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Background and Objectives: Vitamin D is a bone modulator widely used in regenerative medicine. This study aimed to analyze the effects of vitamin D on the osteogenic differentiation and mineralization of human mesenchymal stem cells. Materials and Methods: Spheroids were fabricated using human bone marrow-derived stem cells, and were cultured in the presence of vitamin D at concentrations of 0, 0.1, 1, 10, and 100 nM. Stem cell spheroids were fabricated and the morphological evaluation was conducted on days 1, 3, 7 and 14. Determination of qualitative cellular viability was performed with Live/Dead Kit assay on days 1 and 7. Quantitative cellular viability was evaluated with Cell Counting Kit-8 on days 1, 3, 7, and 14. To analyze the osteogenic differentiation of cell spheroids, alkaline phosphatase activity assays were performed with commercially available kit on days 7 and 14. Real-time polymerase chain reaction was used to determine the expression levels of RUNX2, BSP, OCN, and COL1A1 on days 7 and 14. Results: The stem cells produced well-formed spheroids, and addition of vitamin D did not result in any noticeable changes in the shape. The addition of vitamin D did not significantly change the diameter of the spheroids at 0, 0.1, 1, 10, or 100 nM concentrations. Quantitative cell viability results from days 1, 3, 7 and 14 showed no significant difference between groups (p &gt, 0.05). There was significantly higher alkaline phosphatase activity in the 0.1 nM group when compared with the control group on day 14 (p &lt, 0.05). Real-time polymerase chain reaction results demonstrated that the mRNA expression levels of RUNX2, OCN, and COL1A1 were significantly increased when vitamin D was added to the culture. Conclusions: Based on these findings, we concluded that vitamin D could be applied to the increased osteogenicity of stem cell spheroids.

Background: Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using a hospital cohort. Methods: This nested case-control study included type 2 diabetic patients over the age of 18 years without a history of hearing loss. Of these, 1379 patients newly diagnosed with SNHL or tinnitus were classified as cases, and 5512 patients matched to the cases based on age, sex, and index year were classified as controls. Chi-squared tests were used to compare categorical variables between the two groups. Odds ratios (ORs) and adjusted odds ratios (AOR) were calculated from univariate and multivariable unconditional logistic regression analyses, respectively. Results: There was a significant difference in the prevalence of statin use between the cases and controls (53.7% vs. 61.2%, respectively, p &lt, 0.001). The use of statins in type 2 diabetic patients significantly reduced the risk of SNHL or tinnitus by 24.8% (95% CI 14.2–34.1%, p &lt, 0.001) after controlling for confounders. Similar results were found for the association between statin use and SNHL (AOR = 0.706, 95% CI 0.616–0.811, p &lt, 0.001). The protective effects of statins against SNHL were consistent regardless of age and sex. Conclusion: The use of statins for type 2 diabetic patients was significantly associated with a reduced risk of SNHL, regardless of age and sex. Further studies are needed, especially large cohort studies, to evaluate the long-term protective effects of statins.

Background This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA‐3. Patients and Methods In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)–fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo‐fulvestrant. Median overall survival (OS) and progression‐free survival were estimated using the Kaplan‐Meier method. Results Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib‐fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56–1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63–1.32]) versus placebo‐fulvestrant. Conclusion Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135). Implications for Practice Prognostic factors for overall survival in HR+/HER2− advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression‐free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib‐fulvestrant if they receive the combination before chemotherapy in the advanced setting., This article focuses on whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer in patients from the PALOMA‐3 clinical trial.

Background: Connective tissue growth factor (CTGF) is a cellular communication network factor family protein involved in many cellular functions. The purpose of this study was to determine the effects of CTGF on the proliferation, osteogenic capacity, and mRNA expression of spheroids composed of gingiva-derived mesenchymal stem cells (GMSCs). Methods: CTGF was applied at final concentrations of 0, 25, 50, 100, and 200 ng/mL. Qualitative cell viability was determined using Live/Dead kit assay. Metabolic viability was determined with a colorimetric assay kit. Osteogenic activity was analyzed with alkaline phosphatase activity and Alizarin Red S staining. Quantitative polymerase chain reaction (qPCR) was used to assess the expression levels of RUNX2, BSP, OCN, and COL1A1. Results: In general, there was no significant difference in cell viability between the groups on Days 1, 4, and 7. Addition of CTGF produced an increase in Alizarin Red S staining. qPCR results demonstrated that the mRNA expression levels of RUNX2, BSP, OCN, and COL1A1 were significantly increased with the addition of CTGF. Conclusions: Based on these findings, we conclude that CTGF can be applied for increased osteogenic differentiation of stem cell spheroids.

Background and objectives: NELL-1 is a competent growth factor and it reported to target cells committed to the osteochondral lineage. The secreted, osteoinductive glycoproteins are reported to rheostatically control skeletal ossification. This study was performed to determine the effects of NELL-1 on spheroid morphology and cell viability and the promotion of osteogenic differentiation of stem cell spheroids. Materials and Methods: Cultures of stem cell spheroids of gingiva-derived stem cells were grown in the presence of NELL-1 at concentrations of 1, 10, 100, and 500 ng/mL. Evaluations of cell morphology were performed using a microscope, and cell viability was assessed using a two-color assay and Cell Counting Kit-8. Evaluation of the activity of alkaline phosphatase and calcium deposition assays involved anthraquinone dye assay to determine the level of osteogenic differentiation of cell spheroids treated with NELL-1. Real-time quantitative polymerase chain reaction (qPCR) was used to evaluate the expressions of RUNX2, BSP, OCN, COL1A1, and β-actin mRNAs. Results: The applied stem cells produced well-formed spheroids, and the addition of NELL-1 at tested concentrations did not show any apparent changes in spheroid shape. There were no significant changes in diameter with addition of NELL-1 at 0, 1, 10, 100, and 500 ng/mL concentrations. The quantitative cell viability results derived on Days 1, 3, and 7 did not show significant disparities among groups (p &gt, 0.05). There was statistically higher alkaline phosphatase activity in the 10 ng/mL group compared with the unloaded control on Day 7 (p &lt, 0.05). A significant increase in anthraquinone dye staining was observed with the addition of NELL-1, and the highest value was noted at 10 ng/mL (p &lt, 0.05). qPCR results demonstrated that the mRNA expression levels of RUNX2 and BSP were significantly increased when NELL-1 was added to the culture. Conclusions: Based on these findings, we conclude that NELL-1 can be applied for increased osteogenic differentiation of stem cell spheroids.

The growth of bone morphogenetic protein 7 (BMP-7) has been applied for tissue regeneration due to its osteoinductive properties. The aim of this research is to analyze the enhancing effects of BMP-7 on the osteogenic differentiation and mineralization of human bone marrow-derived stem cells cultured on the bovine bone particle. After the stem cells were loaded onto the bone graft material, their morphology was observed on day 7. Viability assays based on the application of fluorescent stains were used for qualitative analyses. Alkaline phosphatase activity assays and Alizarin red staining were used for the assessment of osteogenic differentiation on days 7 and 14. Next-generation mRNA sequencing was applied to evaluate global gene expression. Gene ontology and pathway analysis was used to propose the underlying mechanism. Fibroblast-like morphology was attained with the stem cells. The cells were shown to be firmly attached to the bone particle. Most of the stem cells produced an intense green fluorescence. The relative cellular viability assay values for BMP-7 groups at 0, 10, and 100 ng/mL on day 7 were 0.295 ± 0.003, 0.250 ± 0.002, and 0.240 ± 0.003, respectively (p &lt, 0.05). Alkaline phosphatase activity was significantly higher in BMP-7 groups at concentration of 100 ng/mL compared to the control on days 7 and 14 (p &lt, 0.05). The results of the mineralization assay showed significantly higher values for BMP-7 groups at 100 ng/mL concentration when compared with the control (p &lt, 0.05). The expression of RUNX2 was increased with application of BMP-7 and mitogen-activated protein kinase pathway was associated with the target genes. Overall, this study shows that in vitro application of BMP-7 increases alkaline phosphorylase activity and mineralization of stem cells culture on deproteinized bovine bone mineral. The study suggests that combining stem cells with osteoinductive growth factors with scaffolds can have synergy effects on osteogenic differentiation.

Background and Objectives: Cuminum cyminum L. has long been used in the treatment of various diseases in multiple geographical regions. This study was performed to determine the effects of C. cyminum methanolic extract (CCT) on the cellular viability, alkaline phosphatase activity and mineralization of human mesenchymal stem cells. Materials and Methods: Bone marrow-derived stem cells were cultured in the presence of CCT at concentrations of 0, 0.001, 0.01, 0.1 and 1 &mu, g/mL. Evaluations of cell morphology were performed on days 1, 3, 7 and 14. Cellular viability was evaluated on days 1, 3, 5 and 7. On the 7th and 14th day, alkaline phosphatase activity measurements and Alizarin red S staining were conducted to assess the osteogenic differentiation of stem cells. A real-time polymerase chain reaction was used to determine the expression levels of RUNX2, BSP, OCN, COL2A1 and &beta, catenin mRNAs. Results: Stem cells in the control group showed fibroblast-like morphology and the addition of CCT at 0.001, 0.01, 0.1 and 1 &mu, g/mL did not generate noticeable changes in morphology compared with the untreated control group. The application of CCT did not produce significant changes in cellular viability or alkaline phosphatase activity compared with controls. Alizarin Red S staining was significantly increased with the application of CCT. Treatment with CCT increased the expressions of RUNX2, BSP and OCN. Conclusions: These results indicate that CCT enhanced the osteogenic differentiation of stem cells derived from bone marrow by regulating the expressions of RUNX2, BSP and OCN. Thus, the use of CCT may be applied to achieve beneficial effects on the mineralization of stem cells.

Insulin-like growth factors (IGFs) plays various roles, including differentiation and mitogenesis, and IGFs are reported to regulate the bone growth and maintenance. This study was performed to analyze the enhancing effects of IGF-2 on osteogenic differentiation and the mineralization of stem cells cultured on deproteinized bovine bone mineral. Stem cell loaded bone graft material was cultured in the presence of the IGF-2 at final concentrations of 10 and 100 ng/mL and the morphology of the cells was observed on Days 1, 3, and 7. The commercially available, two-color assay based on plasma membrane integrity and esterase activity was also used for qualitative analyses on Days 1, 3, and 7. The level of alkaline phosphatase activity and anthraquinone dye assay were used to evaluate osteogenic differentiation on Days 7 and 14. Real-time polymerase chain reaction was applied in order to identify the mRNA expression of BGLAP, Runx2, and &beta, catenin. The stem cells were well-attached with fibroblast morphology and most of the stem cells produced a high intensity of green fluorescence, indicating that there were live cells on Day 1. The relative cellular viability assay values for IGF-2 groups at 0, 10, and 100 ng/mL on Day 1 were 0.419 &plusmn, 0.015, 0.427 &plusmn, 0.013, and 0.500 &plusmn, 0.030, respectively (p &lt, 0.05). The absorbance values at 405 nm for alkaline phosphatase activity on Day 7 for IGF-2 at 0, 10, and 100 ng/mL were 2.112 &plusmn, 0.152, 1.897 &plusmn, 0.144, and 2.067 &plusmn, 0.128, respectively (p &gt, 0.05). The mineralization assay results at Day 7 showed significantly higher values for IGF-2 groups at 10 and 100 ng/mL concentration when compared to the control (p &lt, 0.05). The application of IGF-2 groups of 10 and 100 ng/mL produced a significant increase of BGLAP. Conclusively, this study indicates that the use of IGF-2 on stem cell loaded bone graft increased cellular viability, Alizarin red staining, and BGLAP expression of stem cells. This report suggests the combined approach of stem cells and IGF-2 with scaffold may have synergistic effects on osteogenesis.

The purpose of this case report was to introduce the concept of orthodontic and orthopedic treatment for a growing patient with Tessier number 0 cleft. A 5-year-old boy patient with Tessier number 0 cleft presented congenitally missing maxillary central incisors (MXCI), a bony defect at the premaxilla, a constricted maxillary arch, an anterior openbite, and maxillary hypoplasia. His treatment was divided into three stages: management of the bony defect at the premaxilla and the congenitally missing MXCIs using a fan-type expansion plate, iliac bone grafting, and eruption guidance of the maxillary lateral incisors into the graft area for substitution of MXCIs; management of the maxillary hypoplasia using sequential facemask therapy with conventional and skeletal anchorage; and management of the remaining occlusal problems using fixed orthodontic treatment. The total treatment duration was 15 years and 10 months. Class I canine and Class II molar relationships and normal overbite and overjet were achieved at the end of treatment. Although the long-term use of facemask therapy resulted in significant protraction of the retrusive maxilla, the patient exhibited Class III profile because of continued mandibular growth. However, the treatment result was well maintained after 2 years of retention. The findings from this case suggest that interdisciplinary and customized approaches are mandatory for successful management of maxillary hypoplasia, bony defect, and dental problems in Tessier number 0 cleft. Moreover, considering the potential of orthognathic surgery or distraction osteogenesis, meticulous monitoring of mandibular growth until growth completion is important.

Background The epidemiology of Adamantiades-Behcet's disease varies among ethnic populations worldwide. Trends in the incidence of Adamantiades-Behcet's disease have not been investigated based on the Korean National Health Insurance database. Objectives This study investigated the incidence and mortality of Adamantiades-Behcet's disease by age using nationwide population data in Korea. Methods A nationwide population-based cohort study was performed using the Korean National Health Insurance Claims Database from 2006 to 2015. The incidence of Adamantiades-Behcet's disease was calculated by age, sex, calendar year and habitat. And comorbid metabolic diseases were also analysed in patients with Adamantiades-Behcet's disease. Results The annual incidence of Adamantiades-Behcet's disease per 100 000 person-years was 3.976 (2.587 for males and 5.373 for females) from 2006 to 2015. The incidence of Adamantiades-Behcet's disease peaked among people in their 40s (6.561 per 100 000 person-years). Incidence was significantly higher in subjects with comorbid metabolic conditions, such as diabetes mellitus, hypertension and dyslipidemia. The mortality rate per 1000 person-years increased with age in patients with Adamantiades-Behcet's disease. Conclusions This study showed the incidence, prevalence and mortality of Adamantiades-Behcet's disease. Metabolic conditions increased the risk of Adamantiades-Behcet's disease among Koreans.

The purpose of this study was to investigate the amount and pattern of postsurgical relapse after 2-jaw surgery in cleft lip and palate patients in terms of the sagittal and vertical aspects. The samples consisted of 21 adult patients who had the similar initial skeletodental pattern before surgery and underwent 2-jaw surgery. They were divided into high relapse (n = 11) and low relapse groups (n = 10) (criteria, 30% forward relapse of the B point). After the cephalometric variables of cephalograms taken at 1 month before surgery (T0), immediately after surgery (T1), and at least 1 year after surgery (T2) were measured, the Wilcoxon test, Mann-Whitney U test, and Pearson correlation test were performed for statistical analysis. When compared with the low relapse group, the high relapse group exhibited significant counterclockwise rotation of the distal segment of the mandible resulting in more forward movement of the mandible and significant labioversion of the maxillary incisors during T1-T2. The amount of postsurgical relapse of the mandible had a positive relationship with the amounts of setback and clockwise rotation of the mandible with surgery. In addition, the more decrease in overbite through surgery occurred, the more relapse (forward movement of the mandible) produced. Therefore, for the prevention of significant postsurgical relapse of the mandible in cleft patients, it is necessary to reduce unnecessary clockwise rotation of the mandible and to increase the vertical stability of maxilla during orthognathic surgery.

Although there are several studies on the association between use of proton pump inhibitors (PPIs) and increased Clostridium difficile infection (CDI) risk, detailed studies analyzing the effects of PPI use on CDI risk are lacking. The present study investigated the association of the dose, duration, and types of PPIs with CDI risk. A single-center, cohort study was conducted on patients admitted to a hospital. The exposed cohort comprised patients who were prescribed PPIs at least once during the study period, and a control cohort was prepared by randomly assigning an index date to patients who did not use PPIs ensuring the same distribution of index dates as in the exposed cohort and matching sex, age, hospitalization period, and date of admission. PPI use increased the risk of CDI by 1.8-fold [95% confidence interval (CI) 1.5–2.2]. CDI risk increased by 1.8-fold with esomeprazole (95% CI 1.4–2.2) and 2.0-fold with pantoprazole (95% CI 1.5–2.8). Patients who used a high dose had a higher risk than those who used a medium dose [adjusted hazard ratio (HR) 2.0 vs 1.3]. The risk of CDI increased 4.2-fold when the PPI exposure period was 6 days or shorter than 6 days. Our study showed that PPI use was associated with an increased risk of developing CDI and the risk of CDI was dose dependent. Therefore, PPIs should only be used at proper doses and only for the necessary indications to avoid CDI risk.

Objective Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, which progresses from precursor lesions with no symptom if left untreated. We compared the risk of cervical dysplasia among HPV-positive Korean women based on HPV types and infection patterns. Methods We observed participants of a 5-year multicenter prospective cohort study, comprising HPV-positive women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion of the cervix at their enrollment. Follow-ups, comprising cytology and HPV DNA testing results, were included in the final analysis. Incidence was calculated for each infection pattern (persistent infection, incidental infection, and clearance). To investigate cervical dysplasia risk, we used Cox proportional hazard models adjusted for variables that were significantly different among infection patterns. From April 2010 to September 2017, 71 of 1,027 subjects developed cervical dysplasia more severe than high-grade squamous intraepithelial lesion of the cervix. Results Of these 71 subjects, persistent infection, incidental infection, and clearance were noted in 30, 39, and 2 individuals, respectively. Based on changes in DNA results during follow-up, cumulative incidence was 27.2%, 10.4%, and 0.5% for persistent infection, incidental infection, and clearance, respectively. Compared to clearance, the adjusted hazard ratios for cervical dysplasia were 51.6 and 24.1 for persistent and incidental infections, respectively (p

Prior studies have reported the presence of lung fibrosis and enhanced airway hyperresponsiveness (AHR) in mice with high-fat-diet (HFD)-induced obesity. This study evaluated the role of TGF-β1 in HFD-induced AHR and lung fibrosis in a murine model. We generated HFD-induced obesity mice and performed glucose and insulin tolerance tests. HFD mice with or without ovalbumin sensitization and challenge were also treated with an anti-TGF-β1 neutralizing antibody. AHR to methacholine, inflammatory cells in the bronchoalveolar lavage fluid (BALF), and histological features were evaluated. Insulin was intranasally administered to normal diet (ND) mice, and in vitro insulin stimulation of BEAS-2b cells was performed. HFD-induced obesity mice had increased insulin resistance, enhanced AHR, peribronchial and perivascular fibrosis, and increased numbers of macrophages in the BALF. However, they did not have meaningful eosinophilic or neutrophilic inflammation in the lungs compared with ND mice. The HFD enhanced TGF-β1 expression in the bronchial epithelium, but we found no differences in the expression of interleukin (IL)−4 or IL-5 in lung homogenates. Administration of the anti-TGF-β1 antibody attenuated HFD-induced AHR and lung fibrosis. It also attenuated goblet cell hyperplasia, but did not affect the AHR and inflammatory cell infiltration induced by OVA challenge. The intranasal administration of insulin enhanced TGF-β1 expression in the bronchial epithelium and lung fibrosis. Stimulating BEAS-2b cells with insulin also increased TGF-β1 production by 24 h. We concluded that HFD-induced obesity-associated insulin resistance enhances TGF-β1 expression in the bronchial epithelium, which may play an important role in the development of lung fibrosis and AHR in obesity., Obesity: A trigger for asthma onset Insulin resistance may be an important causative factor underlying the increased risk of asthma and other respiratory issues in obese individuals. Obesity doubles the likelihood of developing asthma, with symptoms that are more difficult to control than in non-obese patients. The connection between these conditions is poorly understood, but researchers led by Jung-Won Park, Yonsei University College of Medicine, Seoul, South Korea, have identified a potential mechanism. They demonstrated that a signaling molecule called TGF-β1 contributes to airway sensitivity and tissue scarring in a mouse model of diet-induced obesity. Subsequent experiments showed that treatment with insulin also gives rise to increased TGF-β1 production in the mouse lung. Since insulin resistance is a common feature of obesity, resulting in abnormally high levels of circulating insulin, this could also account for the increased risk of respiratory problems.

Gefitinib is an oral tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) for non-small-cell lung cancer with EGFR mutations. Although a few studies have analyzed the causes of gefitinib-induced hepatotoxicity, research focusing on the time intervals before and after hepatotoxicity has yet to be reported. Therefore, this study investigated two types of factors: the time to reach gefitinib-induced hepatotoxicity and the time for recovery. From January 2013 to December 2014, a retrospective study was carried out on 473 non-small-cell lung cancer patients who were treated with gefitinib. The following data were collected: sex, age, body weight, height, body surface area, underlying disease, Eastern Cooperative Oncology Group Performance Status, smoking history, gefitinib dose, EGFR mutation, and concomitant drugs. Multivariate models showed that patients with mutations in exon 19 had around two-fold higher hepatotoxicity (≥grade 2). Use of CYP3A4 inhibitors and smoking shortened time to hepatotoxicity ∼5-2-fold, respectively, whereas mutations in exon 21 prolonged time to hepatotoxicity by about 2.4-fold. Termination of gefitinib therapy showed 3.8-fold faster recovery. Our study showed that the concomitant use of CYP3A4 inhibitors, smoking, and exon 21 affected the time to reach gefitinib-induced hepatotoxicity. Among the factors examined in this study including hepatotonic use and gefitinib termination, only cessation of gefitinib therapy significantly accelerated recovery.

CD93 is a membrane-associated glycoprotein, which can be released in a soluble form (sCD93) into the serum. CD93 has received renewed attention as a candidate biomarker of inflammation in various inflammatory and immune-mediated diseases, including asthma.We aimed to evaluate the effects of airway inflammation on CD93 levels in murine models.We established an ovalbumin (OVA)-induced acute asthma murine model (OVA model) and a lipopolysaccharide (LPS)-induced airway inflammation murine model (LPS model). Dexamethasone was administered by gavage to attenuate the airway inflammation.The OVA model demonstrated typical allergic asthma features with increased airway hyper-responsiveness, inflammatory cell infiltration, increased Th2 cytokine levels, compared to the control group. CD93 levels were decreased in lung homogenates and, respiratory epithelial cells, whereas serum sCD93 levels were increased in the OVA model, as compared to the control group. Dexamethasone reversed these effects of OVA. In contrast, in the LPS model, CD93 levels were not affected in neither respiratory epithelial cells nor serum.Our findings demonstrate the potential of using sCD93 as a biomarker for allergic asthma.

The purpose of this study was to compare the alignment pattern of the constricted maxillary dental arch by fixed orthodontic treatment (FOT) in the well-aligned and constricted arches of unilateral cleft lip and palate (UCLP) patients. 19 UCLP patients were divided into Group 1 (well-aligned arch, n = 9) and Group 2 (constricted arch, n = 10). After the cephalometric and maxillary dental arch variables before (T1) and after FOT (T2) were measured, statistical analysis was performed. There were no significant differences in the surgical timing of cheiloplasty, palatoplasty, and secondary alveolar bone grafting and in the surgical method of cheiloplasty between the 2 groups. However, Group 2 had a higher percentage of palatoplasty method, which could leave the denuded bone for secondary healing than Group 1 (P < 0.05). Although Group 2 showed more constriction and asymmetry in the maxillary dental arch compared to Group 1 at the T1 stage (inter-second premolar width, greater segment angle [GSA], and lesser segment angle [LSA], all P < 0.05), these problems could be effectively resolved by FOT. As a result, at the stage T2, there was no significant difference in all the variables between the 2 groups. During T1-T2, there was a different pattern in change of variables between Groups 1 and 2 (anterior segment angle in the greater segment [P < 0.05] in Group 1 and U1-SN [P < 0.01], inter-molar width [P < 0.05], GSA [P < 0.05[, and LSA [P < 0.01] in Group 2). Therefore, according to the maxillary dental arch shape, different strategy is necessary to obtain proper alignment by FOT.

Childhood and adolescence are critical periods that affect adults’ health status. Therefore, the factors influencing the health of children and adolescents should be analyzed. In Korea, a wide range of youth-related health data has been obtained, both on the regional level and on the national level. This report summarizes the current status of studies related to the health of Korean children and adolescents. Data for which open access is offered include the Korea Youth Risk Behavior Web-based Study, the Panel Study on Korean Children, the Korean Youth Panel Survey, the Korean Children and Youth Panel Survey, and the Student Health Examination. In addition, the Health Examination of Korean Youth Outside of School, the Korean Children and Adolescents Obesity Cohort Study, the Korean Children’s Environmental Health Study, the Korea Youth Media Use and Harmful Environment Survey, the Comprehensive Survey of Korean Youth, and the Multicultural Adolescents Panel Study are summarized.

Reactive oxygen species (ROS) are important contributors to tumor cell invasion. ROS enhanced by reactive oxygen species modulator 1 (Romo1) expression has been reported to increase invasive potential and constitutive activation of nuclear factor-κB (NF-κB) in hepatocellular carcinoma (HCC). Therefore, we investigated whether constitutive NF-κB activation due to Romo1 expression is associated with breast cancer tumor cell invasion. In this study, we show that oxidative stress-induced invasion is mediated by Romo1 expression. The Romo1-induced increase of invasive activity was blocked by an inhibitor of κB kinase (IKK). These results demonstrate that tumor cell invasion in response to oxidative stress is associated with Romo1 expression and the NF-κB signaling pathway. Romo1 is therefore a promising therapeutic target for diseases characterized by NF-κB deregulation.

Zinc Oxide nanoparticles (ZnO NPs) in its small size with large reactive surfaces can lead to toxicological injury by generating reactive oxygen species (ROS) and oxidative stress. Recently, ZnO NPs were shown to play a role in acute or chronic toxicities with mammalian cells, where its mechanism of toxicity is not fully characterized yet. In this study, the potential mechanisms of ZnO NPs in inducing and increasing oxidative stress for causing cellular apoptosis were investigated with human keratinocytes. Indeed, ZnO NPs induced significant intracellular ROS and mitochondrial ROS productions. And it seemed that cellular ROS levels induced by ZnO NPs led to the dissipation of the mitochondrial membrane potentials and elicited the cellular apoptosis. The induced ROS production by ZnO NPs was blocked with chelator treatment, which inhibited the ZnO ion. The present study demonstrates that increased levels of ROS by ZnO NPs cause mitochondrial dysfunction and cellular apoptosis.

Background No clear association between hepatitis B virus (HBV) infection and atopic dermatitis (AD) has been established. Some studies have reported that subjects with HBV had an increased risk of atopy; other studies reported an inverse association between HBV seropositivity and allergic diseases. Objective We evaluated the association between AD and hepatitis B antigen (HBsAg) positivity using Korean National Health and Nutrition Examination Survey data. Methods In total, 14,776 participants aged > 19 years were included in the analysis. Multiple logistic regression analyses were used to evaluate the odds ratio of HBsAg positivity in association with AD and asthma. Results: The prevalence of HBsAg positivity was lower in individuals with AD than in those without AD (mean [SE], 0.7% [0.4] vs. 3.7% [0.2]; P < 0.001). However, HBsAg positivity was not significantly associated with asthma (3.7% [0.2] vs. 2.8% [0.8]; P < 0.001). HBsAg positivity decreased the risk of AD significantly (OR = 0.223; 95% CI = 0.069–0.72). Conclusions This study demonstrates an inverse association between AD and HBsAg positivity using a nationwide, population-based, cross-sectional health examination and survey. This article is protected by copyright. All rights reserved.

Quantum dots (QDs) have shown great potential for biomedical use in a broad range including diagnostic agents. However, the regulatory mechanism of dermal toxicity is poorly understood. In this study, we investigated how QDs-induced apoptosis is regulated in human keratinocytes. We also examined the effect of carboxylic acid-coated QDs (QD 565 and QD 655) on reactive oxygen species (ROS) production and apoptosis-related cellular signalling. The viability of keratinocyte was inhibited by two types of QDs in a concentration-dependent manner. QDs induce ROS production and blockade of AKT phosphorylation. Moreover, the cleavage of AKT-dependent pro-apoptotic proteins such as poly (ADP-ribose) polymerase, caspases-3 and caspases-9 was significantly increased. We also found that a decrease in cellular ROS level by ROS scavenger, N-acetylcysteine (NAC), resulting in the abolishment of QDs-induced AKT de-phosphorylation and cellular apoptosis. Interestingly, QD 655 had a more cytotoxic effect including oxidative stress and AKT-dependent apoptosis than QD 565. In addition, QD 655 had the cytotoxic potential in the human skin equivalent model (HSEM). These data show that QD-induced intracellular ROS levels may be an important parameter in QD-induced apoptosis. These findings from this study indicate that intracellular ROS levels might determine the apoptotic potential of keratinocyte by QD via blockade of AKT phosphorylation.

PURPOSE CD93 is receiving renewed attention as a biomarker of inflammation. We aimed to evaluate the potential for serum sCD93 to serve as a novel biomarker for allergic inflammation. MATERIALS AND METHODS We enrolled 348 subjects with an allergic disease [allergic rhinitis (AR), chronic spontaneous urticaria (CSU), or bronchial asthma (BA)], including 14 steroid-naive BA patients who were serially followed-up. RESULTS The serum sCD93 levels (ng/mL) in patients with exacerbated AR (mean±standard deviation, 153.1±58.4) were significantly higher than in patients without AR (132.2±49.0) or with stable AR (122.3±42.1). Serum sCD93 levels in exacerbated CSU (169.5±42.8) were also significantly higher than those in non-CSU (132.4±51.6) and stable CSU (122.8±36.2). This trend was also seen in BA. Serum levels in patients with ICS-naive BA (161.4±53.1) were significantly higher than those in healthy controls without BA (112.2±30.8), low- and medium-dose ICS users. Serum sCD93 levels in high-dose ICS users (72.2±20.6) were significantly lower than those in low- and medium-dose users. The serum sCD93 levels in steroid-naive patients with BA (195.1±72.7) decreased after ICS use for 4 weeks (134.4±42.8) and 8 weeks (100.7±13.4), serially. CONCLUSION Elevated serum sCD93 levels reflected exacerbated status of allergic diseases, including CSU, AR, and asthma. ICS use significantly diminished serum sCD93 levels in steroid-naive patients with BA. This result may suggest sCD93 in serum as a therapeutic marker for allergic inflammation.

Background The area of nanotechnology continues to expand rapidly and zinc oxide (ZnO) nanoparticles (NPs) are widely being used in cosmetics and sunscreens. Although ZnO-NPs are considered materials that can potentially cause skin inflammation, the underlying mechanisms remain elusive. Objective The aim of this study was to investigate the signaling pathways of a cutaneous inflammatory response induced by ZnO-NPs. ZnO-NPs increased the early growth response-1 (Egr-1) expression, promoter activity and its nuclear translocation in HaCaT cells. Methods HaCaT cells and primary keratinocytes were exposed to ZnO NPs over a range of doses and time course. Protein levels and mRNA levels of Egr-1 and mitogen-activated protein kinase (MAPK) were measured by Western blot and ELISA, respectively. As an in vivo study, ZnO-NPs were applicated on mouse skin, and immunohistochemical stain with TNF-α and Egr-1 was done. Results ZnO-NPs activated extracellular signal-regulated kinase (ERK) of MAPK pathways. The up-regulation of Egr-1 expression by ZnO-NPs stimulation was found to be inhibited by an ERK inhibitor, but by neither c-Jun-N-terminal kinase (JNK) nor p38 inhibitor. Antioxidative N-acetyl-cysteine (NAC) strongly inhibited the level of Egr-1 and phosphorylated ERK expression in ZnO-NPs treated cells. ZnO NPs also increased tumor necrosis factor (TNF)-α expression and secretion, which were inhibited by the blockade of Egr-1 expression. Conclusions The present study demonstrated that ZnO-NPs might induce inflammatory response via ROS-ERK-Egr-1 pathway in human keratinocytes.

Background: Silica nanoparticles (SNPs) can easily enter in respiratory system via inhalation because of their low molecular weight and ease of dispersion. Toxicity and adverse effects of SNPs vary according to the physical characteristics of the particle. Methods: To evaluate the toxic and adjuvant effects of 3 types of SNPs in the airway system, six-week-old female BALB/c mice were intranasally administered 3 types of SNPs (spherical [S-SNP], mesoporous [M-SNP], and polyethylene glycol-conjugated [P-SNP]) alone or SNPs/ovalbumin (OVA), three times weekly for 2 weeks. Airway hyper-responsiveness (AHR), bronchoalveolar lavage fluid (BALF), cytokine levels, and histology of the lungs were analyzed. Results: The S-SNPs/OVA group and M-SNPs/OVA group showed significant AHR, compared to the control group. Among all SNP-treated groups, the group administered SNPs/OVA showed greater inflammatory cell infiltration in BALF, extensive pathological changes, and higher cytokine levels (IL-5, IL-13, IL-1 beta, and IFN-gamma) than those administered SNPs alone or saline/OVA. Conclusion: Exposure to SNPs alone and SNPs/OVA induced toxicity in the respiratory system. SNPs alone showed significant toxic effects on the airway system. Meanwhile, SNPs/OVA exerted adjuvant effects to OVA of inducing allergic airway inflammation. In particular, M-SNPs showed the most severe airway inflammation in both direct toxicity and adjuvant effect assays. P-SNPs induced less inflammation than the other types of SNPs in both models.

Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma.

There is increasing interest in the therapeutic potential of stem cells because stem cells are promising candidates for the regeneration of tissue and treatment of diseases. Increasing evidence supports, multipotent stem cells may be obtained postnatally in different organs and tissues including bone marrow, synovium, adipose tissue, muscle and dental pulp. To determine a suitable cell source, the stem cells derived from periosteum and bone marrow of jaw bone(mandible) and long bone(tibia) were compared using rabbit models (JPO: periosteum from jaw-bone, JBM: bone marrow from jaw-bone, LPO: periosteum from long-bone, and LBM: bone marrow from long-bone). This study evaluated the proliferation and multilineage differentiation of the cells and clearly showed that expansion ability of JPO was higher than that of bone marrow derived cells. Comparisons of four different stem cells indicated that JPO group is the highest osteogenic potential. Moreover, this study has demonstrated that JPO, JBM and LBM are superior in terms of osteogensis and JPO, LPO and LBM are superior in terms of chondrogensis. Collectively, stem cells derived from jaw bone periosteium revealed highest osteogenic properties with relatively low morbidity with higher availability. Thus, it can be suggested that that periosteum from the jaw bone may be considered as optimal candidate for source of pluripotent stem cells with multi-germline potential with highest expansion ability and osteogenicity.

Purpose: Among the facilitation of tooth movement in adult orthodontic treatment methods, surgical approaches are gaining popularity but complications following mechanical bone reduction are a problem. In this study, tooth movement was observed after alveolar bone was chemically demineralized to verify whether tooth movement had been facilitated. Materials and Methods: Twelve rabbits were used. In the experimental group, the alveolar bone of the left first molar area was exposed and demineralized. Thirty seven percents phosphoric acid was applied for 5 minutes for demineralization. The opposite first molar area was used as control. Two teeth were pulled with 200 g force and 4 rabbits each were sacrificed at 3, 7, and 14 days after the force was applied. Histologic examination was done with hematoxylin and eosin and tartrate-resistant acid phosphatase staining. Result: The histologic examination results revealed more bone resorption in the demineralized area. As time passed, the number of osteoclasts increased in the compressed area. The amount of tooth movement was larger in the experimental group compared to the control group but the difference was not statistically significant. Conclusion: The demineralization with etchant resulted in limited bone resorption, more tooth movement and less damage of the cementum after applied orthodontic force.

In spite of widely use of zinc oxide (ZnO) nanoparticles (NPs) in cosmetic industry and in our daily lives, insufficient studies have evaluated the potential of their toxic response. This study was conducted to investigate the potential of cytotoxicity induced by ZnO NPs, especially influences of the surface charge and different particle size. Assessment of potential of skin irritation was estimated using human skin equivalent model (HSEM), and an animal model. And the evaluation of skin phototoxicity was tested by the 3T3 neutral red uptake test. Lastly, the potential of skin sensitization was evaluated by a local lymph node assay (LLNA). The results from this study demonstrated that ZnO NPs are not dermal sensitizers and do not induce skin irritation. But they may produce phototoxicity.

Zinc oxide (ZnO) nanoparticles (NPs) are used in the cosmetic industry in cosmetics and sunscreen. ZnO NPs have been reported to elicit various adverse cellular effects, including cytotoxicity. However, the underlying mechanisms of these adverse effects have not been fully characterized. To investigate the potential of cytotoxicity induced by ZnO NPs, we evaluated cytosolic reactive oxygen species levels in human keratinocyte HaCaT cells treated with ZnO NPs having different surface charges and particle sizes. A short period of treatment (30 min) with 100 nm ZnO NPs resulted in a greater increase of cytosolic ROS levels, compared to treatment with 20 nm ZnO NPs at the same concentration. During a long period of treatment (24 h) with ZnO NPs, intracellular ROS was increased in cells treated with 20 μg/mL 20 nm (+/−) charged ZnO. No significant difference according to differences in surface charge was observed. In addition, total levels of caspase-7 and PARP were decreased by ZnO NPs. These results demonstrated that ZnO NPs could induce ROS mediated apoptosis.

The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of a HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, a HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO2 nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity.

Despite widespread use of silicon dioxide (SiO2) NPs in industry and in our daily lives, no studies so far have evaluated the potential of their skin phototoxicity and sensitization. This study was designed to investigate the potential of phototoxicity and sensitization of SiO2 NPs. Assessment of the potential of skin phototoxicity was carried out using the 3T3 neutral red uptake test, an HSEM, and an animal model. The potential of skin sensitization was evaluated by a non-radioisotope local lymph node assay (non-RI LLNA). Findings from the present study suggest that the HSEM may be a reasonable model system for evaluation of skin phototoxicity of NPs. In addition, our data demonstrate that non-RI LLNA may be a useful method for identification of skin sensitization of NPs. In this study, we showed that SiO2 NPs do not induce phototoxicity or skin sensitization.

Quantum dots (QDs) nanoparticles have potential applications in biomedical research, as imaging and diagnostic agents, because of their fluorescent property. Despite the widespread use of nanoparticles, there are many unknowns in understanding on their nanotoxicities and mechanisms. This study evaluated the effects of Quantum Dots (QDs) on gene expression profiles of human keratinocyte HaCaT cells. Total RNA was prepared from the exposure groups to QDs with diverse physicochemical properties (565-PEG-amine, 565-carboxylic acid, 655-carboxylic acid) in various concentrations, and real-time RT-PCR analysis was performed using human oxidative stress and antioxidant defense array. Our study indicated that antioxidant defense and oxidative stress category, such as nitric oxide synthase 2A (NOS2A), dual specificity phosphatase 1 (DUSP1), dual oxidase (DUOX), 24-dehydrocholesterol reductase (DHCR24), peroxidase in homolog (Drosophila)-like (PXDNL), scavenger receptor class A (SCARA3) and thyroid peroxidase (TPO), were represented by all three QDs exposure groups. Therefore, the up-regulation of these enzymes by QDs could increase the production of reactive oxygen species (ROS). The results of our study showed that QDs contained a potential to produce ROS via metabolic pathways, inducing oxidative stress. The results supported that the mechanism of nanotoxicity could be correlated with active oxygen production, oxidative stress, apoptosis, and antioxidant defense mechanisms.

There is an increasing concern regarding the potential toxicity of nanoparticles (NPs), but little literature is available on its skin toxicity and irritation potential. We investigated whether multi-walled carbon nanotubes (MWCNTs) affect skin irritation using HaCaT cell line, the human skin equivalent model (HSEM), and anin vivo model. We evaluated the cytotoxic effects of MWCNTs on HaCaT cells and the HSEM. To confirm in vitro results, we evaluated the irritation potentials of MWCNTs on rabbit skin. In MTT assay, MWCNTs cytotoxicity depended on the concentration of MWCNTs in HaCaT cells. The HSEM skin irriation experiments revealed that MWCNTs have no irritation potential. These HSEM data are consistent with Draize skin irritation test. MWCNTs did not induce the cutaneous irritation of rabbit skin. We suggest that MWCNTs do not induce any acute cutaneous irritation and the HSEM offers a useful alternative method for evaluating the toxicities of toxicants including NPs.

Assessments of skin irritation potentials are important aspects of the development of nanotechnology. Nanosilica is currently being widely used for commercial purposes, but little literature is available on its skin toxicity and irritation potential. This study was designed to determine whether nanosilica has the potential to cause acute cutaneous toxicity, using cultured HaCaT keratinocytes (CHK), a human skin equivalent model (HSEM), and invivo model. Nanosilica was characterized by scanning electron microscopy. We evaluated the cytotoxic effects of nanosilica on CHKs and the HSEM. In addition, we also investigated whether two commercially available nanosilicas with different sizes (7 and 10-20 nm) have different effects. To confirm invitro results, we evaluated the irritation potentials of nanosilicas on rabbit skin. Nanosilicas reduced the cell viabilities of CHKs in a dose-dependent manner. However, the HSEM revealed no irritation at 500 microg/ml of nanosilica. Furthermore, this result concurred with Draize skin irritation test findings. The present study data indicate that nanosilica does not cause acute cutaneous irritation. Furthermore, this study shows that the HSEM used provides more useful screening data than the conventional cell culture model on the relative toxicities of NPs.

Many epidemiologic studies have pointed to a significant association between cigarette smoking and inflammatory skin disease such as psoriasis. Cigarette smoke induces expression of regulators of inflammation such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha. It was recently demonstrated that early growth response-1 (Egr-1) transcription factor is significantly up-regulated in the skin lesions of patients with psoriasis. The mechanism by which cigarette smoke extract (CSE) regulates inflammatory cytokine expression in keratinocyte was still unknown. The aim of this study was to investigate the signalling of CSE-induced Egr-1 expression and the role for Egr-1 in CSE-induced TNF-alpha expression. Cytotoxicity of CSE in HaCaT cells was measured by thiazolyl blue tetrazolium bromide (MTT) assay. CSE-induced Egr-1 expression was investigated by western blot, luciferase reporter assay and confocal microscopy. TNF-alpha expression was measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Involvement of Egr-1 in CSE-induced TNF-alpha secretion was determined by using Egr-1 specific siRNA. CSE increases the Egr-1 expression, promoter activity and its nuclear translocation in human HaCaT keratinocytes. CSE activates mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Up-regulation of Egr-1 expression by CSE stimulation was found to be inhibited by an ERK and JNK but not p38 inhibitor. CSE increases TNF-alpha expression and secretion. This increase is mediated by CSE-induced Egr-1 expression. Our results showed that CSE induces Egr-1 expression via MAPK pathway in human keratinocytes and TNF-alpha expression by Egr-1. This pathway may contribute to the development of inflammatory disease such as psoriasis.

To investigate the mechanism of vascular endothelial growth factor (VEGF)-induced endothelin-1 production in human umbilical vein endothelial cells (HUVECs).Endothelin-1 levels were measured in conditioned medium of women with preeclampsia HUVECs were treated with different concentrations of VEGF(165) and at various time intervals. Next, we measured endothelin-1 levels after HUVECs were also incubated with VEGF and endothelin-converting enzyme-1 (ECE-1) inhibitor or tissue inhibitors of matrix metalloproteinase-2 (TIMP-2). Additionally, the circulating levels of total and free VEGF, matrix metalloproteinase-2 (MMP-2), and endothelin-1 were measured in 20 preeclamptic patients and 20 healthy pregnant controls.HUVECs treated with VEGF increased their endothelin-1 production in a concentration and time-dependent manner. The production of endothelin-1 was inhibited by TIMP-2, but not by the ECE-1 inhibitor. Total VEGF, MMP-2, and endothelin-1 concentrations were higher in preeclampsia and showed significant positive correlations between them.These findings suggest that VEGF-induced endothelin-1 production might be mediated by MMP-2 rather than by ECE-1 upregulation.

Background Breast cancer is an increasingly common malignancy. Several vitamins such as retinoic acid (RA), ascorbic acid (AA), vitamin D and vitamin E are known to prevent the development and progression of breast cancer. Objective We sought to determine whether RA and AA together (RA+AA) acted synergistically in blocking the proliferation of human breast cancer cells. To elucidate the mechanism by which RA+AA inhibited breast carcinoma proliferation, we then evaluated the gene expression profiles of the treated and untreated cells by radioactive cDNA microarray analysis. Methods We cultured the human breast cancer cell line MCF-7 for 3 days with 100 nM RA and/or 1 mM AA, counted the cell numbers and harvested the total RNAs for cDNA microarray analysis. Results RA, AA and RA+AA reduced MCF-7 cell proliferation by 20.7%, 23.3% and 75.7% relative to the untreated cell proliferation, respectively. The synergistic ratio of RA and AA was 1.72. The MCF-7 gene expression profiles showed that 29 genes were up-regulated and 38 genes were down-regulated after RA+AA treatment. The nature of these genes suggests that the mechanism by which RA and AA act synergistically in inhibiting human breast cancer cell proliferation may involve the expression of genes that induce differentiation and block proliferation, and the up-regulation of antioxidant enzymes and proteins involved in apoptosis, cell cycle regulation and DNA repair. Conclusion Combined treatment with RA and AA inhibits the proliferation of human breast cancer cells by altering their gene expression related to antioxidation processes as well as the proliferation inhibitory pathway.

Background : Haploidentical transplantation has become a considerable clinical choice for acute myeloid leukemia (AML) patients lacking a HLA matched donor. We tried to reveal the possible role of a full haplotype mismatch transplantation. Methods : Four patients received stem cell transplantation from their full haplotype mismatched family donors. Conditioning regimen included total-body irradiation, intravenous busulfan, antithymocyte globulin, and fludarabine. Megadose transplants of CD34+ stem cells were in the range of 10.9 /kg and 20.6/kg. Neither GvHD prophylaxis nor post-transplant G-CSF were given. We monitored patients' bone marrow cellularity and chimerism in the peripheral blood using real time PCR. Results : All patients showed stable engraftment. The most frequent side effect was severe mucositis, but all patients recovered successfully without early death. Nobody showed acute GvHD. Two refractory patients were relapsed early after transplantation. Other 2 patients have been in good clinical condition with follow-up duration of 1-4 months. Conclusion : We could overcome the main limitations-a GvHD and a graft failure- of a full haplotype mismatch transplantation with a newly developed conditioning regimen that might be used firstly according to review of literature. Although our study sample numbers and duration of follow-up are not enough yet, at least in patients who were in complete remission and categorized as high-risk AML, we suggest that this treatment modality should be considered actively.

The reverse transcriptase-polymerase chain reaction (RT-PCR) was compared with fluorescence in situ hybridization (FISH) and real-time quantitative RT-PCR (RQ-PCR) for minimal residual disease (MRD) monitoring in 266 post-transplant bone marrow samples from 78 patients with chronic myelogenous leukemia (CML). The sensitivities of FISH to BCR-ABL positive samples determined by first-round (1st) RT-PCR, second-round (2nd) RT-PCR, and RQ-PCR were 64.2%, 25.8%, and 20.7%, respectively. The BCR-ABL/ABL ratio by RQ-PCR had a mean of 0.000 13 in the 1st RT-PCR-negative samples and 1.42 in the 1st RT-PCR-positive samples (P

BACKGROUND: Infection is still a frequent cause of morbidity and mortality in acute myelogenous leukemia (AML) patients receiving chemotherapy. Recently the main cause of infection has changed from gram-negative to gram-positive bacteria and the resistance to antibiotics has increased. This study aimed to access the effectiveness of antimicrobial prophylaxis (AP) with orally absorbable antibiotics. METHODS: Ninety-five AML patients receiving chemotherapy at Catholic Hemopoietic Stem Cell Transplantation Center from March 1999 to July 1999 were randomly divided into the AP group (250 mg ciprofloxacin twice a day, 150 mg roxithromycin twice a day, 50 mg fluconazole once a day) and the control group for a prospective analysis. RESULTS: The incidence of fever was 82.6% in the AP group and 91.6% in the control group (p = 0.15). Though classification and sites of infections showed no difference between the two groups, the catheter associated infection occurred more frequently in the AP group in significance. The time interval between initiation of chemotherapy and onset of fever, white blood cell (WBC) count at the onset of fever, duration of leukopenia (WBC < 1,000/mm3), duration of systemic antibiotic therapy, mortality due to infection and hospitalization period from the data starting chemotherapy showed no differences between the two groups. Infections due to gram negative bacteria decreased to 33.3% in the AP group (vs. 92% in the control group), but infections due to gram positive bacteria increased to 66.7% (vs. 8% in the control group). Gram negative bacteria showed 100% resistance to ciprofloxacin in the AP group and gram-positive bacteria showed 90-100% resistance to erythromycin, regardless of the presence of AP. CONCLUSION: The AP could not reduce the occurrence of infection or infection associated death in AML patients receiving chemotherapy. On considering increased gram-positive infection and resistance to fluoroquinolone and macrolide, routine prescription of AP should be reconsidered. Further studies that assess the effectiveness of AP in other malignancies, aplastic anemia and bone marrow transplantation are required.

Summary. The prognostic relevance of karyotype has been established in adult acute lymphoblastic leukaemia (ALL) patients treated with chemotherapy but not definitively evaluated in an allogeneic bone marrow transplantation (BMT) setting. To determine the factors affecting the outcome of allogeneic BMT for adults with precursor B-lineage ALL in first or second complete remission (CR), a total of 41 consecutive patients with a successful karyotype were enrolled in this study. There were 21 men and 20 women with a median age of 27 (15–43) years. The distribution of French–American–British (FAB) subtypes was as follows: L1 (n = 26), L2 (n = 15). Unfavourable karyotypes (n = 12) were defined as Ph+ or t(4;11). Disease status at the time of transplant was first CR (n = 35) or second CR (n = 6). With a median follow-up of 36 months, the 3-year probabilities of relapse and disease-free survival (DFS) were 36·3 ± 8·4% and 57·3 ± 8·4% respectively. Potential variables predicting worse relapse and DFS were FAB subtype (L2), extramedullary involvement, pre-BMT status (second CR), unfavourable karyotype and type of graft-versus-host disease (GVHD). Further multivariate analysis showed that karyotype and pre-BMT status were independently associated with relapse and DFS. In addition, chronic GVHD was found to be significantly associated with a lower relapse rate.

Aplastic anemia is a rare complication of thymoma and is extremely infrequent after thymectomy. We present a case of a 60-year-old woman with very severe aplastic anemia appearing sixteen months after thymectomy for a thymoma. She underwent thymectomy for a thymoma in April 2000. Preoperative examination revealed no hematologic abnormality. About sixteen months after the operation, she was readmitted because of pancytopenia with cough and fever. Bone marrow aspiration revealed a very severe hypoplasia in all the three cell lines with over 80% fatty tissue, and chest CT revealed no recurrence of thymoma. Her aplastic anemia had responded to cyclosporine A and granulocyte-colony stimulating factor (G-CSF).

Silica nanoparticles (SNPs) are widely used in many scientific and industrial fields despite the lack of proper evaluation of their potential toxicity. This study examined the effects of acute exposure to SNPs, either alone or in conjunction with ovalbumin (OVA), by studying the respiratory systems in exposed mouse models. Three types of SNPs were used: spherical SNPs (S-SNPs), mesoporous SNPs (M-SNPs), and PEGylated SNPs (P-SNPs). In the acute SNP exposure model performed, 6-week-old BALB/c female mice were intranasally inoculated with SNPs for 3 consecutive days. In the OVA/SNPs asthma model, the mice were sensitized two times via the peritoneal route with OVA. Additionally, the mice endured OVA with or without SNP challenges intranasally. Acute SNP exposure induced significant airway inflammation and airway hyper-responsiveness, particularly in the S-SNP group. In OVA/SNPs asthma models, OVA with SNP-treated group showed significant airway inflammation, more than those treated with only OVA and without SNPs. In these models, the P-SNP group induced lower levels of inflammation on airways than both the S-SNP or M-SNP groups. Interleukin (IL)-5, IL-13, IL-1β and interferon-γ levels correlated with airway inflammation in the tested models, without statistical significance. In the mouse models studied, increased airway inflammation was associated with acute SNPs exposure, whether exposed solely to SNPs or SNPs in conjunction with OVA. P-SNPs appear to be relatively safer for clinical use than S-SNPs and M-SNPs, as determined by lower observed toxicity and airway system inflammation.

Osteoporosis associated with estrogen deficiency is defined as an abnormal decrease in bone mass leading to an increased fracture risk. Genistein (GEN), as a phytoestrogen, is a type of soybean-derived isoflavone that possesses structural similarity to estrogen. In this study, we assessed the effect of GEN in ovariectomized (OVX) mice. To determine the effect of GEN on bone metabolism, we investigated gene expression profiles using a radioactive cDNA microarray. Eight-week-old female mice were either sham operated (SHAM) or OVX. From 1 week after the operation, OVX mice were injected daily with intraperitoneal GEN (0.1, 0.5, 1.5 and 3.0 mg/day) or 17beta-estradiol (E2, 0.03 microg/day) for 4 weeks. A cDNA microarray was used to evaluate changes in the expression of 1,152 genes. OVX mice showed bone mineral density (BMD) loss versus SHAM mice (5.8+/-0.4 vs. 6.9+/-0.6 mg/cm2). However, femur BMDs were completely restored by GEN and by E2 administration in OVX mice. Serum osteocalcin in OVX mice treated with 0.5 mg/day of GEN was 1.6-fold (44.30+/-5.73 ng/ml) higher than that in untreated mice. GEN treatment up-regulated 38 genes (e.g., mitogen-activated protein kinase 10) and down-regulated 18 (e.g., matrix metalloproteinase 13). Moreover, GEN was found to have a protective effect on bone loss caused by estrogen deficiency in OVX mice. The present study suggests that GEN modulates bone metabolism-related gene expression, including calciotropic receptor, cytokines, growth factors and bone matrix proteins.

Summary. The aim of this study was to evaluate the outcomes for Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) patients in remission treated with allogeneic bone marrow transplantation (BMT). Twenty-three adults were entered onto this study. The 2-year probabilities of relapse and disease-free survival (DFS) were 39·4 ± 11·6% and 43·5 ± 10·3% respectively. The presence of chronic graft-versus-host disease (GVHD) was found to be an independent predictive factor affecting lower relapse and DFS. To monitor the BCR-ABL transcript, we also analysed 48 bone marrow samples of eight patients using real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR). The kinetics of the BCR-ABL transcript correlated well with the patients' clinical course. In six patients who were in continuous remission after BMT, a rapid decrease in BCR-ABL copy number to the PCR-negative status was observed after the development of chronic GVHD. Meanwhile, routine bone marrow examination of two patients showed PCR positivity with a 3 or 4-log increase of BCR-ABL copy number and subsequent haematological relapse, which occurred 2 and 4 months later respectively. Although our data should be interpreted cautiously, the presence of chronic GVHD may reduce the risk of relapse in Ph+ ALL. Real-time quantitative RT-PCR appears to be a useful test for BCR-ABL transcript monitoring.

Received April 22, 2013 / Revised 1st September 17, 2013, 2nd October 10, 2013 / Accepted October 18, 2013 Correspondence: Yong Sang Lee, MD, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-720, Korea Tel: 82-2-2019-3370, Fax: 82-2-3462-5994, E-mail: medilys@yuhs.ac *These two authors contributed equally in this study. This study was supported by the Korean Thyroid Association-Ilsung Pham Co. Research Grant on 2012.