The role of acetylated apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref-1) in ovarian cancer remains poorly understood. Therefore, this study aimed to investigate the combined effect of recombinant human APE1/Ref-1 (rhAPE1/Ref-1) and aspirin (ASA) on two ovarian cancer cells, PEO-14, and CAOV3.The viability and apoptosis of ovarian cancer cells treated with rhAPE1/Ref-1 or ASA were assessed. Our results demonstrated that ASA induced rhAPE1/Ref-1 acetylation and widespread hyperacetylation in PEO-14 cells. Additionally, co-treatment with rhAPE1/Ref-1 and ASA substantially reduced cell viability and induced PEO-14 cell apoptosis, not CAOV3, in a dose-dependent manner. ASA increased the expression and membrane localization of the receptor for advanced glycation endproducts (RAGEs). Acetylated APE1/Ref-1 showed enhanced binding to RAGEs. In contrast, RAGE knockdown reduced cell death and poly(ADP-ribose) polymerase cleavage caused by rhAPE1/Ref-1 and ASA combination treatment, highlighting the importance of the APE1/Ref-1-RAGE interaction in triggering apoptosis. Moreover, combination treatment with rhAPE1/Ref-1 and ASA effectively induced apoptosis in 3D spheroid cultures of PEO-14 cells, a model that better mimics the tumor microenvironment. These results demonstrate that acetylated APE1/Ref-1 and its interaction with RAGE is a potential therapeutic target for ovarian cancer. Thus, the combination of ASA and APE1/Ref-1 may offer a promising new strategy for inducing cancer cell death.

Purpose: In this study, we investigated the effect of bisphenol-A (BPA) and its major analogs, bisphenol-F (BPF), and bisphenol-S (BPS), on spermatogonial stem cells (SSCs) populations using in vitro SSC culture and in vivo transplantation models. Materials and Methods: SSCs enriched from 6- to 8-day-old C57BL/6-eGFP+ male mice testes were treated with varying concentrations of bisphenols for 7 days to examine bisphenol-derived cytotoxicity and changes in SSC characteristics. We utilized flow cytometry, immunocytochemistry, real-time quantitative reverse transcription-PCR, and western blot analysis. The functional alteration of SSCs was further investigated by examining donor SSC-derived spermatogenesis evaluation through in vivo transplantation and subsequent testis analysis. Results: BPF exhibited a similar inhibitory effect on SSCs as BPA, demonstrating a significant decrease in SSC survival, inhibition of proliferation, and induction of apoptosis. On the other hand, while BPS was comparatively weaker than BPA and BPF, it still showed significant SSC cytotoxicity. Importantly, SSCs exposed to BPA, BPF, and BPS exhibited a significant reduction in donor SSC-derived germ cell colonies per total number of cultured cells, indicating that, like BPA, BPF, and BPS can induce a comparable reduction in functional SSCs in the recipient animals. However, the progress of spermatogenesis, as evidenced by histochemistry and the expressions of PCNA and SSC specific markers, collectively indicates that BPA, BPF, and BPS may not adversely affect the spermatogenesis. Conclusions Our findings indicate that the major BPA substitutes, BPF and BPS, have significant cytotoxic effects on SSCs, similar to BPA. These effects may lead to a reduction in the functional self-renewal stem cell population and potential impacts on male fertility.

Purpose: Rare diseases occur in <50 per 100000 people and require lifelong management. However, essential epidemiological data on such diseases are lacking, and a consecutive monitoring system across time and regions remains to be established. Standardized digital phenotypes are required to leverage an international data network for research on rare endocrine diseases. We developed digital phenotypes for rare endocrine diseases using the observational medical outcome partnership common data model. Materials and Methods: Digital phenotypes of three rare endocrine diseases (medullary thyroid cancer, hypoparathyroidism, pheochromocytoma/paraganglioma) were validated across three databases that use different vocabularies: Severance Hospital’s electronic health record from South Korea; IQVIA’s United Kingdom (UK) database for general practitioners; and IQVIA’s United States (US) hospital database for general hospitals. We estimated the performance of different digital phenotyping methods based on International Classification of Diseases (ICD)-10 in the UK and the US or systematized nomenclature of medicine clinical terms (SNOMED CT) in Korea. Results: The positive predictive value of digital phenotyping was higher using SNOMED CT-based phenotyping than ICD-10-based phenotyping for all three diseases in Korea (e.g., pheochromocytoma/paraganglioma: ICD-10, 58%–62%; SNOMED CT, 89%). Estimated incidence rates by digital phenotyping were as follows: medullary thyroid cancer, 0.34–2.07 (Korea), 0.13–0.30 (US); hypoparathyroidism, 0.40–1.20 (Korea), 0.59–1.01 (US), 0.00–1.78 (UK); and pheochromocytoma/paraganglioma, 0.95–1.67 (Korea), 0.35–0.77 (US), 0.00–0.49 (UK). Conclusion Our findings demonstrate the feasibility of developing digital phenotyping of rare endocrine diseases and highlight the importance of implementing SNOMED CT in routine clinical practice to provide granularity for research.

γ-Radiation resistance is a major obstacle to the success of radiotherapy in colorectal cancer. Antioxidant-related factors contribute to resistance to radiation therapy and, therefore, are targets for improving the therapeutic response. In this study, we evaluated the molecular mechanisms underlying γ-radiation resistance using the colorectal cancer cell line SNUC5 and γ-radiation-resistant variant SNUC5/RR, including analyses of the role of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates antioxidant enzymes, and related epigenetic regulators. Reactive oxygen species (ROS) levels, antioxidant enzyme expression, NRF2 expression, and nuclear translocation were higher in SNUC5/RR cells irradiated with or without 8 Gy than in SNUC5 cells. The DNA demethylase ten-eleven translocation 1 (TET1) expression and TET1 binding to the NRF2 promoter in SNUC5/RR cells were stronger than those in SNUC5 cells, indicating lower methylation of CpG islands in the NRF2 promoter.TET1 knockdown in SNUC5/RR cells suppressed NRF2 expression significantly. Additionally, histone mixed-lineage leukemia (MLL), a histone methyltransferase, was upregulated, leading to increased trimethylation of histone H3 lysine 4, whereas enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, was downregulated, leading to decreased trimethylation of histone H3 lysine 27. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) levels were lower and higher in SNUC5/RR cells than in SNUC5 cells, respectively. MLL and HAT knockdown in SNUC5/RR cells irradiated with or without 8 Gy decreased levels of NRF2 and heme-oxygenase 1, resulting in enhanced γ-radiation sensitivity. These findings support NRF2 as a target for improving the response to radiotherapy in patients with colorectal cancer.

Background: and Purpose: Amyloid-beta (Aβ) plaques are key in Alzheimer’s disease (AD), with Aβ positron emission tomography imaging enabling non-invasive quantification.To address regional Aβ deposition, we developed regional Centiloid scales (rdcCL) and commercialized them through the computed tomography (CT)-based BeauBrain Amylo platform, eliminating the need for three-dimensional T1 magnetic resonance imaging (MRI). Objective: We aimed to establish robust regional Aβ cutoffs using the commercialized BeauBrain Amylo platform and to explore the prevalence of subgroups defined by global, regional, and striatal Aβ cutoffs across cognitive stages. Methods: We included 2,428 individuals recruited from the Korea-Registries to Overcome Dementia and Accelerate Dementia Research project. We calculated regional Aβ cutoffs using Gaussian Mixture Modeling. Participants were classified into subgroups based on global, regional, and striatal Aβ positivity across cognitive stages (cognitively unimpaired [CU], mild cognitive impairment, and dementia of the Alzheimer’s type). Results: MRI-based and CT-based global Aβ cutoffs were highly comparable and consistent with previously reported Centiloid values. Regional cutoffs revealed both similarities and differences between MRI- and CT-based methods, reflecting modality-specific segmentation processes. Subgroups such as global(−)regional(+) were more frequent in non-dementia stages, while global(+)striatal(−) was primarily observed in CU individuals. Conclusions Our study established robust regional Aβ cutoffs using a CT-based rdcCL method and demonstrated its clinical utility in classifying amyloid subgroups across cognitive stages. These findings highlight the importance of regional Aβ quantification in understanding amyloid pathology and its implications for biomarker-guided diagnosis and treatment in AD.

Background: Antithyroid drug (ATD) treatment is the preferred initial treatment for Graves’ disease (GD) in South Korea, despite higher treatment failure rates than radioactive iodine (RAI) therapy or thyroidectomy. This study aimed to evaluate the incidence of treatment failure associated with the primary modalities for GD treatment in real-world practice. Methods: We included 452,001 patients diagnosed with GD between 2004 and 2020 from the Korean National Health Insurance Service-National Health Information Database. Treatment failure was defined as switching from ATD, RAI, or thyroidectomy treatments, and for ATD specifically, inability to discontinue medication for over 2 years. Results: Mean age was 46.2 years, with females constituting 70.8%. Initial treatments for GD included ATDs (98.0%), thyroidectomy (1.3%), and RAI (0.7%), with a noted increment in ATD application from 96.2% in 2004 to 98.8% in 2020. During a median follow- up of 8.5 years, the treatment failure rates were 58.5% for ATDs, 21.3% for RAI, and 2.1% for thyroidectomy. Multivariate analysis indicated that the hazard ratio for treatment failure with ATD was 2.81 times higher than RAI. RAI treatments ≥10 mCi had 37% lower failure rates than doses <10 mCi. Conclusion ATDs are the most commonly used for GD in South Korea, followed by thyroidectomy and RAI. Although the risk of treatment failure for ATD is higher than that of RAI therapy, initial RAI treatment in South Korea is relatively limited compared to that in Western countries. Further studies are required to evaluate the cause of low initial RAI treatment rates in South Korea.

OBJECTIVES: Gender is a major determinant of health behaviors that influences cancer prevention awareness and practices. This study investigated the relationship of the awareness and practice rates of cancer prevention recommendations with gender and socioeconomic status. METHODS: We used data from the Korean National Cancer Prevention Awareness and Practice Survey (2023). The sample included 4,000 men and women aged 20-74 years. We conducted multiple logistic regression analyses to evaluate associations with the awareness and practices of cancer prevention, and a joinpoint regression analysis using age-standardized rates to analyze trends in awareness and practice rates from 2007 to 2023. RESULTS: The awareness rates were 79.4% and 81.2% for men and women, respectively. The overall practice rates were substantially lower (43.1% for men and 48.9% for women). For men, awareness rates did not differ significantly by socio-demographic characteristics, but practice rates increased with age (20-29: 15.9%; 60-74: 53.8%). For women, both awareness (20-29: 73.0%; 60-74: 85.7%) and practice (20-29: 16.8%; 60-74: 67.5%) rates increased with age. The easiest recommendations to follow were “reducing salt intake and avoiding burnt or charred foods” (men: 29.9%; women: 28.4%), whereas the most difficult recommendation was “engaging in regular physical activity” (men: 32.5%; women: 34.4%). CONCLUSIONS While awareness of cancer prevention recommendations was high, the practice of these recommendations was low. Gender influenced changes in awareness and practice rates over time, reflecting a large gap in practice. Future research should explore appropriate intervention points for cancer prevention practices and the development of more effective cancer prevention policies.

Background: The World Health Organization has declared the end of the coronavirus disease 2019 (COVID-19) public health emergency. However, this did not indicate the end of COVID-19. Several months after the infection, numerous patients complain of respiratory or nonspecific symptoms; this condition is called long COVID. Even patients with mild COVID-19 can experience long COVID, thus the burden of long COVID remains considerable. Therefore, we conducted this study to comprehensively analyze the effects of long COVID using multi-faceted assessments. Materials and Methods: We conducted a prospective cohort study involving patients diagnosed with COVID-19 between February 2020 and September 2021 in six tertiary hospitals in Korea. Patients were followed up at 1, 3, 6, 12, 18, and 24 months after discharge. Long COVID was defined as the persistence of three or more COVID-19-related symptoms. The primary outcome of this study was the prevalence of long COVID after the period of COVID-19. Results: During the study period, 290 patients were enrolled. Among them, 54.5 and 34.6% experienced long COVID within 6 months and after more than 18 months, respectively. Several patients showed abnormal results when tested for post-traumatic stress disorder (17.4%) and anxiety (31.9%) after 18 months. In patients who underwent follow-up chest computed tomography 18 months after COVID-19, abnormal findings remained at 51.9%. Males (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.05–0.53; P=0.004) and elderly (OR, 1.04; 95% CI, 1.00–1.09; P=0.04) showed a significant association with long COVID after 12–18 months in a multivariable logistic regression analysis. Conclusion Many patients still showed long COVID after 18 months post SARS-CoV-2 infection. When managing these patients, the assessment of multiple aspects is necessary.

Background: Osteoporosis is a significant public health issue in aging populations. Despite advances in pharmacotherapy, underdiagnosis and undertreatment remain prevalent even in patients with recent fractures. This study examined 20-year trends (2002– 2022) in anti-osteoporotic medication (AOM) usage in South Korea. Methods: Data from the Korean National Health Information Database were retrospectively analyzed. The study included individuals aged ≥50 years and analyzed prescription trends, medication adherence, measured by the medication possession ratio (MPR), and treatment initiation rates post-fracture. The AOMs examined included bisphosphonates, selective estrogen receptor modulators, denosumab (DMAB), teriparatide (TPTD), and romosozumab (ROMO). Results: Over two decades, AOM use has shifted significantly from oral to injectable formulations, with injectables surpassing oral medications in 2020; from 397,440 prescriptions in 2016 to 1,162,779 in 2022. Prescriptions for DMAB surged following its approval as a first-line therapy in 2019, increasing 2.65 times from 217,606 in 2019 to 575,595 in 2022. The MPR improved from 35.4% in 2003 to 73.2% in 2021, with females demonstrating higher adherence than males. Post-fracture treatment rates increased from 31.1% in 2006 to 39.9% in 2021 but remained below 50%. Vertebral fractures had the highest treatment initiation rates, while anabolic agents, such as TPTD and ROMO were underprescribed despite their efficacy. Conclusions This 20-year analysis highlights significant progress in osteoporosis management in South Korea, including a shift towards injectable therapies and improved adherence. However, the persistent undertreatment of high-risk patients underscores the requirement for enhanced access to anabolic agents, clinician education, and policy reforms to optimize post-fracture care.

Purpose: This study evaluated the postoperative quality of life (QoL) after various types of gastrectomy for gastric cancer. Materials and Methods: A multicenter prospective observational study was conducted in Korea using the Korean Quality of Life in Stomach Cancer Patients Study (KOQUSS)-40, a new QoL assessment tool focusing on postgastrectomy syndrome. Overall, 496 patients with gastric cancer were enrolled, and QoL was assessed at 5 time points: preoperatively and at 1, 3, 6, and 12 months after surgery. Results: Distal gastrectomy (DG) and pylorus-preserving gastrectomy (PPG) showed significantly better outcomes than total gastrectomy (TG) and proximal gastrectomy (PG) with regard to total score, indigestion, and dysphagia. DG, PPG, and TG also showed significantly better outcomes than PG in terms of dumping syndrome and worry about cancer. Postoperative QoL did not differ significantly according to anastomosis type in DG, except for Billroth I anastomosis, which achieved better bowel habit change scores than the others. No domains differed significantly when comparing double tract reconstruction and esophagogastrostomy after PG. The total QoL score correlated significantly with postoperative body weight loss (more than 10%) and extent of resection (P<0.05 for both).Reflux as assessed by KOQUSS-40 did not correlate significantly with reflux observed on gastroscopy 1 year postoperatively (P=0.064). Conclusions Our prospective observation using KOQUSS-40 revealed that DG and PPG lead to better QoL than TG and PG. Further study is needed to compare postoperative QoL according to anastomosis type in DG and PG.