Hyun-Ju Cho

Oncogenic H-Ras Up-regulates Expression of Ku80 to Protect Cells from γ-Ray Irradiation in NIH3T3 Cells

The Ras activation contributes to radioresistance, but the mechanism is unclear. This article shows that the expression of the dominant-positive H-Ras increased the Ku80 level, which is one of the key enzymes involved in repairing dsDNA breaks (DSB). After exposing the cells to ionizing radiation and analyzing them using an electrophoretic mobility shift assay and pulsed-field gel electrophoresis, it was found that activated H-Ras expression in NIH3T3 cells increases the DNA-binding activity of Ku80 and increases the DSB repair activity. Ku80 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DSBs and suppress the oncogenic H-Ras-mediated resistance of the cells to gamma-ray irradiation, whereas Ku80 overexpression in the NIH3T3 cells significantly increased the radioresistance. These results suggest that the Ku80 expression induced by oncogenic H-Ras seems to play an important role in protecting cells against gamma-ray irradiation.

Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability

The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mutα (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI.

Prevalence and clinical manifestations of macrolide resistant Mycoplasma pneumoniae pneumonia in Korean children

Purpose Macrolide resistance rate of Mycoplasma pneumoniae has rapidly increased in children. Studies on the clinical features between macrolide susceptible-M. pneumoniae (MSMP) and macrolide resistant-M. pneumoniae (MRMP) are lacking. The aim of this study was to identify the macrolide resistance rate of M. pneumoniae in Korean children with M. pneumoniae penupmonia in 2015 and compare manifestations between MSMP and MRMP. Methods Among 122 children (0–18 years old) diagnosed with M. pneumoniae pneumonia, 95 children with the results of macrolide sensitivity test were included in this study. Clinical manifestations were acquired using retrospective medical records. Results The macrolide resistant rate of M. pneumoniae was 87.2% (82 of 94 patients) in children with M. pneumoniae pneumonia. One patient showed a mixed type of wild type and A2063G mutation in 23S rRNA of M. pneumoniae. There were no significant differences in clinical, laboratory, and radiologic findings between the MSMP and MRMP groups at the first visit to our hospital. The time interval between initiation of macrolide and defervescence was significantly longer in the MRMP group (4.9±3.3 vs. 2.8±3.1 days, P=0.039). Conclusion The macrolide resistant rate of M. pneumoniae is very high in children with M. pneumoniae pneumonia in Korea. The clinical manifestations of MRMP are similar to MSMP except for the defervescence period after administration of macrolide. Continuous monitoring of the occurrence and antimicrobial susceptibility of MRMP is required to control its spread and establish strategies for treating second-line antibiotic resistant M. pneumoniae infection.

Persistent asthma phenotype related with late-onset, high atopy, and low socioeconomic status in school-aged Korean children

BackgroundTreatment guidelines for asthma have been established based on asthma severity; there are limitations in the identification of underlying pathophysiology and prediction of prognosis in heterogeneous phenotypes of asthma. Although the complex interactions between environmental and genetic factors affect the development and progression of asthma, studies on asthma phenotypes considering environmental factors are limited. This study aimed to identify asthma phenotypes using latent class analysis including environmental factors in school-age children.MethodsWe included 235 children (6–8 years) with parent-reported, physician-diagnosed asthma from the Children’s HEalth and Environmental Research (CHEER) study, which is a 4-year prospective follow-up study with 2-year intervals. At every survey, pulmonary function tests, methacholine challenge tests and blood tests with questionnaire were conducted.ResultsFour asthma phenotypes were identified. Cluster 1 (22% of children) was characterized by high prevalence of atopy and mild symptoms; subjects in cluster 2 (17%) consisted of less atopy and normal lung function, but intermittent troublesome; cluster 3 (29%) experienced late-onset atopic troublesome asthma with decreased lung function in combination with low socioeconomic status; and cluster 4 was associated with early-onset and less-atopic infrequent asthma.ConclusionsLate-onset, high atopy, and low socioeconomic status are associated with troublesome persistent asthma phenotype in school-age children. Environmental factors might be implicated in the clinical heterogeneity of asthma. Asthma phenotypes considering diverse factors might be more helpful in the identification of asthma pathogenesis and its prevention.

Association of atopy phenotypes with new development of asthma and bronchial hyperresponsiveness in school-aged children

BACKGROUND Although previous studies have investigated the association between atopy phenotypes and allergic diseases, atopy characterizations in association with the development of allergic diseases remain poorly understood. OBJECTIVE To identify atopy phenotypes in school-age children and to evaluate the association between atopy phenotypes and allergic diseases. METHODS We enrolled 616 children with atopy defined as 1 or more positive allergen responses on skin prick tests and 665 children without atopy from the Childrens Health and Environmental Research (CHEER) study. All children were followed up for 4 years at 2-year intervals. Atopy phenotypes were classified using latent class analysis. RESULTS Four atopy phenotypes were characterized: later sensitization to indoor allergens (cluster 1); multiple early sensitization (cluster 2); early sensitization to outdoor allergens, especially Alternaria, and later sensitization to indoor allergens, including Aspergillus (cluster 3); and early sensitization to indoor allergens and later sensitization to outdoor allergens (cluster 4). New cases of asthma during follow-up were increased in clusters 2 and 3 (adjusted odds ratio [aOR], 2.76 and 4.25, respectively). The risk of new-onset bronchial hyperresponsiveness was highest in cluster 3 (aOR, 5.03). Clusters 2 and 4 had an increased risk of allergic rhinitis (aOR, 7.21 and 2.37, respectively). CONCLUSION Identification of atopy phenotypes facilitates prediction of the development of asthma and bronchial hyperresponsiveness in school-age children. Our study suggests prevention of additional sensitization is required to modify the progression of allergic diseases.

Different Functional Genes of Upper Airway Microbiome Associated with Natural Course of Childhood Asthma

Microbial colonization of the airway plays a role in the pathogenesis of asthma; however, the effect of the upper airway microbiome on childhood asthma is not fully understood. We analyzed the metagenome of airway microbiome to understand the associated role of upper airway microbiome with the natural course of childhood asthma.

High degree of supervision improves adherence to inhaled corticosteroids in children with asthma

Purpose Adherence to treatment with inhaled corticosteroids (ICS) is a critical determinant of asthma control. The objective of this study was to assess factors that determine adherence to ICS therapy in children with asthma. Methods Fifty-eight children with asthma, aged 5 to 16 years, used ICS with or without a spacer for 3 months. Adherence rates as measured from questionnaires and canisters, asthma symptom scores, and inhalation technique scores were assessed every 30 days. The degree of supervision by caregivers was assessed at day 30. Results Adherence rates measured using canisters were lower at day 60 than at day 30 (P=0.044) and did not change thereafter (74.4%±17.4% at day 30, 66.5%±18.4% at day 60, and 67.4%±22.2% at day 90). Adherence rates at days 60 and 90 and during the total study period were significantly different when measured by using questionnaires versus canisters (P<0.001, P=0.022, and P=0.001, respectively). In the comparison of adherence rates repeatedly measured at days 30, 60, and 90 and adherence rates during the total study period among the 3 groups, adherence rates in the high-degree supervision group were significantly higher than those in the low-degree supervision group (82.0±16.0 vs. 66.1±14.5, 75.4±14.4 vs. 56.2±18.4, 75.0±18.3 vs. 55.0±19.7 [P=0.027]; 77.9±12.2 vs. 59.1±11.4 [P=0.021]) after adjustment for sex and age. Conclusion The level of caregiver supervision is an important factor affecting adherence to ICS therapy in children with asthma. Therefore, a high degree of supervision may be required to increase adherence to ICS therapy in children with asthma.

Association of high-level humidifier disinfectant exposure with lung injury in preschool children

BACKGROUND Children aged ≤6years reportedly account for 52% of victims of humidifier disinfectant-associated lung injuries. OBJECTIVES To evaluate the association of humidifier disinfectants with lung injury risk among children aged ≤6years. METHODS Patients with humidifier disinfectant-associated lung injuries (n=214) who were clinically evaluated to have a definite (n=108), probable (n=49), or possible (n=57) association with humidifier disinfectants as well as control patients (n=123) with lung injury deemed unlikely to be associated with humidifier disinfectant use were evaluated to determine factors associated with increased risk of humidifier disinfectant-associated lung injury using unconditional multiple logistic regression analysis. RESULTS For estimated airborne humidifier disinfectant concentrations, risk of humidifier disinfectant-associated lung injury increased ≥two-fold in a dose-dependent manner in the highest quartile (Q4, 135-1443μg/m3) compared with that in the lowest quartile (Q1, ≤33μg/m3). Registered patients using more than two humidifier disinfectant brands were at an increased risk of humidifier disinfectant-associated lung injury (adjusted OR, 2.2; 95% confidence interval, 1.3-3.8) compared with those using only one brand. With respect to the duration of humidifier disinfectant use, risk of humidifier disinfectant-associated lung injury increased ≥two-fold in the lowest quartile (≤5months) compared with that in the highest quartile (≥14months; adjusted OR 0.3; 95% confidence interval, 0.2-0.6). CONCLUSIONS Younger children are more vulnerable to HDLI when exposed to HD chemicals within short period in early life.

Clinical phenotypes of bronchial hyperresponsiveness in school-aged children

BACKGROUND Bronchial hyperresponsiveness (BHR), one of the key features of asthma, has a diverse natural course in school-aged children, but studies on BHR phenotypes are lacking. OBJECTIVE To classify BHR phenotypes according to onset age and persistence in children and investigate the characteristics and factors associated with each phenotype in a longitudinal study. METHODS This study analyzed 1,305 elementary school children from the Childrens Health and Environmental Research (CHEER) study, a 4-year, prospective, follow-up study with 2-year intervals starting at a mean age of 7years. Total serum IgE levels and blood eosinophil counts were measured, and allergy workup, including methacholine challenge tests with the International Study of Asthma and Allergies in Childhood questionnaire, was performed at each survey. RESULTS The 4 BHR phenotypes were classified as non-BHR (n = 942 [72.2%]), early-onset transient BHR (n = 201 [15.4%]), late-onset BHR (n = 87 [6.7%]), and early-onset persistent BHR (n = 75 [5.7%]). Early-onset persistent BHR is characterized by an increased eosinophil count, total serum IgE level, sensitization rate, decreased lung function, and increased risk of newly diagnosed asthma during follow-up (adjusted odds ratio, 3.89; 95% confidence interval, 1.70-8.88). The 2 early-onset phenotypes were associated with peripheral airway dysfunction. The late-onset BHR phenotype was related to increased risks of allergic rhinitis symptoms at baseline and later sensitization against inhalant allergens. CONCLUSION The early-onset persistent BHR phenotype in school-aged children is associated with high atopic burden and increased risk of newly diagnosed asthma, whereas the late-onset BHR phenotype related with later sensitization and allergic rhinitis symptoms. Diverse BHR phenotypes in children have specific characteristics that require targeted follow-ups.

Effects of a mixture of chloromethylisothiazolinone and methylisothiazolinone on peripheral airway dysfunction in children

Background Children who were only exposed to a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) as humidifier disinfectant (HD) components were evaluated for humidifier disinfectant-associated lung injury (HDLI) from 2012. This study was to evaluate the pulmonary function using, impulse oscillometry (IOS) for children exposed to a mixture of CMIT/MIT from HD. Methods Twenty-four children who were only exposed to a mixture of CMIT/MIT, with no previous underlying disease, were assessed by IOS. Diagnostic criteria for HDLI were categorized as definite, probable, possible, or unlikely. Home visits and administration of a standardized questionnaire were arranged to assess exposure characteristics. Results Definite and probable cases showed higher airborne disinfectant exposure intensity during sleep (32.4 ± 8.7 μg/m3) and younger age at initial exposure (3.5 ± 3.3 months) compared with unlikely cases (17.3 ± 11.0 μg/m3, p = 0.026; 22.5 ± 26.2 months, p = 0.039, respectively). Reactance at 5 Hz was significantly more negative in those with high-density exposure during sleep (mean, -0.463 kPa/L/s vs. low density, -0.296, p = 0.001). The reactance area was also higher with high-density exposure during sleep (mean, 3.240 kPa/L vs. low density, 1.922, p = 0.039). The mean bronchodilator response with high-density exposure was within the normal range for reactance. Conclusions Significant peripheral airway dysfunction were found in children with high levels of inhalation exposure to a mixture of CMIT/MIT during sleep. Strict regulation of a mixture of CMIT/MIT exposure were associated with positive effects on lung function of children.