Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively targets cancer cells and induces apoptosis. However, many cancers, including bladder cancer, develop resistance to TRAIL, limiting the efficacy of TRAIL-based therapies. This study investigated whether betulinic acid (BA), a pentacyclic triterpenoid with anticancer and chemosensitizing properties, increases TRAIL-mediated apoptosis in TRAIL-resistant human bladder cancer cells. Combination treatment with BA and TRAIL significantly increased cytotoxicity and apoptosis compared to either treatment alone. This combination treatment also increased reactive oxygen species (ROS) production, increased Bax expression and Bid cleavage (tBid formation), and downregulated Bcl-2 levels. These effects were accompanied by caspase activation via extrinsic and intrinsic pathways, leading to cytochrome c release via mitochondrial membrane destabilization, thereby contributing to increased apoptosis. Furthermore, the combination treatment inhibited phosphoinositide 3-kinase (PI3K) and Akt phosphorylation; this effect was amplified by a PI3K inhibitor but abrogated by ROS inhibition. Collectively, our results suggest that BA sensitizes bladder cancer cells to TRAILinduced apoptosis via ROS-dependent activation of the apoptotic pathway and inhibition of PI3K/Akt signaling. Therefore, the BA and TRAIL combination exhibits potential to overcome TRAIL resistance in human bladder cancer.

Objective: This study aimed to evaluate reproductive outcomes according to the timing of testicular sperm retrieval. Methods: The study included 282 infertile couples divided into three groups: group A (freeze-thawed testicular sperm extraction [TESE] sperm, n=233), group B (fresh TESE sperm collected 1 day before ovum pickup, n=22), and group C (fresh TESE sperm collected on the same day as ovum pickup, n=27). The indications for TESE were surgically uncorrectable azoospermia or ejaculation failure, often accompanied by medical comorbidities such as diabetes mellitus and spinal cord injury. The outcome parameters assessed were fertilization rates, embryo quality, and clinical pregnancy rates. Results: The mean paternal age was 36.8±5.7 years, and the mean maternal age was 32.6±3.5 years. The mean duration of infertility was 2.9±1.8 years. The fertilization rates were 70.7%, 78.9%, and 73.0% for groups A, B, and C, respectively (p=0.047). The percentages of good-quality embryos were 68.2%, 65.3%, and 48.4%, respectively (p=0.007); specifically, the percentage of good-quality embryos was significantly lower in group C compared with the other two groups. Clinical pregnancy rates per transfer were similar at 51.1%, 50.0%, and 48.1% (p=0.958), with no differences observed in miscarriage rates. Conclusion Testicular sperm retrieval can be safely performed 1 day before ovum pickup, resulting in favorable fertility outcomes.

Objective: Perinatal depression often remains undertreated due to concerns about antidepressant exposure during fertility treatment, pregnancy, or breastfeeding. Non-pharmacological, home-based interventions such as transcranial direct current stimulation (tDCS) present a promising alternative; however, real-world evidence in perinatal populations remains limited. Methods: This prospective observational study included 38 women who received infertility, pregnancy, or postpartum treatment at four hospitals in South Korea. Participants self-administered anodal tDCS targeting the left dorsolateral prefrontal cortex for 20–28 sessions over 4 weeks. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and weeks 2, 4, and 8. Subjective health perception was measured at baseline using a 5-point Likert scale. Results: Time had a significant effect on depressive symptoms (Wald χ2=90.75, p<0.001), with the largest reduction observed during the first 2 weeks. The CES-D scores remained significantly lower than baseline at week 8, 4 weeks after treatment ended. Subjective health perception was significantly associated with baseline depression severity (Wald χ2=26.41, p<0.001), and its interaction with time was also significant (Wald χ2=320.18, p<0.001). Participants with poorer perceived health (scores 4–5) experienced greater depressive symptom reductions than those with more favorable perceptions (scores 1–2). Conclusion Home-based tDCS was feasible and associated with clinically meaningful improvement in depressive symptoms among perinatal women. Those who initially perceived their health more negatively showed greater response, suggesting subjective health perception may serve as a useful moderator and potential marker to inform personalized treatment strategies.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background/Aims: Recent studies have shown an increased risk of lower gastrointestinal bleeding in patients who use both nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs). We analyzed the risk of lower gastrointestinal bleeding and compared this risk between NSAID+PPI users and NSAID-only users. Methods: In this retrospective, observational study, data from five hospitals were analyzed using a common data model to determine the risk of lower gastrointestinal bleeding and compare this risk between NSAID+PPI users (target cohort) and NSAID-only users (comparative cohort). Cox proportional hazard models and the Kaplan-Meier estimations were employed after extensive propensity score matching. Results: Among 24,530 individuals in the target cohort and 57,264 in the comparative cohort, 8,728 propensity score-matched pairs were analyzed. The risk of lower gastrointestinal bleeding was significantly higher in NSAID+PPI users than in NSAID-only users (hazard ratio [HR], 2.843;95% confidence interval [CI], 1.998 to 4.044; p<0.001). Similar findings were also noted in elderly patients >65 years (HR, 2.737), males (HR, 2.963), and females (HR, 3.221). However, the risk of lower gastrointestinal bleeding was comparable between NSAID+mucoprotective agent users and NSAID-only users (HR, 2.057; 95% CI, 0.714 to 5.924; p=0.172). Conclusions The risk of lower gastrointestinal bleeding was higher in NSAID+PPI users than in NSAID-only users. However, the risk of lower gastrointestinal bleeding was comparable between NSAID+mucoprotective agent users and NSAID-only users.

Background/Aims: Despite of the coronavirus disease 2019 (COVID-19) pandemic, there is little data regarding its impact on colorectal cancer (CRC)-related clinical practice. This study aimed to assess the changes in its impact during the COVID-19 pandemic. Methods: This was a retrospective national population-based study using the Health Insurance Review and Assessment database from January 2019 to December 2021. The number of patients in 2020 and 2021 was compared with those in 2019 for the diagnostic and therapeutic colonoscopy, CRC-related operation, and any treatment for CRC. Results: The annual number of patients undergoing diagnostic colonoscopies decreased by 6.9% in 2020 but increased 8.1% in 2021, compared to those in 2019; number of patients undergoing therapeutic colonoscopies increased by 6.0% and 37.7% in 2020 and 2021, respectively; number of patients operated for CRC decreased by 4.2% in 2020 and increased by 2.3% in 2021. The number of patients treated for CRC decreased by 2.8% in 2020 and increased by 4.4% in 2021. Diagnostic and therapeutic colonoscopies and any CRC-related treatment decreased by 43.8%, 37.5%, and 11.3% in March 2020, during the first surge of COVID-19, but increased by 26.0%, 58.1%, and 9.5% in June 2021, respectively. CRC-related operations decreased by 24.1% in April 2020 and increased by 12.6% in August 2021. Conclusions Negative impact of the COVID-19 pandemic on clinical practices related to CRC completely recovered within second year. It could be considered for the development of an optimal strategy on CRC management in response to the pandemic-driven crisis.

Background: Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients. Methods: We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed regression models were used to investigate the associations between their characteristics and the IVT candidates or the use of IVT among the candidates. Results: Among 84,103 AIS patients, 41.0% were female, with a mean age of 69 ± 13 years and presentation NIHSS of 4 [interquartile range, 1–8]. Out of these patients, 13,757 (16.4%) were eligible for IVT, of whom 8,179 (59.5%) received IVT. Female sex (adjusted risk ratio [RR], 0.90; 95% confidence interval [CI], 0.86–0.94) and lower years of education (adjusted RR, 0.90; 95% CI, 0.84–0.97 for 0–3 years, compared to ≥ 13 years) were associated with a decreased likelihood of presenting as eligible for IVT after AIS; meanwhile, young age (adjusted RR, 1.12; 95% CI, 1.01–1.24 for ≤ 44 years, compared to 75–84 years) was associated with an increased likelihood of being an IVT candidate. Among those who were eligible for IVT, only age was significantly associated with the use of IVT (adjusted RR, 1.09; 95% CI, 1.03–1.16 for age 65–74 and adjusted RR, 0.83; 95% CI, 0.76–0.90 for ≥ 85 years, respectively). Conclusion Most patients with AIS present outside IVT eligibility in South Korea, and only 60% of eligible patients were ultimately treated. We identified increased age, female sex and lower education as key features on which to focus interventions for improving IVT utilization.

Background: and Purpose Previous research on patients with acute ischemic stroke (AIS) has shown a 0.5% incidence of major gastrointestinal bleeding (GIB) requiring blood transfusion during hospitalization. The existing literature has insufficiently explored the long-term incidence in this population despite the decremental impact of GIB on stroke outcomes. Methods: We analyzed the data from a cohort of patients with AIS admitted to 14 hospitals as part of a nationwide multicenter prospective stroke registry between 2011 and 2013. These patients were followed up for up to 6 years. The occurrence of major GIB events, defined as GIB necessitating at least two units of blood transfusion, was tracked using the National Health Insurance Service claims data. Results: Among 10,818 patients with AIS (male, 59%; mean age, 68±13 years), 947 (8.8%) experienced 1,224 episodes of major GIB over a median follow-up duration of 3.1 years. Remarkably, 20% of 947 patients experienced multiple episodes of major GIB. The incidence peaked in the first month after AIS, reaching 19.2 per 100 person-years, and gradually decreased to approximately one-sixth of this rate by the 2nd year with subsequent stabilization. Multivariable analysis identified the following predictors of major GIB: anemia, estimated glomerular filtration rate <60 mL/min/1.73 m2 , and a 3-month modified Rankin Scale score of ≥4. Conclusion Patients with AIS are susceptible to major GIB, particularly in the first month after the onset of AIS, with the risk decreasing thereafter. Implementing preventive strategies may be important, especially for patients with anemia and impaired renal function at stroke onset and those with a disabling stroke.