development, swallowing dysfunction, and poor eye fixation at 22 months. The child was managed with neurodevelopmental treatment, oromotor facilitation, and light perception training. After 14 months, improvement of gross motor function was observed, including more stable head control, rolling, and improvement of visual perception. CM III has been known as a condition with poor prognosis. However, with the improvement in operative techniques and intensive rehabilitations, the prognosis is more promising than ever before. Therefore, more attention must be paid to the rehabilitation issues concerning patients with CM III.
doi:10.5535/arm.2014.38.3.401
PMCID: PMC4092183  PMID: 25024966
Chiari III malformation; Developmental disabilities; Cortical blindness; Rehabilitation
24.  Evolving Marine Biomimetics for Regenerative Dentistry 
Marine Drugs  2014;12(5):2877-2912.
New products that help make human tissue and organ regeneration more effective are in high demand and include materials, structures and substrates that drive cell-to-tissue transformations, orchestrate anatomical assembly and tissue integration with biology. Marine organisms are exemplary bioresources that have extensive possibilities in supporting and facilitating development of human tissue substitutes. Such organisms represent a deep and diverse reserve of materials, substrates and structures that can facilitate tissue reconstruction within lab-based cultures. The reason is that they possess sophisticated structures, architectures and biomaterial designs that are still difficult to replicate using synthetic processes, so far. These products offer tantalizing pre-made options that are versatile, adaptable and have many functions for current tissue engineers seeking fresh solutions to the deficiencies in existing dental biomaterials, which lack the intrinsic elements of biofunctioning, structural and mechanical design to regenerate anatomically correct dental tissues both in the culture dish and in vivo.
doi:10.3390/md12052877
PMCID: PMC4052322  PMID: 24828293
regenerative dentistry; biomimetics; marine invertebrates; bone; dentine
25.  Pax6 Expressed in Osteocytes Inhibits Canonical Wnt Signaling 
Molecules and Cells  2013;35(4):305-312.
The transcription factor Pax6, which belongs to the paired box-containing gene family, regulates developmental processes, especially in the eyes, central nervous tissues and craniofacial structures. However, the role of Pax6 in bone has never been studied exclusively. Here we report that Pax6 is expressed at both the mRNA and protein level in the calvaria and long bones of adult mice as well as osteocyte-like MLOY4 cells and suppresses the canonical Wnt signaling pathway. Moreover, the expression levels of Pax6 were much higher in the calvaria than the long bones, and Pax6 was also expressed at E16 to E18 in both the calvaria and long bones. Knockdown of Pax6 in MLOY4 cells did not affect cell proliferation or survival; however, the expression of Sost, an osteocyte marker gene, was significantly decreased. In addition, the overexpression of Pax6 suppressed the canonical Wnt signaling pathway by enhancing the expression of Sost. Furthermore, we also demonstrated that Pax6 binds to the Sost promoter and that stimulation of Sost transcription by Pax6 was dependent on a specific Pax6-binding sequence within the promoter. In conclusion, the results of the present study suggest that Pax6 is expressed in bone and may play an important role in osteocyte differentiation by controlling canonical Wnt signaling.
doi:10.1007/s10059-013-2310-0
PMCID: PMC3887889  PMID: 23529217
canonical Wntβ-catenin signaling; osteocytes; Pax6; Sost; Wnt3a

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