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Thymic stromal lymphopoietin (TSLP) may have a key role in the initiation and maintenance of allergic inflammatory diseases, including atopic dermatitis. The present study revealed that UVB radiation exposure could induce TSLP expression in human keratinocytes and a human skin equivalent model. In addition, we investigated the regulatory mechanism of UVB-induced TSLP expression in keratinocytes. TSLP expression was upregulated by transfection with pcDNA3-hypoxia-inducible factor (HIF)-1α (P402A and P564A), which stably expresses HIF-1α protein. UVB-induced TSLP induction in keratinocytes was suppressed in the treatment of mitogen-activated protein kinase inhibitors or small interfering RNAs against HIF-1α. The results of chromatin immunoprecipitation assays indicate the direct involvement of HIF-1α in UVB-mediated TSLP induction. Taken together, these findings indicate that UVB exposure may increase TSLP expression through a HIF-1α-dependent mechanism via the c-JUN N-terminal kinase and extracellular signal-regulated kinase pathways in human keratinocytes. Our data showed that UVB-induced TSLP might increase secretion of the T-helper type 2-attracting chemokine (c-c motif) ligand 17 by human dendritic cells. The present study suggests an important role of HIF-1α in UVB-mediated immune response in keratinocytes.

Silica nanoparticles (NPs) are widely applied in many fields, such as chemical industry, medicine, cosmetics, and agriculture. However, the hazardous effects of silica NPs exposure are not completely understood. In this study, the two different sizes (20 nm and 100 nm) and different charges (negatively charged [NC] and weakly negatively charged [WNC]) of silica NPs were used. The present study investigated the cytotoxicity and reactive oxygen species (ROS) generation of silica NPs on keratinocytes. The phototoxicity test of silica NPs was performed on skin fibroblast cells. In addition, skin irritation and skin sensitization of silica NPs were studied on HSEM and mouse skin, respectively. The cell viability of NC 20 nm silica NPs was decreased. However, there are no cytotoxicity for NC 100 nm silica NPs and WNC silica NPs (20 and 100 nm). The results for silica NPs-induced ROS generation are consistent with the cytotoxicity test by silica NPs. Further, NC and WNC silica NPs induced no phototoxicity, acute cutaneous irritation, or skin sensitization. These results suggested that silica NPs-induced ROS generation was the determinant of cytotoxicity. This study showed that the smaller size (20 nm) of silica NPs had more toxicity than the larger size (100 nm) of silica NPs for NC silica NPs. Moreover, we observed an effect of surface charge in cytotoxicity and ROS generation, by showing that the NC silica NPs (20 nm) had more toxic than the WNC silica NPs (20 nm). These findings suggested that the surface charge of silica NPs might be the important parameter for silica NPs-induced toxicity. Further study is needed to assess the effect of surface modification of nanotoxicity.

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.

In spite of widely use of zinc oxide (ZnO) nanoparticles (NPs) in cosmetic industry and in our daily lives, there are insufficient data on their potential of skin absorption. This study was conducted to investigate the potential of skin absorption induced by ZnO NPs, especially influences of the surface charge and different particle size. Assessment of potential of skin absorption was estimated using 3D EpiDerm™ model (EPI-200) as human skin equivalent model (HSEM). This study demonstrated no evidence of significant penetration of ZnO NPs into the HSEM after 24 h exposure.

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.

The sixty-six lines of the Cotton Maxims (Maxims Ⅱ) consist of a series of so-called gnomic verses which are supposed to be "pieces of universally accepted knowledge in the form of versified sentences." In reading of Maxims Ⅱ, however, readers are puzzled over how the whole poem could be understood as a unit, for some of the maxims, including the "wulf" maxim, are not look like "pieces of universally accepted knowledge" to modern ears. The crux of the poem is its ambiguous use of "the reiterated sceal or scyle," for the whole work of Maxims Ⅱ, "the various items of the sceal series," "are exceedingly difficult to connect in any logical or even emotional sequence, although sometimes two or three items do have a demonstrable relationship." The paper focuses on the interpretation of the "wulf" maxim, expounding the Anglo-Saxon concept of "wulf" and identifying the specific meaning of sceal in the context of Anglo-Saxon popular thought and culture. The literal translation of the wolf gnome of Maxims Ⅱ is quite simple either in two ways: "the wolf, wretched solitary being, is typically in the forest" or "the wolf, wretched solitary being, ought to be in the forest." However, in content, the gnome is not so simple. In order to interpret the gnome in a precise and proper way, modern readers should recognize the Anglo-Saxon's way of thinking, their culture, and both their pagan and Christian belief in nature and God. "The wolf, wretched solitary being, is typically in the forest" is our interpretation; "The wolf, wretched solitary being, ought to be in the forest" is their interpretation.

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.

To understand the role of the chitin synthase genes of Aspergillus nidulans, we analyzed the expression of chsA, chsB, and chsC both by Northern blotting and by a vital reporter system with sgfp encoding a modified version of green fluorescent protein, sGFP. chsA was expressed specifically during asexual differentiation, but not during either vegetative growth or sexual differentiation. The expression of chsB was ubiquitous throughout the fungal body and relatively independent of the change in developmental status of the cells. chsC was expressed moderately during sexual development as well as during the early phase of vegetative growth, but was expressed weakly in old vegetative mycelia and in asexual structures. Furthermore its expression was spatially differentiated, i.e., relatively strong in young cleistothecia and in mature ascospores, but negligible in Hülle cells. Osmostress caused by high concentrations (up to 1.2M) of KCl or NaCl stimulated the expression of chsA and chsC, but not that of chsB. Sodium acetate, especially at high concentration (3%), strongly enhanced the expression of all the three genes. Neither heat shock nor the sugar carbon sources tested (glucose, sucrose, or lactose) affected the expression of any of the three chitin synthase genes.

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.

Ferroelectric capacitors are severely degraded by integrating interlayer dielectrics (ILD) and intermetallic dielectrics (IMD) due to their undesired hydrogen attack and stress effect. In this paper, it was found that the dielectrics film stress plays more dominant role in degrading submicron 32Mb ferroelectric capacitors (0.48 2 0.92 w m 2 ) than hydrogen attack due to the Ir ATE electrode, which works for blocking hydrogen attack, but generates sever stress variation. Since the Ir film shows severe stress variation from compressive to tensile during heating and cooling cycles, it is desired to prepare compressive ILD and IMD films for compensating the tensile stress. Using P-OX films with compressive stress, the 32Mb ferroelectric capacitors show excellent hysteresis loops with the P r value of 15 w C/cm 2 after completing full integration, which is comparable to 18 w C/cm 2 before the integration. The submicron ferroelectric capacitor prepared by compressive P-OX ILD and IMD materials was successfully ...

As the capacitor size greatly decreases from 1.44 in 4Mb to 0.44 w m 2 in 32Mb FRAM, the hydrogen-damage is severely increased, thus giving rise to the difficulty in protecting the ferroelectric capacitor from the hydrogen attack by using conventional encapsulating barrier layers (EBL). Therefore, it is strongly required to reduce the hydrogen-induced degradation of very small ferroelectric capacitor during the backend integration process. In this paper, we developed double EBL technology by covering whole ferroelectric capacitors again after the Cap-EBL process. The Al 2 O 3 ILD-EBL layer was prepared again after depositing inter-layer dielectrics (ILD) layer, thus eliminating further hydrogen damage during inter-metal dielectrics (IMD) process. Using the double EBL technology, the fully integrated ferroelectric capacitor for 32Mb FRAM exhibits excellent ferroelectric properties such as remnent polarization of 15 w C/cm 2 at 3V. As a result, novel hydrogen-damage free 0.25 w m 15F 2 32Mb FRAM was success...

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).

Zinc oxide (ZnO) nanoparticles (NPs) are widely used in cosmetics and sunscreen. In spite of the broad application of ZnO NPs on human skin, there are limited literatures on the potential toxicities of ZnO NPs at the cellular and molecular levels. The aim of this study was to investigate the signaling pathways of ZnO NPs-induced early growth response-1 (Egr-1) expression and the role of Egr-1 in ZnO NPs-induced cytokine expression. ZnO NPs increased the Egr-1 expression, promoter activity and its nuclear translocation in HaCaT cells. ZnO NPs activated extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinase (MAPK) pathways. 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. Our results showed that ZnO NPs induces Egr-1 expression via MAPK pathway in human keratinocytes and cytokine expression by Egr-1. These pathways may contribute to NPs-induced cutaneous toxicity.

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.

A reliable Ir diffusion barrier was prepared on polysilicon plugged substrate with a contact size of 0.6 μm. Using a Ti adhesion layer and stress-relief process, it was possible to integrate the Ir barrier into a high density 4 Mb ferroelectric random access memory device. After heat treating sol-gel derived Pb(Zr1−xTix)O3 (PZT) films at 700 °C, the Ir barrier contact displayed an ohmic behavior and showed a low resistance of 130 Ω per contact in 1k serial contact array. The PZT films on Pt/IrO2/Ir poly-plugged substrate exhibited excellent ferroelectric properties such as remnant polarization and coercive voltage of 25 μC/cm2 and 1.15 V, respectively. Auger depth profile and transmission electron microscopy analyses confirmed that no appreciable oxidation was formed between the Ir barrier and the polysilicon plug.

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.

The plasma soluble interleukin-2 receptor (sIL-2R) level was higher in 137 patients with acute leukemia (1,489 +/- 1,798 U/ml, including 98 cases of acute myeloid leukemia (AML), 1,063 +/- 1,414 U/ml, and 39 cases of acute lymphoblastic leukemia (ALL), 2,561 +/- 2,194 U/ml), compared to 49 normal control subjects, 421 +/- 151 U/ml). The ALL patients showed elevated plasma sIL-2R levels more frequently than the AML patients (92.3% vs 44.9%). No patient with either hypoplastic AML or AML with multilineage dysplasia and only 1 of 13 patients with acute promyelocytic leukemia (APL) had an elevated plasma sIL-2R level. All the My+ ALL patients (15 cases) showed elevated plasma sIL-2R levels. Plasma sIL-2R levels were significantly lower after chemotherapy in the ALL patients, but were not significantly lower in the AML patients. IL-2R was expressed on the leukemic cells in 36 (53.7%) of 67 AML and in 9 (21.4%) of 42 ALL cases. None of the AML M3, M4, M5, M6, or M7 subgroups showed IL-2R expression. The My+ ALL patients (42.9%, 6/14) showed IL-2R expression more frequently than the other ALL subgroups (10.7%, 3/28) (p = 0.025). The plasma sIL-2R level was correlated with the proportion of leukemic cells expressing IL-2R in acute leukemia. However, there were many cases, particularly ALL cases, who had elevated plasma sIL-2R levels without IL-2R expression on their leukemic cells. These results suggest that the plasma sIL-2R level is a valuable marker for monitoring ALL after chemotherapy, particularly in My+ ALL cases, and that the T cell immune reaction to leukemia appears to be much higher in ALL patients than in AML patients.

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.

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 (P0.001), and means of 0.000 39 and 0.51 in the 2nd RT-PCR-negative and -positive samples (P0.001). The mean ratios of BCR-ABL/ABL by RQ-PCR were significantly different in N/N (1st/2nd RT-PCR) or N/P and P/P (P0.001), but not in N/N and N/P, which showed that the discriminative power of RQ-PCR is confined to the 1st RT-PCR level. In this respect, monitoring of the 1st RT-PCR might be useful for estimating normalized BCR-ABL levels after transplantation. Nested RT-PCR was of limited use, as RQ-PCR quantified the BCR-ABL transcripts in 60 (91%) of 66 samples determined to be negative by 2nd RT-PCR. FISH was significantly correlated with RQ-PCR in FISH-positive samples (n=24, r=0.79, P=0.001). An increase of FISH preceded that of RQ-PCR in a few cases with molecular relapse. By analyzing a large number of samples post-transplant, we found that RQ-PCR might be the most useful assay for MRD monitoring; however, FISH and RT-PCR were found to be useful complementary tools.

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.

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.

Objectives: This study evaluated a range of fixation methods to determine which is best for the postoperative stabilization of a mandibular osteotomy using three-dimensional finite element analysis of the stress distribution on the plate, screw and surrounding bone and displacement of the lower incisors. Materials and Methods: The model was generated using the synthetic skull scan data, and the surface model was changed to a solid model using software. Bilateral sagittal split ramus osteotomy was performed using the program, and 8 different types of fixation methods were evaluated. A vertical load of 10 N was applied to the occlusal surface of the first molar. Results: In the case of bicortical screws, von-Mises stress on the screws and screw hole and deflection of the lower central incisor were minimal in type 2 (inverted L pattern with 3 bicortical repositioning screws). In the case of plates, von-Mises stress was minimal in type 8 (fixation 5 mm above the inferior border of the mandible with 1 metal plate and 4 monocortical screws), and deflection of the lower central incisor was minimal in types 6 (fixation 5 mm below the superior border of the mandible with 1 metal plate and 4 monocortical screws) and 7 (fixation 12 mm below the superior border of the mandible with 1 metal plate and 4 monocortical screws). Conclusion: Types 2 and 6 fixation methods provide better stability than the others.

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 an HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, an 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.

Background and Objectives: Patients with severe aplastic anemia (SAA) who do not have suitably HLA-matched related donor generally receive immunosuppressive therapy (IST) as first-line treatment and are considered for transplantation from matched unrelated donor (MUD) if they fail to respond to IST. To determine the optimal total body irradiation (TBI) dose as conditioning regimen in unrelated marrow transplantation for adult SAA patients, we conducted a prospective study to evaluate minimal dose of TBI sufficient to achieve sustained engraftment when it is used in combination with fixed dose of cyclophosphamide (CY). Methods: Between May 1998 and December 2003 twenty-eight patients were enrolled with a median age of 23 years old (20–44). All patients were multiply transfused and had received 1 or 2 course of intensive IST. Conditioning regimen consisted of CY (120mg/kg) plus TBI and they were divided into 3 group according to the fractionated TBI dose: group 1 (1200 cGy, n=5), group 2 (1000 cGy, n=9), and group 3 (800 cGy, n=14). Donor/recipient pairs were matched for HLA-A, -B by serology and -DRB1 by low-resolution DNA typing (n=15) or HLA-A, -B, and -DRB1 by high-resolution typing (n=13). Patients received CsA+MTx (n=4) or FK506+MTx (n=24) as GVHD prophylaxis. Results: All patients except one (group 2) achieved sustained engraftment. The incidence of acute GVHD more than grade II was not significantly different (60% in group 1, 38% in group 2, and 43% in group 3), but chronic GVHD developed more frequently in group 1 and 2 (60% & 80%, respectively) compared to group 3 (15%). Patients who received 800 cGy (group 3) had significantly better survival than those 1000 and 1200 cGy (93% in group 3, 44% in group 2, and 40% in group 1; group 3 vs group 1 and 2, p Conclusions: Thus, a TBI dose of 800 cGy in combination with CY (120mg/kg) was sufficient to allow for engraftment in adult patients with SAA who received MUD BMT. Outcome in patients who received 800 cGy of TBI was superior to survival that among patients 1000 and 1200 cGy.