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Background: Abdominal aortic aneurysm (AAA) is more common in Non-small cell lung cancer (NSCLC) patients. Considering that ruptured AAA is potentially fatal, timely management of AAA would result in long-term survival benefits. We assess the prevalence and characteristics of AAA in resectable NSCLC patients who would benefit from AAA surveillance., Methods: 1,019 resectable NSCLC patients in Severance and Kangbuk Samsung Hospitals were reviewed from January 2019 to November 2020. The control group comprised 2,899 cancer-free people who had a health check-up CT scan in Severance between January 2018 and December 2019., Results: Among resectable primary NSCLC patients, 39/1,019 (3.8%; odds ratio [OR], 19.19; 95% confidence interval [CI], 8.10-46.46) had AAA compared with 6/2,899 (0.2%) in the control (P<0.001). In multivariable regression analysis, male (OR, 13.24; 95% CI, 1.50-117.48; P = 0.020), aging (OR, 1.10; 95% CI, 1.04-1.15; P<0.001), current smoker (OR, 4.20; 95% CI, 1.20-14.62; P = 0.024), and coronary artery disease (OR, 3.13; 95% CI, 1.48-6.62; P = 0.003) were independent risk factors for AAA in NSCLC., Conclusion: The present study found that the incidence of AAA in resectable early-stage lung cancer patients was significantly higher than in the cancer-free control group. Therefore, we suggest that early-stage NSCLC patients, especially smokers older than 60 years, undergo regular AAA surveillance as part of their lung cancer monitoring., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Gwon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A significant crop pest, Mythimna loreyi, migrates annually to Korea and has been frequently observed in rice and corn fields. However, the phenology of this pest, particularly in relation to its ecological interactions and host crop seasons in Korea, remains poorly understood. This study aims to clarify the timing of the second generation of M. loreyi in Korea to enhance pest management strategies. To achieve this, we developed temperature-dependent models for developmental and ovipositional rates, studying these processes across five constant temperatures (15, 20, 25, 30, and 35°C). Our models, which showed a high correlation with observed data (r2 ≥ 0.93), include a theoretical approach that combines the developmental variation of immatures with the necessary degree-days for 50% egg laying and complete egg development. These predictions allow for the forecasting of the second generation's occurrence, with relatively small deviations (one to three days) observed at two different field sites. The insights from this study are critical for both understanding the ecology of M. loreyi and for informing practical management decisions, such as optimal placement of barriers to prevent immigration and strategies for controlling local populations., Competing Interests: No authors have competing interests., (Copyright: © 2024 Baek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: MegaShield® is a newly developed temperature-sensitive anti-adhesive containing micronized acellular dermal matrix. The aim of this study was to investigate the efficacy and safety of MegaShield® compared with Guardix-SG® in the prevention of adhesions in patients undergoing bilateral total thyroidectomy., Method: We conducted a multicenter trial between October 2018 and March 2020 in patients undergoing total thyroidectomy. The patients were randomly assigned to either the MegaShield® group or the Guardix-SG® group. The primary outcome was the esophageal movement using marshmallow six weeks after the surgery and the secondary outcome was the assessed adhesion score. The safety assessment was also evaluated., Results: The study included 70 patients each in the MegaShield® and control (Guardix-SG®) groups. Baseline clinical characteristics, the mean score of marshmallow esophagography, and the sum of adhesion scores were not statistically different between the two groups. Inferiority test demonstrated that the efficacy of MegaShield® is not inferior to that of Guardix-SG®. There were no device-related complications in both groups., Conclusion: The efficacy and safety of MegaShield® were not inferior than those of Guardix-SG®. MegaShield® demonstrated the potential of ADM as a potential future anti-adhesive agent., Trial Registration: The name of trial registry CRIS (Clinical Research Information Service) https://cris.nih.go.kr/cris/index.jsp. (The full trial protocol can be accessed) Registration number: KCT0003204., Competing Interests: The authors of this manuscript have read the journal’s policy and declare the following competing interests: this study’s protocol and test devices were sponsored by L&C bio; however, a grant was finally sponsored by the Ministry of Health & Welfare. There are no patents, products in development, or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The Asian corn borer, Ostrinia furnacalis, is a serious insect pest that can infest corn leaves and stems. Due to its internal feeding behavior, its larvae are not exposed to insecticides that are usually sprayed for pest control. To minimize crop damage caused by O. furnacalis, improving insect resistance trait of corn has been considered as an optimal control tactic. This study screened 27 corn varieties for their insect resistance trait and selected three varieties of Ilmichal (IM), P3394, and Kwangpyeongok (KP) that showed insect resistance trait. O. furnacalis larvae did not show any significant difference in preference between these three insect-resistant corn varieties and a control susceptible variety. However, these resistant varieties after ingestion significantly interfered with larval development of O. furnacalis. This suggests that the insect resistance trait is induced by antibiosis, but not by antixenosis. Indeed, larvae fed with these varieties suffered from low chymotrypsin (CHY) activities in the midgut juice. To determine the target CHY inhibited by resistant corn varieties, a total of nine CHY genes (Of-CHY1~Of-CHY9) were predicted from the transcriptome of O. furnacalis. Six genes (Of-CHY1~Of-CHY6) were expressed in all developmental stages and tissues. Especially, Of-CHY3 was highly expressed in the midgut of O. furnacalis larvae. RNA interference (RNAi) using double-stranded RNA (dsRNA) specific to Of-CHY3 (2 μg of dsRNA injected to each L5 larva) resulted in significant reduction of Of-CHY3 expression level at 24 h post-treatment. Feeding L3 larvae with this dsRNA also significantly suppressed the expression level of Of-CHY3 and reduced its enzyme activity at 24 h post-treatment. A recombinant Escherichia coli expressing dsRNA specific to Of-CHY3 was constructed using L4440 vector. Feeding such recombinant bacteria suppressed the expression level of Of-CHY3 and prevented larval development of O. furnacalis. These results suggest that the three resistant varieties can produce a resistance factor(s) to inhibit the CHY activity of O. furnacalis and suppress larval growth. This study suggests that CHY might be an inhibition target in O. furnacalis for breeding insect-resistant corns., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Lunit INSIGHT CXR (Lunit) is a commercially available deep-learning algorithm-based decision support system for chest radiography (CXR). This retrospective study aimed to evaluate the concordance rate of radiologists and Lunit for thoracic abnormalities in a multicenter health screening cohort., Methods and Materials: We retrospectively evaluated the radiology reports and Lunit results for CXR at several health screening centers in August 2020. Lunit was adopted as a clinical decision support system (CDSS) in routine clinical practice. Subsequently, radiologists completed their reports after reviewing the Lunit results. The DLA result was provided as a color map with an abnormality score (%) for thoracic lesions when the score was greater than the predefined cutoff value of 15%. Concordance was achieved when (a) the radiology reports were consistent with the DLA results ("accept"), (b) the radiology reports were partially consistent with the DLA results ("edit") or had additional lesions compared with the DLA results ("add"). There was discordance when the DLA results were rejected in the radiology report. In addition, we compared the reading times before and after Lunit was introduced. Finally, we evaluated systemic usability scale questionnaire for radiologists and physicians who had experienced Lunit., Results: Among 3,113 participants (1,157 men; mean age, 49 years), thoracic abnormalities were found in 343 (11.0%) based on the CXR radiology reports and 621 (20.1%) based on the Lunit results. The concordance rate was 86.8% (accept: 85.3%, edit: 0.9%, and add: 0.6%), and the discordance rate was 13.2%. Except for 479 cases (7.5%) for whom reading time data were unavailable (n = 5) or unreliable (n = 474), the median reading time increased after the clinical integration of Lunit (median, 19s vs. 14s, P < 0.001)., Conclusion: The real-world multicenter health screening cohort showed a high concordance of the chest X-ray report and the Lunit result under the clinical integration of the deep-learning solution. The reading time slight increased with the Lunit assistance., Competing Interests: KNJ has received research grant funding from Lunit Inc. for activities not related to the present article. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors have no potential conflicts of interest to disclose.

Few large-scale studies have been conducted to show the joint effects of mortality associated with physical activity and sedentarism. Therefore, we examined the relationship between all-cause mortality and behavioral patterns among adults in the United States. Data of 17,730 non-institutionalized US civilians aged ≥20 years were extracted from the 2007-2014 National Health and Nutrition Examination Survey. We set the criteria for metabolic equivalents as 600 according to the WHO guideline, and sedentary time as 300 min/day according to the median. The Cox proportional hazards model was adjusted for demographic and lifestyle characteristics. During the 58.54±28.18 months follow-up, all-cause mortality rate was 4% and heart-related and cancer mortality rate was 1%. Participants in the high metabolic equivalents and low sedentary time group had a lower risk of all-cause (hazard ratio = 0.41, 95% confidence interval = 0.34-0.50), cardiovascular (hazard ratio = 0.36; 95% confidence interval = 0.23-0.55), and cancer (hazard ratio = 0.55; 95% confidence interval = 0.37-0.83) mortality, compared to those in the low metabolic equivalents and high sedentary time group. Sufficient physical activity and less sedentary behavior reduce all-cause and cause-specific mortality in adults in the United States, especially cardiovascular mortality among the elderly. Additional nationwide policies to improve behavioral patterns among adults need to be implemented in the United States., Competing Interests: The authors have declared that no competing interests exist.

Serum insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) levels can be used to monitor the safety of recombinant human growth hormone (rhGH) therapy. In this study, we evaluated the changes in serum IGF-I and IGFBP-3 levels during rhGH therapy as a marker of height outcome in prepubertal children. Totally, 705 prepubertal children with short stature were enrolled from the LG Growth Study Database. Data for three groups of subjects were obtained as follows: Idiopathic GH deficiency (IGHD; n = 486); idiopathic short stature (n = 66); small for gestational age (n = 153). Serum IGF-I and IGFBP-3 levels at the baseline and after the 1st and 2nd year of rhGH therapy, as well as the Δheight standard deviation score (SDS), were obtained. Δheight SDS after the 1st and 2nd year of rhGH therapy had notably increased compared to that at the baseline for all three groups. IGF-I and IGFBP-3 levels in all three groups were significantly increased compared to those at the baseline (p <0.001). Δheight SDS was positively correlated with ΔIGF-1 SDS after the 1st year of therapy, ΔIGFBP-3 SDS after the 2nd year of therapy in the IGHD group, and ΔIGF-I SDS and ΔIGFBP-3 SDS after the 2nd year of therapy (p < 0.05), regardless of whether the height at the baseline was a covariate. The increase in IGF-I and IGFBP-3 levels during rhGH therapy was related to the growth response in children with IGHD. Therefore, it may be valuable to measure the change in serum IGF-I and IGFBP-3 levels, especially the latter, during rhGH treatment to predict the growth response upon long-term treatment., Competing Interests: The authors have declared that no competing interests exist.

Objective: The chest X-ray (CXR) is the most readily available and common imaging modality for the assessment of pneumonia. However, detecting pneumonia from chest radiography is a challenging task, even for experienced radiologists. An artificial intelligence (AI) model might help to diagnose pneumonia from CXR more quickly and accurately. We aim to develop an AI model for pneumonia from CXR images and to evaluate diagnostic performance with external dataset., Methods: To train the pneumonia model, a total of 157,016 CXR images from the National Institutes of Health (NIH) and the Korean National Tuberculosis Association (KNTA) were used (normal vs. pneumonia = 120,722 vs.36,294). An ensemble model of two neural networks with DenseNet classifies each CXR image into pneumonia or not. To test the accuracy of the models, a separate external dataset of pneumonia CXR images (n = 212) from a tertiary university hospital (Gachon University Gil Medical Center GUGMC, Incheon, South Korea) was used; the diagnosis of pneumonia was based on both the chest CT findings and clinical information, and the performance evaluated using the area under the receiver operating characteristic curve (AUC). Moreover, we tested the change of the AI probability score for pneumonia using the follow-up CXR images (7 days after the diagnosis of pneumonia, n = 100)., Results: When the probability scores of the models that have a threshold of 0.5 for pneumonia, two models (models 1 and 4) having different pre-processing parameters on the histogram equalization distribution showed best AUC performances of 0.973 and 0.960, respectively. As expected, the ensemble model of these two models performed better than each of the classification models with 0.983 AUC. Furthermore, the AI probability score change for pneumonia showed a significant difference between improved cases and aggravated cases (Δ = -0.06 ± 0.14 vs. 0.06 ± 0.09, for 85 improved cases and 15 aggravated cases, respectively, P = 0.001) for CXR taken as a 7-day follow-up., Conclusions: The ensemble model combined two different classification models for pneumonia that performed at 0.983 AUC for an external test dataset from a completely different data source. Furthermore, AI probability scores showed significant changes between cases of different clinical prognosis, which suggest the possibility of increased efficiency and performance of the CXR reading at the diagnosis and follow-up evaluation for pneumonia., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: TK, DK, ML, and SUK are paid employees of JLK Inc. and JJ was a paid employee of JLK Inc. at the time of study. KGK received a research grant from JLK Inc. for activities not related to the present article. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Purpose: This study evaluated the performance of a commercially available deep-learning algorithm (DLA) (Insight CXR, Lunit, Seoul, South Korea) for referable thoracic abnormalities on chest X-ray (CXR) using a consecutively collected multicenter health screening cohort., Methods and Materials: A consecutive health screening cohort of participants who underwent both CXR and chest computed tomography (CT) within 1 month was retrospectively collected from three institutions' health care clinics (n = 5,887). Referable thoracic abnormalities were defined as any radiologic findings requiring further diagnostic evaluation or management, including DLA-target lesions of nodule/mass, consolidation, or pneumothorax. We evaluated the diagnostic performance of the DLA for referable thoracic abnormalities using the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, and specificity using ground truth based on chest CT (CT-GT). In addition, for CT-GT-positive cases, three independent radiologist readings were performed on CXR and clear visible (when more than two radiologists called) and visible (at least one radiologist called) abnormalities were defined as CXR-GTs (clear visible CXR-GT and visible CXR-GT, respectively) to evaluate the performance of the DLA., Results: Among 5,887 subjects (4,329 males; mean age 54±11 years), referable thoracic abnormalities were found in 618 (10.5%) based on CT-GT. DLA-target lesions were observed in 223 (4.0%), nodule/mass in 202 (3.4%), consolidation in 31 (0.5%), pneumothorax in one 1 (<0.1%), and DLA-non-target lesions in 409 (6.9%). For referable thoracic abnormalities based on CT-GT, the DLA showed an AUC of 0.771 (95% confidence interval [CI], 0.751-0.791), a sensitivity of 69.6%, and a specificity of 74.0%. Based on CXR-GT, the prevalence of referable thoracic abnormalities decreased, with visible and clear visible abnormalities found in 405 (6.9%) and 227 (3.9%) cases, respectively. The performance of the DLA increased significantly when using CXR-GTs, with an AUC of 0.839 (95% CI, 0.829-0.848), a sensitivity of 82.7%, and s specificity of 73.2% based on visible CXR-GT and an AUC of 0.872 (95% CI, 0.863-0.880, P <0.001 for the AUC comparison of GT-CT vs. clear visible CXR-GT), a sensitivity of 83.3%, and a specificity of 78.8% based on clear visible CXR-GT., Conclusion: The DLA provided fair-to-good stand-alone performance for the detection of referable thoracic abnormalities in a multicenter consecutive health screening cohort. The DLA showed varied performance according to the different methods of ground truth., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to investigate the diagnostic performance of chest computed tomography (CT) for opportunistic screening and longitudinal follow-up of osteoporosis in breast cancer patients, compared to dual-energy X-ray absorptiometry (DXA). The association between L1 vertebral attenuation on chest CT and incidental fracture was also evaluated. We retrospectively reviewed 414 consecutive breast cancer patients who underwent both non-enhanced chest CT and DXA within a 3-month interval and had at least two DXA and two chest CT examinations over more than 1 year. The attenuation value of the L1 trabecular bone was measured on an axial CT image and compared to the corresponding DXA T-score. The diagnostic performance of L1 vertebral attenuation on CT for osteoporosis was calculated at different thresholds (90 HU, 100 HU, 110 HU), and the correlation between L1 vertebral attenuation values and DXA T-scores was statistically analyzed. Overall fracture-free survival was estimated and compared with the threshold of 90 HU on CT and -2.5 T-score on DXA. Of 414 patients (median age, 53.0 years), 88 (21.3%) had either vertebral or non-vertebral fractures. The median follow-up duration between initial and final DXA was 902.9 days. There was a moderate correlation between L1 vertebral attenuation value and DXA T-score (ρ = 0.684, CI 0.653-0.712). Fracture-free survival was significantly lower in patients with attenuation values ≤90 HU on CT and T-scores ≤-2.5 on DXA (P < .001). Multivariate analysis revealed that attenuation values ≤90 HU on CT (P < .001), T-scores ≤-2.5 on DXA (P = .003), and age ≥65 years (P = .03) were independent significant prognostic factors associated with overall fracture-free survival. The sensitivities and specificities of L1 attenuation value were 54.9% and 85.8% at 90-HU threshold, 74.0% and78.4% at 100-HU threshold, and 83.9% and 70.1% at 110-HU threshold, respectively. In conclusion, CT can be used for predicting osteoporosis and discriminating incidental fracture risk in breast cancer patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Topical corticosteroids (TCs) are widely used to treat dermatological conditions such as eczema and psoriasis. It can be a safe and effective treatment when used appropriately. However, misguided information and corticosteroid phobia appear to contribute to inadequate adherence to therapy, leading to unsatisfactory treatment outcomes. Therefore, community pharmacists (CPs) are in a prime position to inform patients about the appropriate use of medicine. The aim of this study was to examine how the knowledge and perceptions of CPs, as well as other factors, associate CPs' patient counseling practice around the use of TCs. A structured, validated questionnaire was distributed to CPs in the Republic of Korea, and additional focus group discussions were implemented to obtain a deeper understanding of the survey findings. We analyzed the survey results by applying a modified knowledge-perception-practice model. In addition, we used path analysis to validate the model and assessed how knowledge level and perceptions of barriers affect CPs' counseling behavior. We ran a multiple regression to identify factors that associate CPs' practice levels. A total of 1018 surveys were analyzed. In general, respondents had sufficient knowledge to provide appropriate patient counseling on TC use. An increase in knowledge level positively associated the quality of practice, and more knowledge increased the perception of barriers that negatively associated patient counseling. Location in rural areas and pharmacists' perception of counseling barriers negatively associated the quality of practice. A higher level of knowledge, training in ADEs, higher proportion of OTC TC sales, and increased time for counseling positively associated the quality of practice. Therefore, minimizing barriers such as negative perceptions is very important in facilitating CPs' counseling practice around TC use., Competing Interests: The authors have declared that no competing interests exist. The author Nam Gyu Kim's current affiliation is Wellmarker Bio Co, but they were not affiliated with that company during their involvement in this study, and Wellmarker Bio Co had no part in the research presented here. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: The National Lung Screening Trial (NLST) revealed that low-dose computed tomography (LDCT) screening could reduce lung cancer mortality in heavy smokers. Lung screening with LDCT was implemented in July 2019 as part of the National Cancer Screening Program in Korea for heavy smokers who meet NLST criteria [smokers aged 55-74 years with 30 pack-years (PY) or more, excluding former smokers with more than 15 years since smoking cessation]. This study evaluated NLST-eligible heavy smokers' adherence to general medical checkup and cancer screening guidelines., Methods: Using the Korea National Health and Nutrition Examination Survey (KNHANES) from 2010 to 2012, we compared adherence of Korean adults (55-74 years, n = 5,480) to general medical checkup and cancer (gastric, colorectal, breast, and cervical) screening guidelines according to self-reported smoking status. Smoking and PY data were available, but no data indicating when former smokers ceased smoking were available. Accordingly, smoking status was only classified as NLST (smokers with a history ≥ 30 PY) and non-NLST. Individuals who met NLST criteria were subdivided into current (NLST-current) and former smokers (NLST-former). Multivariable logistic regression was used to evaluate adherence to screening recommendations as a function of the study group (NLST-current, NLST-former, non-NLST) using possible covariates (sociodemographic factors, health-related behaviors, comorbidities, and self-reported health status)., Results: Weighted prevalence of NLST-current was 9.7%, of NLST-former was 9.6%, and of non-NLST was 80.7%. Overall screening rates were 70.7% (medical checkup), 59.1% (stomach cancer), 58.1% (colorectal cancer), 59.1% (breast cancer), and 48.9% (cervical cancer). Adherence to colorectal cancer screening and medical checkup was lower in NLST-current than non-NLST (AOR 0.59; 95% CI 0.44-0.78 for colorectal cancer; AOR 0.70; 95% CI 0.52-0.95 for medical checkup). Screening practices for other cancers were not different., Conclusions: Current heavy smokers meeting NLST criteria were less likely to have colorectal cancer screening or general medical checkup. Understanding the screening practices of this target population might enable the development of more effective plans to implement lung screening and improve screening compliance for other cancers., Competing Interests: No authors have competing interests

Background: The duration of antidepressant use affects the treatment of depression. Using the National Health Insurance database, which covers almost the entire national population, we verified the factors associated with the inadequate short-term use of initially prescribed antidepressants and their effects on the relapse and recurrence of depressive episodes., Methods: There were 752,190 patients included who had been newly prescribed antidepressants in 2012 with the diagnosis of depressive disorder. They were followed-up until December 31, 2015. They were classified as short-term and long-term antidepressant users depending on whether they used a specific initial antidepressant for at least four weeks. Sociodemographic, clinical, and medical utilization factors affecting the duration of antidepressant use were investigated. We also identified whether the duration of antidepressant use affected the risk of relapse and recurrence, which was defined by the restarting of antidepressants., Results: Initial antidepressants were taken for less than 28 days by 458,057 (60.84%) patients. Tricyclic antidepressants were used as the initial antidepressant more frequently than selective serotonin reuptake inhibitors (64.5% versus 19.3%). The type of initial antidepressant, polypharmacy, psychiatric and medical comorbidities, type of insurance coverage, and type of medical institution visited were associated with short-term use. Short-term use marginally increased the risk of relapse and recurrence of depressive episodes (Hazard ratio: 1.06, 95% confidence intervals 1.048-1.075)., Conclusions: Short-term antidepressant use is widespread in Korea, and assessment in various aspects are necessary to set proper treatment plans., Competing Interests: The authors have declared that no competing interests exist.

Objective: Suicide in adolescents is a major problem worldwide and previous history of suicide ideation and attempt represents the strongest predictors of future suicidal behavior. The aim of this study was to develop prediction model to identify Korean adolescents of high risk suicide (= who have history of suicide ideation/attempt in previous year) using machine learning techniques., Methods: A nationally representative dataset of Korea Youth Risk Behavior Web-based Survey (KYRBWS) was used (n = 59,984 of middle and high school students in 2017). The classification process was performed using machine learning techniques such as logistic regression (LR), random forest (RF), support vector machine (SVM), artificial neural network (ANN), and extreme gradient boosting (XGB)., Results: A total of 7,443 adolescents (12.4%) had a previous history of suicidal ideation/attempt. In the multivariable analysis, sadness (odds ratio [OR], 6.41; 95% confidence interval [95% CI], 6.08-6.87), violence (OR, 2.32; 95% CI, 2.01-2.67), substance use (OR, 1.93; 95% CI, 1.52-2.45), and stress (OR, 1.63; 95% CI, 1.40-1.86) were associated factors. Taking into account 26 variables as predictors, the accuracy of models of machine learning techniques to predict the high-risk suicidal was comparable with that of LR; the accuracy was best in XGB (79.0%), followed by SVM (78.7%), LR (77.9%), RF (77.8%), and ANN (77.5%)., Conclusions: The machine leaning techniques showed comparable performance with LR to classify adolescents who have previous history of suicidal ideation/attempt. This model will hopefully serve as a foundation for decreasing future suicides as it enables early identification of adolescents at risk of suicide and modification of risk factors., Competing Interests: NO authors have competing interests.

Purpose: The aim of this registry study was to analyze the long-term safety and effectiveness of recombinant human growth hormone (rhGH) in South Korean pediatric patients (≥2 years of age) with growth hormone deficiency GHD) of idiopathic or organic etiology, idiopathic short stature, Turner syndrome, small for gestational age and chronic renal failure., Methods: The study patients were followed-up till two years after the epiphyseal closure, with visits scheduled every six months. The outcome measures included the incidence of adverse events (AEs, in particular, neoplasia, glucose intolerance and hypothyroidism), as well as height standard deviation score (Ht SDS) and annual height velocity. The results of the interim analysis of a 5-year accumulated data for 2,024 patients (7,342 patient-years, PY) are presented., Results: A total of 14 neoplasms were diagnosed (191/100,000 PY); 7 out of 9 malignancies were recurrent craniopharyngioma found in patients with organic GHD. Seven cases of glucose intolerance (95/100,000 PY) and 22 cases of hypothyroidism (300/100,000 PY) were detected; about half of the cases (4 and 10 cases each) were considered to be related with rhGH treatment. Most of the growth-retarded patients showed continuous improvement in Ht SDS, with the most prominent effect observed within a year of treatment initiation. The beneficial effect of rhGH on Ht SDS gain was maintained for 2-4 years., Conclusions: The incidence of AEs of interest in rhGH-treated patients was low, and most of the neoplasms were benign and/or non-related to rhGH. Most patients benefited from the therapy in terms of height increment., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: YJR, JHY, JHC, HWC, JHK, SC and ITH are the members of the Observational Study Monitoring Board of LG Growth Study (LGS), and ITH, CHS and HSK are Steering Committee members of the LGS. EYK is a full-time employee of LG Chem, Ltd who provided funding for the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Reproduction is a process that is extremely sensitive to changes in nutritional status. The nutritional control of oogenesis via insulin signaling has been reported; however, the mechanism underlying its sensitivity and tissue specificity has not been elucidated. Here, we determined that Drosophila Makorin RING finger protein 1 gene (Mkrn1) functions in the metabolic regulation of oogenesis. Mkrn1 was endogenously expressed at high levels in ovaries and Mkrn1 knockout resulted in female sterility. Mkrn1-null egg chambers were previtellogenic without egg production. FLP-FRT mosaic analysis revealed that Mkrn1 is essential in germline cells, but not follicle cells, for ovarian function. As well, AKT phosphorylation via insulin signaling was greatly reduced in the germline cells, but not the follicle cells, of the mutant clones in the ovaries. Furthermore, protein-rich diet elevated Mkrn1 protein levels, without increased mRNA levels. The p-AKT and p-S6K levels, downstream targets of insulin/Tor signaling, were significantly increased by a nutrient-rich diet in wild-type ovaries whereas those were low in Mkrn1exS compared to wild-type ovaries. Taken together, our results suggest that nutrient availability upregulates the Mkrn1 protein, which acts as a positive regulator of insulin signaling to confer sensitivity and tissue specificity in the ovaries for proper oogenesis based on nutritional status., Competing Interests: The authors have declared that no competing interests exist.

Background: Epidemiological data suggests that obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. We investigate the effects of cyclical intermittent hypoxia (CIH), akin to the underlying pathophysiology of OSA, on lung cancer progression and metastatic profile in a mouse model., Methods: Intrathoracic injection of Ad5CMVCre virus into a genetically engineered mouse (GEM) KrasG12D+/-; p53fl/fl; myristolated-p110αfl/fl-ROSA-gfp was utilized to induce a solitary lung cancer. Male mice were then exposed to either CIH or Sham for 40-41 days until harvest. To monitor malignant progression, serial micro CT scans with respiratory gating (no contrast) was performed. To detect spontaneous metastases in distant organs, H&E and immunohistochemistry were performed., Results: Eighty-eight percent of injected Ad5CMVCre virus was recovered from left lung tissue, indicating reliable and accurate injections. Serial micro CT demonstrated that CIH increases primary lung tumor volume progression compared to Sham on days 33 (p = 0.004) and 40 (p<0.001) post-injection. In addition, CIH increases variability in tumor volume on day 19 (p<0.0001), day 26 (p<0.0001), day 33 (p = 0.025) and day 40 (p = 0.004). Finally, metastases are frequently detected in heart, mediastinal lymph nodes, and right lung using H&E and immunohistochemistry., Conclusions: Using a GEM mouse model of metastatic lung cancer, we report that male mice with solitary lung cancer have accelerated malignant progression and increased variability in tumor growth when exposed to cyclical intermittent hypoxia. Our results indicate that cyclical intermittent hypoxia is a pathogenic factor in non-small cell lung cancer that promotes the more rapid growth of developing tumors., Competing Interests: This is not an industry-supported study. JCG: External Advisory Boards: KSQ Therapeutics, ITUS, Compass Therapeutics; Sponsored research: Compass Therapeutics, ITUS. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend intra-access flow (Qa) measurement as the preferred vascular access surveillance method over static intra-access pressure ratio (SIAPR). Recently, it has become possible to perform Qa measurement during hemodialysis using thermodilution method called blood temperature monitoring (BTM) with the Twister device. The aim of this study was to investigate the correlation between Qa by BTM and SIAPR and to compare the performance of two tests in prediction of vascular access stenosis., Methods: The study was performed from January 2016 to November 2017 and included 97 patients with arteriovenous fistulas (AVF). Qa by BTM and SIAPR were simultaneously measured every 1~3 months with a total of 449 measurements during study period., Results: In our study population, mean age was 59.9±10.0 years and 61.9% were diabetes. The mean Qa obtained by BTM was 1186±588 mL/min. There was no correlation between Qa by BTM and venous SIAPR (r = 0.061, P = 0.196). Angiography identified 36 stenotic AVFs (37.1%) among the study subjects. They included 13 cases with only inflow stenosis, 6 with only outflow stenosis, and 17 with stenosis on both sides. Receiver-operating characteristic (ROC) curve analysis showed that Qa by BTM had higher discriminative ability to diagnose vascular access stenosis compared to SIAPR (P <0.001). The Qa less than 583 mL/min showed the highest diagnostic accuracy in vascular stenosis prediction., Conclusion: Intradialytic measurement of Qa by BTM showed better diagnostic power over venous SIAPR in prediction of vascular access stenosis., Competing Interests: The authors have declared that no competing interests exist.

Background: Sarcopenia, defined as decreased skeletal muscle mass, is prevalent and associated with poor prognosis in various solid tumors. This study aimed to determine the prognostic role of sarcopenia in patients with advanced gastric cancer (AGC)., Methods: This retrospective study consisted of 140 consecutive patients who underwent palliative chemotherapy for AGC. A cross-sectional area of muscle at the level of the third lumbar vertebra (L3) was measured using baseline computed tomography (CT) scans. Sarcopenia was defined as a L3 skeletal muscle index of ≤ 49 cm2/m2 for men and ≤ 31 cm2/m2 for women using Korean-specific cutoffs. We compared the overall survival (OS) and clinical characteristics of patients with and without sarcopenia., Results: The median age was 67 years, and 133 (95%) patients had metastatic disease. Sarcopenia was present in 67 patients (47.9%) and was significantly related to male sex (p < 0.001) and low body mass index (p = 0.002). Patients with sarcopenia had a significantly shorter OS than those without sarcopenia (median, 6.8 months vs. 10.3 months, respectively; p = 0.033). In the multivariable analysis, sarcopenia was an independent prognostic factor of poor OS (hazard ratio, 1.51, p = 0.029); no response to chemotherapy (p < 0.001), no second-line chemotherapy (p < 0.001), metastatic sites ≥ 3 (p < 0.001), and low serum albumin level (p = 0.033) were also independent prognostic factors of poor OS., Conclusion: Sarcopenia, as determined by baseline CT, can be used to predict poor prognosis in AGC patients treated with palliative chemotherapy., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0191075.].

Background: Sarcopenia is prevalent and a known adverse prognostic effector in lung cancer (LCA). However, the relationship between sarcopenia and histology remains uncertain in LCA., Methods: Consecutive patients with newly diagnosed LCA (n = 778) between June 2012 and February 2015 were retrospectively reviewed to identify factors associated with sarcopenia. Sarcopenia was defined as CT-determined L3 muscle index (muscle area at L3/height2) of < 55 cm2/m2 for men and < 39 cm2/m2 for women., Results: Mean patient age was 67.7 ± 10.8 years, and most (73.1%) were male. The most prevalent histology was adenocarcinoma (44.0%) and 71.6% of patients had stage III or IV disease. The overall prevalence of sarcopenia was 48.2% (60.3% in men, and 15.3% in women). Univariable analysis showed sarcopenia was significantly associated with male gender, age (≥ 65 years), smoking status, lower BMI (< 23 kg/m2), advanced stage (III and IV), and high comorbidity score (Charlson index ≥ 3). Furthermore, the prevalence of sarcopenia was higher in squamous cell carcinoma (54.9%) and small cell LCA (56.4%) than in adenocarcinoma (39.8%). Multivariable analyses showed sarcopenia was independently associated with a male gender (odds ratio [OR], 11.13), elderly (OR, 2.02) and low BMI (OR, 6.28), stage IV (OR, 1.98), and high comorbidity (OR, 1.93). However, no significant association was found between histologic subtypes and sarcopenia., Conclusions: Sarcopenia was found to be significantly associated with old age, male gender, an advanced stage, comorbidities, and low BMI in LCA. However, histology subtype was not an independent factor for the presence of sarcopenia.

Lung cancer specialists play an important role in designing and implementing lung cancer screening. We aimed to describe their 1) attitudes toward low-dose lung computed tomography (LDCT) screening, 2) current practices and experiences of LDCT screening and 3) attitudes and opinions towards national lung cancer screening program (NLCSP). We conducted a national web-based survey of pulmonologists, thoracic surgeons, medical oncologists, and radiological oncologists who are members of Korean Association for Lung Cancer (N = 183). Almost all respondents agreed that LDCT screening increases early detection (100%), improves survival (95.1%), and gives a good smoking cessation counseling opportunity (88.6%). Most were concerned about its high false positive results (79.8%) and the subsequent negative effects. Less than half were concerned about radiation hazard (37.2%). Overall, most (89.1%) believed that the benefits outweigh the risks and harms. Most (79.2%) stated that they proactively recommend LDCT screening to those who are eligible for the current guidelines, but the screening propensity varied considerably. The majority (77.6%) agreed with the idea of NLCSP and its beneficial effect, but had concerns about the quality control of CT devices (74.9%), quality assurance of radiologic interpretation (63.3%), poor access to LDCT (56.3%), and difficulties in selecting eligible population using self-report history (66.7%). Most (79.2%) thought that program need to be funded by a specialized fund rather than by the National Health Insurance. The opinions on the level of copayment for screening varied. Our findings would be an important source for health policy decision when considering for NLCSP in Korea.

Plants have attracted attention as bio-drug production platforms because of their economical and safety benefits. The preliminary efficacy of ZMapp, a cocktail of antibodies produced in N. benthamiana (Nicotiana benthamiana L.), suggested plants may serve as a platform for antibody production. However, because the amino acid sequences of the Fab fragment are diverse and differences in post-transcriptional processes between animals and plants remain to be elucidated, it is necessary to confirm functional equivalence of plant-produced antibodies to the original antibody. In this study, Obinutuzumab, a third generation anti-CD20 antibody, was produced in N. benthamiana leaves (plant-obinutuzumab) and compared to the original antibody produced in glyco-engineered Chinese hamster ovary (CHO) cells (CHO-obinutuzumab). Two forms (with or without an HDEL tag) were generated and antibody yields were compared. The HDEL-tagged form was more highly expressed than the non-HDEL-tagged form which was cleaved in the N-terminus. To determine the equivalence in functions of the Fab region between the two forms, we compared the CD20 binding affinities and direct binding induced cell death of a CD20-positive B cells. Both forms showed similar CD20 binding affinities and direct cell death of B cell. The results suggested that plant-obinutuzumab was equivalent to CHO-obinutuzumab in CD20 binding, cell aggregation, and direct cell death via binding. Therefore, our findings suggest that Obinutuzumab is a promising biosimilar candidate that can be produced efficiently in plants.

Background and Aim: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is commonly used to obtain tissue external to the gastrointestinal tract. EUS-FNA is relatively safe, but occasionally adverse events have been reported. There is scarcity of data on risk factors of adverse events. The aim of this study is to identify risk factors associated with EUS-FNA., Methods: In this multicenter case-control study, we retrospectively reviewed 4,097 cases between 2009 and 2012 at 15 hospitals in Korea. Among the patients there were 104 cases (2.5%) who had adverse events of which 12 (0.29%) were severe. We matched 520 controls (1:5 ratios) stratified by hospital to analyze the potential risk factors., Results: The most common adverse events were pancreatitis (45/104, 43.3%) and infection (46/104, 44.2%). Endoscopic retrograde cholangiopancreatography (ERCP) on the same day was a risk factor of all adverse events [OR = 2.41, 95% CI (1.41, 4.12)], pancreatitis [OR = 2.31, 95% CI (1.02, 5.25)], and infection [OR = 2.75, 95% CI (1.31, 5.78)]. More than 15 to-and-fro movements during puncture increased the risk of pancreatitis [OR = 2.30, 95% CI (1.11, 4.77)] and infection [OR = 3.65, 95% CI (1.55, 8.59)]. A higher number of punctures was positively correlated with pancreatitis [OR = 1.34, 95% CI (1.08, 1.67)] but negatively correlated with infection [OR = 0.66, 95% CI (0.48, 0.89)]., Conclusions: EUS-FNA is a safe procedure in which serious adverse events are rare. We define some risk factors of adverse events during EUS-FNA, including ERCP on the same day, a higher number of punctures, and more than 15 to-and-fro movements.

The Sewol ferry incident on April 16, 2014 in South Korea claimed the lives of 304 individuals, including about 250 high school students on a school trip. The majority of South Korean citizens were watching live updates on the capsized Sewol ferry, anxiously watching on TV how the vessel fully sunk over time. They were desperately hoping for the rescue of the survivors inside. However, their anxiety had become shock, anger, and helplessness, and the disaster has become a daunting, collective trauma, not just to the victims and their families, but also to the citizens who were exposed only through the media. In this study, we interviewed victims' families two years after the incident. We explored how they have experienced changes in their social relationships. We conducted semi-structured interviews of 54 family members of the student victims. We qualitatively examined the data applying a thematic analysis. Changes in their social relationships were largely divided into the relationships in the proximal environment and the relationships in distal environments. The former included subcategories such as immediate family, coworkers, friends, relatives, survived students and their parents, and concepts corresponding to each subcategory. The latter involved subcategories such as neighbors, other citizens, the victims' family committee, government, and society, and concepts subject to each subcategory. Based on these findings, rehabilitation plans for trauma victims and their families should take into account the significant changes in their social relationships and the further consequences of those changes.

Purpose: Medical students must understand the principles of ultrasonography (US), because US examinations are an important component of patient care in clinical practice. Pocket-sized ultrasound devices have the benefits of accessibility and ease of use. The primary objective of the present study was to evaluate the educational value of these devices in terms of improving medical student interest and understanding of US and sonographic anatomy., Methods: We added a US training program comprised of a self-study learning module and a hands-on training session to a two-week block curriculum of medical imaging for first year medical students (n = 40). Multiple pocket-sized US devices were used on a small-group basis during a single afternoon. Students were asked to complete a questionnaire before and after the US training session; these two questionnaires contained 6 and 10 questions, respectively, which were rated by students using a five-point Likert scale. In addition, understanding of sonographic anatomy was tested before and after the training program., Results: Forty students completed the two questionnaires and the anatomy-related tests. Students found the program educationally valuable (4.37 ± 0.54 of 5) and reported that US practice was useful for improving their understanding of the principles of US examinations (4.23 ± 0.66 of 5) and sonographic anatomy (4.40 ± 0.55 of 5). Overall confidence at performing US examinations and understanding of sonographic anatomy were significantly increased after US training (increased overall confidence score, 1.87 ± 0.91 and improvement in sonographic anatomy score, 6.55 ± 1.55, p values < 0.001)., Conclusion: US training using pocket-sized ultrasound devices was found to be educationally valuable for medical students in terms of improving understanding of US principles and familiarizing students with sonographic anatomy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with memory loss and cognitive impairments. An AD transgenic (Tg) pig model would be useful for preclinical testing of therapeutic agents. We generated an AD Tg pig by somatic cell nuclear transfer (SCNT) using a multi-cistronic vector that harbored three AD-related genes with a total of six well-characterized mutations: hAPP (K670N/M671L, I716V, and V717I), hTau (P301L), and hPS1 (M146V and L286P). Four AD Tg cell lines were established from Jeju black pig ear fibroblasts (JB-PEFs); the resultant JB-PEFAD cells harbored transgene integration, expressed transgene mRNAs, and had normal karyotypes. Tg line #2-1, which expressed high levels of the transgenes, was used for SCNT; cleavage and blastocyst rates of embryos derived from this line were lower than those of Non-Tg. These embryos yielded three piglets (Jeju National University AD-Tg pigs, JNUPIGs) revealed by microsatellite testing to be genetically identical to JB-PEFAD. Transgenes were expressed in multiple tissues, and at especially high levels in brain, and Aβ-40/42, total Tau, and GFAP levels were high in brains of the Tg animals. Five or more copies of transgenes were inserted into chromosome X. This is the first report of an AD Tg pig derived from a multi-cistronic vector.

Objective: To investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents., Methods: Data collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred., Results: A total of 505,859 children received systemic fluoroquinolone during the study period-297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs., Conclusion: The dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Objectives: Despite a sharp increase in e-cigarette use, there is debate about whether e-cigarettes are a viable alternative for harm reduction, and the forms that regulation should take. Healthcare providers can be effective in offering guidance to patients and their families and shaping regulatory policy. We described lung cancer specialists' attitudes toward e-cigarettes and its regulation., Methods: We undertook a nationwide survey of pulmonologists, thoracic surgeons, medical and radiological oncologists who are members of Korean Association for Lung Cancer. Survey items included beliefs and attitudes toward e-cigarettes, attitudes toward e-cigarette regulation and preparedness on discussing e-cigarettes with their patients., Results: Most respondents believed that e-cigarettes are not safer than conventional tobacco cigarettes (75.7%) or smokeless tobacco (83.2%), and feared that discussing e-cigarettes with the patients would encourage use (65.4%). They did not consider it a smoking cessation treatment (78.3%), and thus would not recommend it to smokers who do not want to quit (82.2%) or who failed to quit with conventional smoking cessation treatment (74.1%). Most respondents supported all examples of e-cigarette regulations, including the safety and quality check (97.8%), warning label (97.8%), advertisement ban (95.1%), restriction of flavoring (78.4%), minimum purchasing age (99.5%), and restriction of indoor use (94.6%). Most learned about e-cigarettes from media and advertisements, or conversation with patients rather than through professional scientific resources, and reported discomfort when discussing e-cigarette with patients., Conclusion: Lung cancer specialist physicians in Korea doubt the safety of e-cigarette and use of e-cigarette as smoking cessation treatment, and supported strict regulation. However, only 20% reported that they obtained information on e-cigarettes from the scientific literature and many lacked adequate knowledge based on scientific evidence, suggesting the need for better preparedness. Nevertheless, the views of professionals revealed from our study could help to develop clinical guidelines and regulatory guidance.

Background: As the global population ages, disabling hearing impairment (HI) have been increased rapidly. The impact of HI on health-related quality of life (HRQoL) is of great importance to aid the development of strategic plans and to guide therapeutic interventions., Purpose: To evaluate HRQoL in Korean adults with different degrees of HI using EuroQol five-dimensional (EQ-5D) and EQ-visual analogue scale (VAS), the preference-based generic measures of HRQoL., Methods: Using a representative dataset from the Korea National Health and Nutrition Examination Survey (KNHANES) from January 2010 to December 2012, EQ-5D questionnaire and EQ- VAS scores of subjects with HI were compared with those of subjects without HI. Logistic regression analysis, with adjustment for covariates, was used to evaluate the impact of HI on HRQoL scales. HI was defined according to the hearing thresholds of pure-tone averages at 0.5, 1, 2, and 3 kHz of the better hearing ear as follows; mild HI (26 to < 40 dB) and moderate to severe HI (≥ 40 dB)., Results: Of the 16,449 Korean adults in KNHANES (age, 45.0 ± 0.2 years; male, 49.7%), 1757 (weighted prevalence, 7.6%) had mild HI and 890 (3.6%) had moderate to severe HI. Subjects with HI had impaired HRQoL as compared with subjects without HI (EQ-5D, 0.96 ± 0.00 vs. 0.88±0.00 vs. 0.86 ± 0.01 for control vs. mild HI vs. moderate to severe HI, p < 0.001; EQ-VAS, 75.10 ± 0.18 vs. 67.48 ± 0.63 vs. 66.24 ± 0.92 for control vs. mild HI vs. moderate to severe HI, p < 0.001). After adjusting for socio-demographic factors (age, gender, household income, education level, presence of spouse) and health-related behaviors (smoking status, alcohol intake, regular exercise), psychological stress, and the presence of comorbidities (diabetes, hypercholesterolemia, hypertension, decreased eGFR, and tinnitus), EQ-VAS remained impaired in the moderate to severe HI group (61.72±1.69) as compared with the control group (65.68 ± 1.26, p = 0.004), but EQ-5D impairment disappeared (0.86 ± 0.02 vs.0.88±0.01 for moderate to severe HI vs. control, p = 0.058)., Conclusion: After adjusting for socio-demographic and psychosocial factors and comorbidities, Korean adults with moderate to severe HI rated their health statuses lower than subjects without HI., Competing Interests: The authors have declared that no competing interests exist.

Background: Advanced lung cancer inflammation index (ALI, body mass index [BMI] x serum albumin/neutrophil-lymphocyte ratio [NLR]) has been shown to predict overall survival (OS) in small cell lung cancer (SCLC). CT enables skeletal muscle to be quantified, whereas BMI cannot accurately reflect body composition. The purpose was to evaluate prognostic value of modified ALI (mALI) using CT-determined L3 muscle index (L3MI, muscle area at L3/height2) beyond original ALI., Methods: L3MIs were calculated using the CT images of 186 consecutive patients with SCLC taken at diagnosis, and mALI was defined as L3MI x serum albumin/NLR. Using chi-squared test determined maximum cut-offs for low ALI and low mALI, the prognostic values of low ALI and low mALI were tested using Kaplan-Meier method and Cox proportional hazards analysis. Finally, deviance statistics was used to test whether the goodness of fit of the prognostic model is improved by adding mALI as an extra variable., Results: Patients with low ALI (cut-off, 31.1, n = 94) had shorter OS than patients with high ALI (median, 6.8 months vs. 15.8 months; p < 0.001), and patients with low mALI (cut-off 67.7, n = 94) had shorter OS than patients with high mALI (median, 6.8 months vs. 16.5 months; p < 0.001). There was no significant difference in estimates of median survival time between low ALI and low mALI (z = 0.000, p = 1.000) and between high ALI and high mALI (z = 0.330, p = 0.740). Multivariable analysis showed that low ALI was an independent prognostic factor for shorter OS (HR, 1.67, p = 0.004), along with advanced age (HR, 1.49, p = 0.045), extensive disease (HR, 2.27, p < 0.001), supportive care only (HR, 7.86, p < 0.001), and elevated LDH (HR, 1.45, p = 0.037). Furthermore, goodness of fit of this prognostic model was not significantly increased by adding mALI as an extra variable (LR difference = 2.220, p = 0.136)., Conclusion: The present study confirms mALI using CT-determined L3MI has no additional prognostic value beyond original ALI using BMI. ALI is a simple and useful prognostic indicator in SCLC., Competing Interests: The authors have declared that no competing interests exist.

Background: The prognostic significance of sarcopenia, an important component of cancer cachexia, has been demonstrated in oncologic patients. Catabolic drivers have been suggested to be key features of cancer cachexia., Objective: To determine the relationship between systemic inflammatory markers and CT-determined muscle mass in patients with SCLC., Methods: Cross-sectional muscle areas were evaluated at the level of the third lumbar vertebra (L3) using baseline CT images in 186 SCLC patients. Sarcopenia was defined as a L3 muscle index (L3MI, muscle area at L3/height2) of < 55 cm2/m2 for men and of < 39 cm2/m2 for women. Systemic inflammatory markers investigated included serum white blood cell count (WBC), neutrophil: lymphocyte ratio (NLR), C-reactive protein (CRP), and albumin., Results: Mean L3MI was 47.9 ± 9.7 cm2/m2 for men and 41.6 ± 7.0 cm2/m2 for women. Sarcopenia was present in 128 patients (68.8%), and sarcopenic patients had significant serum lymphocyte counts and albumin levels (p = 0.002 and 0.041, respectively), and higher NLRs and CRP levels (p = 0.011 and 0.026) than non-sarcopenic patients. Multivariable analysis revealed that CRP independently predicted L3MI (β = -0.208; 95% CI, -0.415 to -0.002; p = 0.048), along with gender and BMI (p values < 0.001) and performance status (p = 0.010)., Conclusion: The present study confirms a significant linear relationship exists between CT-determined muscle mass and CRP in SCLC patients. This association might provide a better understanding of the mechanism of cancer cachexia.

Somatic cell nuclear transfer (SCNT) is a well-known laboratory technique. The principle of the SCNT involves the reprogramming a somatic nucleus by injecting a somatic cell into a recipient oocyte whose nucleus has been removed. Therefore, the nucleus donor cells are considered as a crucial factor in SCNT. Cell cycle synchronization of nucleus donor cells at G0/G1 stage can be induced by contact inhibition or serum starvation. In this study, acteoside, a phenylpropanoid glycoside compound, was investigated to determine whether it is applicable for inducing cell cycle synchronization, cytoprotection, and improving SCNT efficiency in canine fetal fibroblasts. Primary canine fetal fibroblasts were treated with acteoside (10, 30, 50 μM) for various time periods (24, 48 and 72 hours). Cell cycle synchronization at G0/G1 stage did not differ significantly with the method of induction: acteoside treatment, contact inhibition or serum starvation. However, of these three treatments, serum starvation resulted in significantly increased level of reactive oxygen species (ROS) (99.5 ± 0.3%) and apoptosis. The results also revealed that acteoside reduced ROS and apoptosis processes including necrosis in canine fetal fibroblasts, and improved the cell survival. Canine fetal fibroblasts treated with acteoside were successfully arrested at the G0/G1 stage. Moreover, the reconstructed embryos using nucleus donor cells treated with acteoside produced a healthy cloned dog, but not the embryos produced using nucleus donor cells subjected to contact inhibition. In conclusion, acteoside induced cell cycle synchronization of nucleus donor cells would be an alternative method to improve the efficiency of canine SCNT because of its cytoprotective effects.

Background: Skeletal muscle mass (SMM) plays a crucial role in systemic glucose metabolism., Objective: To obtain reference data on absolute and relative values of SMM for Korean children and adolescents., Methods: Cross-sectional results from 1919 children and adolescents (1024 boys) aged 10-18 years that underwent dual-energy X-ray absorptiometry (DXA) during the Korean National Health and Nutrition Examination Survey 2009-2011 were analyzed. SMMs were evaluated as follows; absolute SMM (appendicular skeletal muscle mass [ASM]) and relative SMMs, namely, height-adjusted skeletal muscle index (SMI; ASM/height2), %SMM (ASM/weight x 100), and skeletal muscle-to-body fat ratio (MFR; ASM/body fat mass)., Results: Percentile curves illustrated the developmental patterns of the SMMs of Korean children and adolescents. ASM and SMI increased with age in both genders, and increased from age 10 throughout adolescence in boys, whereas in girls, they increased until age 13 and then stabilized. In boys, %SMM and MFR were highest at age 15 and then slowly stabilized or decreased, whereas in girls, they peaked at age 10 to 11 and then decreased through adolescence. Cut-off values for low MFR were identified and a significant association was found between a low MFR and high risk of metabolic syndrome. However, this association was found to be dependent on gender and the level of BMI., Conclusion: This study provides reference values of absolute and relative SMM for Korean children and adolescents. Detailed body composition analyses including skeletal muscle and fat mass might provide improved measures of metabolic risk.

The present study investigated whether infants reason about others' social preferences based on the intentions of others' interactive actions. In Experiment 1, 12-month-old infants were familiarized with an event in which an agent either successfully helped a circle to climb up a hill (successful-helping condition) or failed to help the circle to achieve its goal (failed-helping condition). During the test, the infants saw the circle approach either the helper (approach-helper event) or the hinderer (approach-hinderer event). In the successful-helping condition, the 12-month-old infants looked for longer at the approach-hinderer event than at the approach-helper event, but in the failed-helping condition, looking times were about equal for the two test events. These results suggest that 12-month-old infants could not infer the circle's preference when the helper's action did not lead to its intended outcome. In Experiment 2, 16-month-olds were tested in the failed-helping condition; they looked longer at the approach-hinderer event than at the approach-helper event, which suggests that they could reason about the third party's social preferences based on the exhibited intentions. In Experiment 3, 12-month-olds were familiarized with events in which the final outcomes of helping and hindering actions were ambiguous. The results revealed that 12-month-old infants are also sensitive to intentions when inferring other's social preferences. The results suggest that by 12-months of age, infants expect an agent to prefer and approach another who intends to help the circle to achieve its goal, regardless of the outcome. The current research has implications for moral reasoning and social evaluation in infancy.

In a previous report, we identified Sebox as a new candidate maternal effect gene that is essential for embryonic development and primarily impacts the two-cell (2C) stage. The present study was conducted to determine the mechanism of action for Sebox in this capacity, as shown by changes in the expression levels of other known MEG mRNAs after Sebox RNA interference (RNAi) in oocytes. Sebox-knockdown metaphase II (Mll) oocytes displayed normal morphology, but among the 23 MEGs monitored, 8 genes were upregulated, and 15 genes were unchanged. We hypothesized that the perturbed gene expression of these MEGs may cause the arrest of embryo development at the 2C stage and examined the expression of several marker genes for the degradation of maternal factors and zygotic genome activation. We found that some maternal mRNAs, c-mos, Gbx2, and Gdf9, were not fully degraded in Sebox-knockdown 2C embryos, and that several zygotic genome activation markers, Mt1a, Rpl23, Ube2a and Wee1, were not fully expressed in conjunction with diminished embryonic transcriptional activity. In addition, Sebox may be involved in the formation of the subcortical maternal complex through its regulation of the upstream regulator, Figla. Therefore, we concluded that Sebox is important in preparing oocytes for embryonic development by orchestrating the expression of other important MEGs.

Bacterial microcompartments (MCPs) show great promise for the organization of engineered metabolic pathways within the bacterial cytoplasm. This subcellular organelle is composed of a protein shell of 100-200 nm diameter that natively encapsulates multi-enzyme pathways. The high energy cost of synthesizing the thousands of protein subunits required for each MCP demands precise regulation of MCP formation for both native and engineered systems. Here, we study the regulation of the propanediol utilization (Pdu) MCP, for which growth on 1,2-propanediol induces expression of the Pdu operon for the catabolism of 1,2-propanediol. We construct a fluorescence-based transcriptional reporter to investigate the activation of the Ppdu promoter, which drives the transcription of 21 pdu genes. Guided by this reporter, we find that MCPs can be expressed in strains grown in rich media, provided that glucose is not present. We also characterize the response of the Ppdu promoter to a transcriptional activator of the pdu operon, PocR, and find PocR to be a necessary component of Pdu MCP formation. Furthermore, we find that MCPs form normally upon the heterologous expression of PocR even in the absence of the natural inducer 1,2-propanediol and in the presence of glucose, and that Pdu MCPs formed in response to heterologous PocR expression can metabolize 1,2-propanediol in vivo. We anticipate that this technique of overexpressing a key transcription factor may be used to study and engineer the formation, size, and/or number of MCPs for the Pdu and related MCP systems.

Background: Adipose tissue, mainly composed of adipocytes, plays an important role in metabolism by regulating energy homeostasis. Obesity is primarily caused by an abundance of adipose tissue. Therefore, specific targeting of adipose tissue is critical during the treatment of obesity, and plays a major role in overcoming it. However, the knowledge of cell-surface markers specific to adipocytes is limited., Methods and Results: We applied the CELL SELEX (Systematic Evolution of Ligands by EXponential enrichment) method using flow cytometry to isolate molecular probes for specific recognition of adipocytes. The aptamer library, a mixture of FITC-tagged single-stranded random DNAs, is used as a source for acquiring molecular probes. With the increasing number of selection cycles, there was a steady increase in the fluorescence intensity toward mature adipocytes. Through 12 rounds of SELEX, enriched aptamers showing specific recognition toward mature 3T3-L1 adipocyte cells were isolated. Among these, two aptamers (MA-33 and 91) were able to selectively bind to mature adipocytes with an equilibrium dissociation constant (Kd) in the nanomolar range. These aptamers did not bind to preadipocytes or other cell lines (such as HeLa, HEK-293, or C2C12 cells). Additionally, it was confirmed that MA-33 and 91 can distinguish between mature primary white and primary brown adipocytes., Conclusions: These selected aptamers have the potential to be applied as markers for detecting mature white adipocytes and monitoring adipogenesis, and could emerge as an important tool in the treatment of obesity.

Background: Brown adipocytes play an important role in regulating the balance of energy, and as such, there is a strong correlation between obesity and the amount of brown adipose tissue. Although the molecular mechanism underlying white adipocyte differentiation has been well characterized, brown adipocyte differentiation has not been studied extensively. Here, we investigate the potential role of dual-specificity phosphatase 10 (DUSP10) in brown adipocyte differentiation using primary brown preadipocytes., Methods and Results: The expression of DUSP10 increased continuously after the brown adipocyte differentiation of mouse primary brown preadipocytes, whereas the phosphorylation of p38 was significantly upregulated at an early stage of differentiation followed by steep downregulation. The overexpression of DUSP10 induced a decrease in the level of p38 phosphorylation, resulting in lower lipid accumulation than that in cells overexpressing the inactive mutant DUSP10. The expression levels of several brown adipocyte markers such as PGC-1α, UCP1, and PRDM16 were also significantly reduced upon the ectopic expression of DUSP10. Furthermore, decreased mitochondrial DNA content was detected in cells expressing DUSP10. The results obtained upon treatment with the p38 inhibitor, SB203580, clearly indicated that the phosphorylation of p38 at an early stage is important in brown adipocyte differentiation. The effect of the p38 inhibitor was partially recovered by DUSP10 knockdown using RNAi., Conclusions: These results suggest that p38 phosphorylation is controlled by DUSP10 expression. Furthermore, p38 phosphorylation at an early stage is critical in brown adipocyte differentiation. Thus, the regulation of DUSP10 activity affects the efficiency of brown adipogenesis. Consequently, DUSP10 can be used as a novel target protein for the regulation of obesity.

Thioredoxin-interacting protein (Txnip) regulates intracellular redox state and prompts oxidative stress by binding to and inhibiting Thioredoxin (Trx). In addition, via a Trx-independent mechanism, Txnip regulates glucose metabolism and thus maintains intracellular glucose levels. Previously, we found Txnip mRNA highly expressed in immature germinal vesicle (GV) oocytes, but currently there is no report describing the role of Txnip in oocytes. Therefore, we conducted the present study to determine the function of Txnip in mouse oocytes' maturation and meiosis by using RNA interference (RNAi) method. Upon specific depletion of Txnip, 79.5% of oocytes were arrested at metaphase I (MI) stage. Time-lapse video microscopy analysis revealed that the formation of granules in the oocyte cytoplasm increased concurrent with retarded cytoplasmic streaming after Txnip RNAi treatment. Txnip RNAi-treated oocytes had upregulated glucose uptake and lactate production. To confirm the supposition that mechanism responsible for these observed phenomena involves increased lactate in oocytes, we cultured oocytes in high lactate medium and observed the same increased granule formation and retarded cytoplasmic streaming as found by Txnip RNAi. The MI-arrested oocytes exhibited scattered microtubules and aggregated chromosomes indicating that actin networking was disturbed by Txnip RNAi. Therefore, we conclude that Txnip is a critical regulator of glucose metabolism in oocytes and is involved in maintaining cytoplasmic streaming in mouse oocytes.

Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of αβ-TCR(+), CD4(-), CD8(-) double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common γ subunit of the activating Fc receptors, FcRγ, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRγ, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRγ plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcRγ(+), but not FcRγ(-) LPR DN T cells could suppress Fas(+) CD4(+) and CD8(+) T cell proliferation in vitro and attenuated CD4(+) T cell-mediated graft-versus host disease. Although FcRγ expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRγ(+), but not FcRγ(-), DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRγ acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcRγ can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRγ may be a novel marker for functional DN Tregs.

LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1β and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation.

The frequency of individual genetic mutations conferring drug resistance (DR) to Mycobacterium tuberculosis has not been studied previously in Central America, the place of origin of many immigrants to the United States. The current gold standard for detecting multidrug-resistant tuberculosis (MDR-TB) is phenotypic drug susceptibility testing (DST), which is resource-intensive and slow, leading to increased MDR-TB transmission in the community. We evaluated multiplex allele-specific polymerase chain reaction (MAS-PCR) as a rapid molecular tool to detect MDR-TB in Panama. Based on DST, 67 MDR-TB and 31 drug-sensitive clinical isolates were identified and cultured from an archived collection. Primers were designed to target five mutation hotspots that confer resistance to the first-line drugs isoniazid and rifampin, and MAS-PCR was performed. Whole-genome sequencing confirmed DR mutations identified by MAS-PCR, and provided frequencies of genetic mutations. DNA sequencing revealed 70.1% of MDR strains to have point mutations at codon 315 of the katG gene, 19.4% within mabA-inhA promoter, and 98.5% at three hotspots within rpoB. MAS-PCR detected each of these mutations, yielding 82.8% sensitivity and 100% specificity for isoniazid resistance, and 98.4% sensitivity and 100% specificity for rifampin resistance relative to DST. The frequency of individual DR mutations among MDR strains in Panama parallels that of other TB-endemic countries. The performance of MAS-PCR suggests that it may be a relatively inexpensive and technically feasible method for rapid detection of MDR-TB in developing countries.

Objectives: Dyslipidemia is one of the important modifiable risk factors for cardiovascular disease. Thus, to know the prevalence of dyslipidemia is the 1(st) step to make guidelines of screening and management plan. Although, American Academy of Pediatrics updated the guidelines for lipid in childhood, Asian study is rare., Methods: The authors aimed to make a reference of each serum lipid level of Korean children and adolescents (2,363 subjects aged 10 to 18 years) from the data of Korea National Health and Nutrition Examination Survey IV (2007-2009)., Results: The mean serum concentrations for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) were 158 mg/dL, 90 mg/dL, 90 mg/dL, and 49 mg/dL, respectively. The 95th percentile values for TC, LDL-C, and TG were 203 mg/dL, 129 mg/dL, and 185 mg/dL, respectively. The 5th percentile value for HDL-C was 36 mg/dL. The prevalence of hypercholesterolemia, high LDL-C, high TG, and low HDL-C was 6.5%, 4.7%, 10.1%, and 7.1%, respectively. Considering the risk factors such as obesity, hypertension, smoking, and diabetes, approximately 0.41% of the subjects were potentially eligible for pharmacological treatment., Conclusions: This information may be useful in not only Korean but also Asian planning programs for the prevention of cardiovascular disease through lipid control from childhood.

TCRαβ(+) CD4(-)CD8(-)NK(-) double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4(+) T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4(+) T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4(+) T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells.

The generation of induced pluripotent stem (iPS) cells is a powerful tool in regenerative medicine, and advances in nanotechnology clearly have great potential to enhance stem cell research. Here, we introduce a liposomal magnetofection (LMF) method for iPS cell generation. Efficient conditions for generating virus-free iPS cells from mouse embryonic fibroblast (MEF) cells were determined through the use of different concentrations of CombiMag nanoparticle-DNA(pCX-OKS-2A and pCX-cMyc)-lipoplexes and either one or two cycles of the LMF procedure. The cells were prepared in a short reprogramming time period (≤ 8 days, 0.032-0.040%). Among the seven LMF-iPS cell lines examined, two were confirmed to be integration-free, and an integration-free LMF-iPS cell line was produced under the least toxic conditions (single LMF cycle with a half-dose of plasmid). This cell line also displayed in vitro/in vivo pluripotency, including teratoma formation and chimeric mouse production. In addition, the safety of CombiMag-DNA lipoplexes for the transfection of MEF cells was confirmed through lactate dehydrogenase activity assay and transmission electron microscopy. These results demonstrated that the LMF method is simple, effective, and safe. LMF may represent a superior technique for the generation of virus-free or integration-free iPS cell lines that could lead to enhanced stem cell therapy in the future.

Ezh2 is a histone trimethyltransferase that silences genes mainly via catalyzing trimethylation of histone 3 lysine 27 (H3K27Me3). The role of Ezh2 as a regulator of gene silencing and cell proliferation in cancer development has been extensively investigated; however, its function in heart development during embryonic cardiogenesis has not been well studied. In the present study, we used a genetically modified mouse system in which Ezh2 was specifically ablated in the mouse heart. We identified a wide spectrum of cardiovascular malformations in the Ezh2 mutant mice, which collectively led to perinatal death. In the Ezh2 mutant heart, the endocardial cushions (ECs) were hypoplastic and the endothelial-to-mesenchymal transition (EMT) process was impaired. The hearts of Ezh2 mutant mice also exhibited decreased cardiomyocyte proliferation and increased apoptosis. We further identified that the Hey2 gene, which is important for cardiomyocyte proliferation and cardiac morphogenesis, is a downstream target of Ezh2. The regulation of Hey2 expression by Ezh2 may be independent of Notch signaling activity. Our work defines an indispensible role of the chromatin remodeling factor Ezh2 in normal cardiovascular development.

Previously, we found that the growth arrest-specific gene 6 (Gas6) is more highly expressed in germinal vesicle (GV) oocytes than in metaphase II (MII) oocytes using annealing control primer (ACP)-PCR technology. The current study was undertaken to investigate the role of Gas6 in oocyte maturation and fertilization using RNA interference (RNAi). Interestingly, despite the specific and marked decrease in Gas6 mRNA and protein expression in GVs after Gas6 RNAi, nuclear maturation including spindle structures and chromosome segregation was not affected. The only discernible effect induced by Gas6 RNAi was a change in maturation promoting factor (MPF) activity. After parthenogenetic activation, Gas6 RNAi-treated oocytes at the MII stage had not developed further and arrested at MII (90.0%). After stimulation with Sr(2+), Gas6-silenced MII oocytes had markedly reduced Ca(2+) oscillation and exhibited no exocytosis of cortical granules. In these oocytes, sperm penetration occurred during fertilization but not pronucleus (PN) formation. By roscovitine and colcemid treatment, we found that the Gas6 knockdown affected cytoplasmic maturation directly, independent to the changed MPF activity. These results strongly suggest that 1) the Gas6 signaling itself is important to the cytoplasmic maturation, but not nuclear maturation, and 2) the decreased Gas6 expression and decreased MPF activity separately or mutually influence sperm head decondensation and PN formation.

The COP9 (constitutive photomorphogenic) signalosome (CSN), composed of eight subunits, is a highly conserved protein complex that regulates processes such as cell cycle progression and kinase signalling. Previously, we found the expression of the COP9 constitutive photomorphogenic homolog subunit 3 (CSN3) and subunit 5 (CSN5) changes as oocytes mature for the first time, and there is no report regarding roles of COP9 in the mammalian oocytes. Therefore, in the present study, we examined the effects of RNA interference (RNAi)-mediated transient knockdown of each subunit on the meiotic cell cycle in mice oocytes. Following knockdown of either CSN3 or CSN5, oocytes failed to complete meiosis I. These arrested oocytes exhibited a disrupted meiotic spindle and misarranged chromosomes. Moreover, down-regulation of each subunit disrupted the activity of maturation-promoting factor (MPF) and concurrently reduced degradation of the anaphase-promoting complex/cyclosome (APC/C) substrates Cyclin B1 and Securin. Our data suggest that the CSN3 and CSN5 are involved in oocyte meiosis by regulating degradation of Cyclin B1 and Securin via APC/C.