Background/Aims: Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. Methods: Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. Results: Methylome and transcriptome analyses of liver biopsies revealed significant (p<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA<, and SERPING1, as well as hypomethylation (p<0.0005) and upregulation (p<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.

Objectives: This study aimed to investigate the association between oral health behaviors and dental scaling to suggest effective preventive oral health behaviors. Methods: This cross-sectional survey examined linked datasets derived from the Korean National Health Insurance Service and Korean National Health and Nutrition Examination Survey, 2014-2017. The data of 4,258 adults aged ≥19 years were included. A multivariate regression analysis was performed to evaluate the effect of oral health behaviors on willingness to undergo dental scaling. Results: The multivariate regression analysis revealed that the participants whose oral hygiene habits included a thrice-daily tooth brushing frequency were 1.5% more likely to undergo dental scaling (95% confidence interval [CI], 1.167-1.881) than the others. Furthermore, those whose oral hygiene habits included a thrice-daily tooth brushing frequency and the daily use of dental floss or an interdental brush were 1.6% more likely to undergo dental scaling (95% CI, 1.194-2.032) than their counterparts. Conclusions The group with the most favorable oral health behaviors underwent dental scaling more frequently. Better personal oral health habits may lead to willingness to undergo dental scaling, and incremental dental hygiene improvements can be achieved through further oral health education. Educational programs are needed to raise awareness of and promote improvements in individual oral health behaviors.

Background/Aims: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events, including endocrine dysfunctions, which can have serious consequences on patient health and quality of life. The clinical course and characteristics of immune-related hypophysitis (irH) are not well established. This study aimed to analyze the clinical course and characteristics of irH. Methods: This single-center, retrospective study analyzed data from electronic medical records of Asan Medical Center, spanning January 2017 through June 2021. It included adult patients with solid tumors who underwent thyroid and adrenal function tests, along with gonadotropin and/or growth hormone evaluations, following the initiation of ICI treatment within the same period. The study explored the clinical characteristics of ICI-treated patients with and without irH, the incidence of irH, the time to irH onset, and the associated hormonal changes. Results: Twenty-one patients were included in this analysis. Clinical characteristics did not differ significantly between the irH (n = 13) and non-irH (n = 8) groups. Deficiency rates in the irH group were 23.1% for thyroid-stimulating hormone (n = 3), 76.9% for adrenocorticotropic hormone (n = 10), 61.5% for gonadotropin (n = 8), and 15.4% for growth hormone (n = 2). The overall incidence was 0.9 per person-year, with 6-month and 1-year cumulative incidences of 38.8% and 57.1%, respectively. The median time from ICI initiation to irH diagnosis was 7.7 months. Time to levothyroxine replacement was shorter in the irH group. Conclusions The findings provide evidence that could facilitate the prediction of ICI-induced irH based on clinical course and characteristics.

Purpose: Missing teeth is one of the most important indicators of oral health behavior and the result of dental caries, periodontal disease, and injuries. This study examined a trend in the incidence of severe partial edentulism (SPE) using the Korean National Health Insurance Service (KNHIS) data. Materials and Methods: Data of adults aged ≥20 years were obtained from the KNHIS for the 2014–2018 period. SPE was defined in dental information within a population with a treatment history of dental scaling as having 1 to 8 natural teeth. Crude incidence rates (CIRs) and age-standardized incidence rates (AIRs) with 95% confidence interval were calculated per 100000 persons. The Cochran Armitage trend (CAT) test and average annual percentage change were used to analyze SPE trends. Results: The CIRs among Korean adults were from 346.29 to 391.11 in 2014–2016 and from 391.11 to 354.09 in 2016–2018. The AIRs trend statistically increased by 4.31% from 346.29 to 376.80 and decreased by 4.72% from 376.80 to 342.10. The AIRs in men increased by 4.00% and decreased by 3.01%. The AIRs in women decreased by 2.18% and increased by 2.11% (CAT; p<0.01). The AIRs by region and income also showed trends of increase and decrease. Conclusion The study showed that the incidence trend of SPE increased and decreased from 2014 to 2018. This result would be able to aid in the planning of public oral health, and may also serve as fundamental data for verifying the impact of the public oral health policies implemented.

Purpose: Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline–based therapy. We aimed to evaluate the prognostic implications of serum β-2 microglobulin (β2M) in the context of PINK and proposed a new prognostic model. Materials and Methods: A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum β2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum β2M into PINK was proposed and validated in an independent validation cohort (n=88). Results: The patients’ median age was 53.5 years (range, 19 to 80 years). Patients with high serum β2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum β2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum β-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort. Conclusion Serum β2M is an independent prognostic factor for ENKTL patients. The new serum β2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis.Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

Pembrolizumab is an immune checkpoint inhibitor that selectively blocks the programmed cell death (PD)-1 receptor. Although it has a dramatic effect on the treatment of advanced malignancies, instability of immune tolerance may cause immune-related adverse events in the skin. A 62-year-old male with a history of metastatic urothelial carcinoma was referred to the dermatology department and presented with a widespread mucocutaneous rash. Itching appeared 7 days after the first administration of pembrolizumab, and on the third day after the second administration, an erythematous maculopapular rash that coalesced into large flaccid bullae on the whole body with a positive Nikolsky’s sign developed. A biopsy revealed a subepidermal bulla with basal keratinocyte necrosis. Pembrolizumab was discontinued due to the diagnosis of toxic epidermal necrolysis (TEN), and intravenous methylprednisolone was started. Herein, we report a case of TEN induced by pembrolizumab to highlight immune-related cutaneous adverse events in patients receiving anti-PD-1 therapy.

Background: Patients with stable psoriasis showing clearear-clear response can consider extending the dosing interval of biologics. However, few studies have reported the treatment outcomes following irregular dosing intervals of biologics in patients with psoriasis. Objective: We compared treatment outcomes after regular and irregular dosing intervals of biologics in patients with psoriasis. Methods: This single-center, retrospective observational study included patients who received biologics for treatment of plaque psoriasis between January 1, 2014 and December 31, 2019. We compared patient demographics, clinical characteristics, biologics administered, and treatment outcomes based on the regularity of the dosing interval. Results: Among 95 patients investigated, 63 (66.3%) received biologics at regular dosing intervals. We observed no significant intergroup differences in the final Psoriasis Area Severity Index (PASI) scores (1.2 vs. 1.8, p=0.16) and in the percentage improvement in PASI scores from baseline levels (−89.8% vs. −90.8%, p=0.68). The rate at which biologics were switched was higher in the irregular-dosing group than in the regular-dosing group; however, the difference was statistically nonsignificant (28.1% vs. 12.7%, p=0.06). We observed a significant intergroup difference in patients who were administered guselkumab at baseline (12 [21.8%] vs. 0 [0.0%], p=0.01). Conclusion This study showed that compared with regular dosing intervals, irregular dosing intervals of biologics were associated with high rates of switching of these agents, although we observed no statistically significant differences with regard to PASI scores. Therefore, it is important to adhere to the standard dosing schedule prescribed for biologics, and guselkumab may improve patient compliance.

BACKGROUND: Various cell-culture systems have been used to evaluate drug toxicity in vitro. However, factors that affect cytotoxicity outcomes in drug toxicity evaluation systems remain elusive. In this study, we used multilayered sheets of cardiac-mimetic cells, which were reprogrammed from human fibroblasts, to investigate the effects of the layer number on drug cytotoxicity outcomes. METHODS: Cell sheets of cardiac-mimetic cells were fabricated by reprogramming of human fibroblasts into cardiacmimetic cells via coculture with cardiac cells and electric stimulation, as previously described. Double-layered cell sheets were prepared by stacking the cell sheets. The mono- and double-layered cell sheets were treated with 5-fluorouracil (5-FU), an anticancer drug, in vitro. Subsequently, apoptosis and lipid peroxidation were analyzed. Furthermore, effects of cardiacmimetic cell density on cytotoxicity outcomes were evaluated by culturing cells in monolayer at various cell densities. RESULTS: The double-layered cell sheets exhibited lower cytotoxicity in terms of apoptosis and lipid peroxidation than the mono-layered sheets at the same 5-FU dose. In addition, the double-layered cell sheets showed better preservation of mitochondrial function and plasma membrane integrity than the monolayer sheets. The lower cytotoxicity outcomes in the double-layered cell sheets may be due to the higher intercellular interactions, as the cytotoxicity of 5-FU decreased with cell density in monolayer cultures of cardiac-mimetic cells. CONCLUSION The layer number of cardiac-mimetic cell sheets affects drug cytotoxicity outcomes in drug toxicity tests.The in vitro. cellular configuration that more closely mimics the in vivo configuration in the evaluation systems seems to exhibit lower cytotoxicity in response to drug.

BACKGROUND: Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. METHODS: Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTS: At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells. CONCLUSION The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.