Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Background: As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. Results: In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. Conclusions This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

Purpose: This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer. Materials and Methods: We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer. Results: Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)–negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05). Conclusion Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.

BACKGROUND/AIMS: Dysbiosis is an important factor in the pathogenesis of irritable bowel syndrome (IBS). Several studies have reported promising results using probiotics for the treatment of IBS. This study evaluated the efficacy of novel probiotics isolated from Kimchi, a Korean fermented food, and the feces of healthy Vietnamese people in a murine model of IBS.METHODS: Lactobacillus paracasei DK121 was isolated from Kimchi, and L. salivarius V4 and L. plantarum V7 were isolated from the feces of healthy Vietnamese people residing in Korea. Forty rats were allocated to receive one of the study strains, a mixture of the strains, or the vehicle. After 5 days of administration, the rats were restrained in a cage to induce IBS. The effects of the probiotics on IBS were analyzed by evaluating the stool weights and stool consistency scores.RESULTS: The primary outcome was analyzed upon the completion of a three-week experiment. The rats in the V7 group showed lower stool weights than those in the control group at week 2 (median: 1.10 [V7] vs. 2.35 [control], p=0.04, Mann-Whitney U-test) and week 3 (median: 1.10 [V7] vs. 2.80 [control], p=0.017). The rats in the DK121 (median: 2.00, p=0.007), V7 (median: 2.00, p=0.004), and mixture (median: 1.50, p=0.001) groups showed better stool consistency scores at week 2 than the control group (median: 3.00).CONCLUSIONS: The novel probiotics have beneficial effects on defecation in a murine model of IBS. Human studies confirming the efficacy are warranted.

Background: Malnutrition is a well-known risk factor of falls, although studies examining the association between nutritional status and falls are rare. We aimed to investigate the association between nutritional status and falls according to gender among Korean older adults. Methods: The study included 10,675 participants (4,605 men and 6,070 women) aged 65 years and older and used data from the 2011 Survey of Living Conditions and Welfare Needs of Korean Older Persons. Nutritional status of the participants was assessed using the Nutritional Screening Initiative checklist, and the participants were categorized into the following groups: “good,” “moderate nutritional risk,” and “high nutritional risk.” Odds ratios (OR) of fall risk in the above groups based on gender were evaluated using multivariate logistic regression analyses. Results: Fallers in both genders showed significant association with older age, lower household income, inadequate exercise, and poor nutritional status compared with non-fallers. Considering the good nutritional status group as the reference group, the high nutritional risk group showed a higher risk of falls in men (OR, 1.59; 95% confidence interval [CI], 1.26–1.99); both moderate and high nutritional risk groups showed a higher risk of falls after adjusting for confounding factors in women (OR, 1.39; 95% CI, 1.19–1.62 and OR, 1.90; 95% CI, 1.61–2.24, respectively). Conclusion The risk of falls was associated with poor nutritional status, and statistical significance of the association between nutritional status and falls was stronger in women than in men.

Background: Recent studies suggest that acanthosis nigricans (AN) is associated with insulin resistance in obese children. However, very few studies have assessed insulin resistance and obesity according to the degree of AN. Therefore, this study aimed to investigate the correlation between the degree of obesity and insulin resistance according to the severity of AN. Methods: A total of 141 participants (83 boys and 58 girls) aged 6−17 years were recruited for the Intervention for Childhood and Adolescents obesity via Activity and Nutrition study between 2016 and 2017. The participants were categorized into four groups according to the severity of AN: grade 0 (n=69), grade 1 (n=19), grade 2–3 (n=35), and grade 4 (n=18). All participants underwent physical examination and blood tests. We compared the mean homeostatic model assessment (HOMA-IR) and body mass index Z score (BMI Z-score) in each group using ANCOVA and linear regression model. Results: The HOMA-IR, which represents insulin resistance, increased with increasing AN severity (grade 0 group: 3.25±0.070; grade 1 group: 3.97±0.103; grade 2–3 group: 4.76±0.079; AN grade 4: 6.40±0.107; P for trend<0.001). Similarly, the BMI Z-score, which represents the degree of obesity, increased with increasing AN severity (grade 0 group: 2.29±0.052; grade 1 group: 2.42±0.080; grade 2–3 group: 2.44±0.062, grade 4: 2.67±0.089; P for trend<0.001). Conclusion Insulin resistance and the degree of obesity increase with the severity of AN in Korean obese children.

Purpose: Hereditary cancer syndrome means that inherited genetic mutations can increase a person's risk of developing cancer. We assessed the frequency of germline mutations using an nextgeneration sequencing (NGS)–based multiple-gene panel containing 64 cancer-predisposing genes in Korean breast cancer patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC). Materials and Methods: A total of 64 genes associated with hereditary cancer syndrome were selected for development of an NGS-based multi-gene panel. Targeted sequencing using the multi-gene panel was performed to identify germline mutations in 496 breast cancer patients with clinical features of HBOC who underwent breast cancer surgery between January 2002 and December 2017. Results: Of 496 patients, 95 patients (19.2%) were found to have 48 deleterious germline mutations in 16 cancer susceptibility genes. The deleterious mutations were found in 39 of 250 patients (15.6%) who had breast cancer and another primary cancer, 38 of 169 patients (22.5%) who had a family history of breast cancer (≥ 2 relatives), 16 of 57 patients (28.1%) who had bilateral breast cancer, and 29 of 84 patients (34.5%) who were diagnosed with breast cancer at younger than 40 years of age. Of the 95 patients with deleterious mutations, 60 patients (63.2%) had BRCA1/2 mutations and 38 patients (40.0%) had non-BRCA1/2 mutations. We detected two novel deleterious mutations in BRCA2 and MLH1. Conclusion NGS-based multiple-gene panel testing improved the detection rates of deleterious mutations and provided a cost-effective cancer risk assessment.

Purpose: Endocrine therapy is a standard treatment for hormone receptor-positive breast cancer, which accounts for 60%–75% of all breast cancer. Hormone receptor positivity is a prognostic and predictive biomarker in breast cancer. Approximately 50%–80% of breast cancer is also positive for androgen receptor (AR), but the prognostic and predictive value of AR expression in breast cancer is controversial. Here, we investigated AR expression and its prognostic value in patients with surgically resected breast cancer in Korea. Methods: We retrospectively reviewed the medical records of patients who had surgically resected breast cancer to collect AR expression data and other clinicopathological data. The optimal cut-off for AR positivity was determined using a receiver operating characteristic curve analysis. Results: We reviewed 957 patients with surgically resected breast cancer from June 2012 to April 2013. The median follow-up was 62 months, and relapse events occurred in 101 (10.6%) patients. Unlike the cut-off value of 1% or 10% in previous reports, 35% was determined to be best for predicting relapse-free survival (RFS) in this study. At the cut-off value of 35%, 654 (68.4%) patients were AR-positive. AR expression was more prevalent in luminal A (87.6%) and luminal B (73.1%) types than in human epidermal growth factor receptor 2-positive (56.2%) or triple-negative (20.6%) types. AR expression of ≥ 35% was significantly related to longer RFS in a multivariate analysis (hazard ratio, 0.430; 95% confidence interval, 0.260–0.709; p = 0.001). Conclusion We propose a cut-off value of 35% to best predict RFS in patients with surgically resected breast cancer. AR expression was positive in 68.4% of patients, and AR positivity was found to be an independent prognostic factor for longer RFS.

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.
Academies and Institutes ; Asian Continental Ancestry Group ; DNA ; Humans ; Korea ; Methods ; Paraffin ; Point Mutation ; Precision Medicine ; Prevalence

PURPOSE: To report the long-term surgical outcomes of a muscle union procedure in patients with paralytic strabismus. METHODS: We retrospectively reviewed the medical records of 20 patients who underwent muscle union procedure for paralytic strabismus from September 2010 to March 2018. We analyzed the clinical results before and at the final visit after surgery. We also compared the outcomes of the first year after surgery between patients with sixth cranial nerve palsy, with third cranial nerve palsy and with medial rectus muscle rupture after endoscopic sinus surgery. RESULTS: The mean follow-up duration was 42 ± 20 months (12–79 months). The mean age at surgery was 40 ± 19 years (7–65 years). Eleven patients underwent surgery for sixth cranial nerve palsy, six patients underwent surgery for third cranial nerve palsy, and three patients underwent surgery for medial rectus rupture after endoscopic sinus surgery. The mean horizontal deviation at the primary eye position was 58 ± 19 prism diopters before surgery and decreased to 14 ± 17 prism diopters at the final visit. The success rate at the last visit was 60%. The mean horizontal deviation at postoperative 1 year was 4 ± 9 prism diopters in the sixth nerve palsy group and 26 ± 16 prism diopters in the third nerve palsy group (p = 0.002). The success rate was 91% in the sixth nerve palsy group and 33% in the third nerve palsy group at postoperative 1 year (p = 0.017). There were no complications during surgery or anterior segment ischemia for any of the patients. CONCLUSIONS A muscle union procedure had good long-term surgical outcomes in patients with paralytic strabismus, especially in patients with sixth cranial nerve palsy. However, in the case of third cranial nerve palsy or rupture of the medial rectus muscle, the effects were limited.