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.

Background: Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid- 2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/ GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.

Background/Aims: Rectal hyposensitivity (RH), as defined by the London Classification, has been linked to sensory dysfunction caused by diabetes mellitus and Parkinson’s disease (PD); however, its clinical interpretation has not been sufficiently validated. In this study, we aim to explore the correlations between rectal sensory thresholds and the clinical characteristics of patients with functional defecatory disorders. Methods: We reviewed data from patients who underwent high-resolution anorectal manometry and acquired their clinical characteristics using a standardized questionnaire. The associations between RH based on either 1 (borderline RH) or 2 (RH) abnormal rectal sensory thresholds and patients’ clinical and demographic characteristics were analyzed using linear and logistic regression models in the overall sex-stratified populations. Results: We enrolled 2540 patients, of whom 1046 (41.2%) were men. Overall, 150 (5.9%) patients were diagnosed with RH, whereas 422 (16.6%) had borderline RH. Multivariate linear regression analysis revealed that the Cleveland Clinic Constipation Score (CCCS) increased linearly with the increase in the number of abnormal rectal sensory thresholds (effect per threshold: 0.900 [standard deviation: 0.188]). Upon stratification by sex, borderline RH was positively associated with diabetes mellitus, PD, and CCCS (adjusted odds ratio [aOR] = 2.11, 95% confidence interval [1.08, 4.15]; aOR = 1.49 [1.03, 2.14]; aOR = 1.03 [1.01, 1.05], respectively) in women. However, RH was positively associated with only the CCCS. Conclusions Defining RH based on 1 or more abnormal sensory thresholds showed better clinical correlation with patient characteristics. However, further prospective studies are needed to validate these findings before proposing revisions to the current London classification criteria.

Background/Aims: Post-infectious irritable bowel syndrome (PI-IBS) is characterized by chronic gastrointestinal symptoms that arise following an episode of infectious enteritis. The incidence rates vary, ranging from 5% to 32% and the risk factors are not well known. We aim to investigate the incidence and risk factors of PI-IBS in enteritis patients admitted to university hospitals in Korea. Methods: This multi-center prospective study was conducted in patients hospitalized for infectious enteritis. Each patient underwent 1 outpatient visit and 3 telephone surveys during the first year after discharge to determine if PI-IBS occurred within the follow-up period. Results: In the 3-month survey, 7 out of 354 patients (2%) were diagnosed with PI-IBS, and after 1 year, only 1 patient met the criteria for IBS.No statistically significant difference was found between the PI-IBS group and the non-PI-IBS group in terms of age, sex, underlying diseases, medication history, gastrointestinal symptoms, enteritis location, causative strain, hospitalization and treatment periods, and laboratory findings. Female sex (P = 0.003), enteropathogenic Escherichia coli (EPEC) infection (P = 0.044), and a longer total treatment period (P = 0.018) were independent risk factors for diarrhea lasting ≥ 3 months after enteritis. Conclusions The incidence of PI-IBS in Korea was relatively low, and most cases improved over time. No risk factors associated with the development of PI-IBS were found. However, persistent diarrhea after enteritis was associated with female sex, EPEC infection, and severe or long-lasting enteritis. IBS symptoms may persist after severe enteritis but usually improve with time.

Objective: Multiple cohort studies have investigated the potential link between anesthesia and dementia. However, mixed findings necessitate closer examination. This study aimed to investigate the association between anesthesia exposure and the incidence of dementia, considering different anesthesia types and anesthetic agents. Methods: This nationwide cohort study utilized data from the South Korean Health Insurance Review and Assessment Service database, covering 62,541 participants, to investigate the correlation between anesthesia exposure and dementia incidence. Results: Results revealed an increased risk of dementia in individuals who underwent general (hazard ratio [HR], 1.318;95% confidence interval [CI], 1.061−1.637) or regional/local anesthesia (HR, 2.097; 95% CI, 1.887−2.329) compared to those who did not. However, combined general and regional/local anesthesia did not significantly increase dementia risk (HR, 1.097; 95% CI, 0.937−1.284). Notably, individual anesthetic agents exhibited varying risks; desflurane and midazolam showed increased risks, whereas propofol showed no significant difference. Conclusion This study provides unique insights into the nuanced relationship between anesthesia, individual anesthetic agents, and the incidence of dementia. While confirming a general association between anesthesia exposure and dementia risk, this study also emphasizes the importance of considering specific agents. These findings under-score the need for careful evaluation and long-term cognitive monitoring after anesthesia.

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: and Purpose: Mild cognitive impairment (MCI) is a transitional stage to dementia, Alzheimer’s disease being a major cause. Although amyloid beta-positive (Aβ+) MCI has been well-characterized, Aβ-negative (Aβ−) MCI has not. This study compared the comprehensive clinical and behavioral characteristics of Aβ+ and Aβ− MCI in a large multicenter cohort to better understand the heterogeneity of MCI, and to identify contributing factors to cognitive impairment. Methods: A total of 686 MCI participants were included. Aβ positivity was determined using Aβ positron emission tomography imaging with a direct conversion Centiloid cutoff value of 25.5. Standardized assessment and questionnaires were used to collect a wide range of clinical information, including vascular risk factors, cognition, daily living function, neuropsychiatric symptoms, and lifestyle behavior. Groups were compared using independent t-tests and χ2 tests. Results: Aβ+ participants (n=406) were older, predominantly female, and more likely to be ApoE4 carriers. In contrast, Aβ− participants (n=280) showed higher vascular risk factors, including diabetes, elevated body mass index, and higher C-reactive protein levels.Aβ+ participants exhibited worse global cognition and functional decline, with a higher prevalence of delusions and appetite disturbances. Meanwhile, Aβ− participants reported greater social engagement, but poorer sleep quality. Conclusions This study highlights the distinct clinical and lifestyle profiles of Aβ+ and Aβ− MCI, illuminating the heterogeneity of MCI and its underlying factors in the Korean population.

Background: Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia. Methods: Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort. Results: An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027). Conclusion C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.

Background/Aims: Small bowel capsule endoscopy (SBCE) has become the standard for initial evaluation in the diagnosis of small bowel lesions. Although optimal visualization of the mucosa is important, patients experience difficulty in consuming a large volume of bowel preparation agents. This study aimed to compare the efficacy and safety of 1-L polyethylene glycol (PEG) with ascorbic acid (AA) and 2-L PEG with AA. Methods: In this prospective, multicenter, non-inferiority study, patients who received SBCE were randomly assigned to consume 1-L PEG with AA or 2-L PEG with AA for small bowel preparation. The primary outcome was adequate small bowel visibility quality (SBVQ). The secondary outcomes included diagnostic yield, cecal complete rate, and adverse events. Results: One hundred and forty patients were enrolled in this study, 70 patients per group. In the per-protocol analysis, there were no significant differences in the adequate SBVQ rate (94.0% vs 94.3%; risk difference, –0.3; 95% confidence interval, –8.1 to 7.6; p=1.000), diagnostic yield rate (49.3% vs 48.6%, p=0.936), or cecal complete rate (88.1% vs 92.9%, p=0.338) between the 1-L PEG with AA group and 2-L PEG with AA group. The incidence of adverse events did not differ significantly between the groups (12.9% vs 11.9%, p=0.871). Conclusions One liter-PEG with AA is not inferior to 2-L PEG with AA in terms of adequate SBVQ for SBCE. One liter-PEG with AA can be recommended as the standard method for bowel cleansing for SBCE.

Background: Postoperative pain management is challenging in patients with oral cancer, especially those undergoing reconstructive surgery. Patient-controlled analgesia (PCA) is widely used, and fentanyl (FTN) concentration adjustments may improve pain control. This study aimed to evaluate the effects of FTN PCA concentration and reconstructive surgery on postoperative pain in patients with oral cancer. Methods: This retrospective observational study analyzed 140 patients with oral cancer who underwent surgery under general anesthesia. Patients were categorized based on FTN PCA dosage (FTN 700 mcg and ketorolac 150 mg vs. FTN 1400 mcg and ketorolac 150 mg). Pain was assessed using the visual analog scale (VAS) at multiple time points postoperatively (0, 12, 24, 36, 48, 60, and 72 h). PCA usage patterns, including demand count, delivery count, and delivery/demand ratios, were compared across subgroups. Missing data were imputed using linear interpolation. Results: PCA usage and pain control were evaluated between the FTN 700 mcg (N = 40) and 1400 mcg (N = 100) groups, stratified by reconstruction status. Demographic characteristics showed no significant difference.In the reconstructive surgery subgroup, patients in the FTN 1400 mcg group showed lower PCA refill counts (1.45 ± 0.69 vs. 1.61 ± 0.58) and fewer delivery counts (17.1 ± 21.3 vs. 25.1 ± 28.5) compared to those in the FTN 700 mcg group, achieving similar or superior pain control with fewer interventions. Similarly, patients without reconstructive surgery in the FTN 1400 mcg group demonstrated lower PCA refill counts, shorter PCA usage times, and fewer delivery counts. VAS scores decreased consistently over time across all groups but remained higher in the reconstruction groups. Logistic regression analysis revealed that patients with reconstructive surgery in the FTN 1400 mcg group were more likely to achieve a VAS score of ≤ 3.0 at 72 h postoperatively (P = 0.022). These findings indicate FTN 1400 mcg’s superiority in managing postoperative pain. Conclusion Comparing FTN PCA dosages, 1400 mcg demonstrated superior pain control to 700 mcg in patients undergoing oral cancer surgery, particularly those who underwent reconstructive surgery. This finding underscores the importance of optimizing FTN dosages to enhance postoperative pain management, reduce PCA-related demands, and achieve better patient outcomes.