Echinochrome A (Ech A) isolated from marine organisms is a therapeutic effector for various cardiovascular diseases, but its precise mechanisms are unclear.This study identified the role and mechanisms mediating the effects of Ech A on the migration of vascular smooth muscle cells (VSMCs) induced by high-mobility group box 1 (HMGB1). Compared to the control cells, the migration of VSMCs stimulated with HMGB1 (100 ng/ml) was markedly increased, which was significantly attenuated in cells pretreated with MPIIIB10 (100 ng/ml), a neutralizing monoclonal antibody for osteopontin (OPN). In VSMCs stimulated with HMGB1, the increased expression of OPN mRNA and protein was accompanied by an increased OPN promoter activity. In reporter gene assays using OPN promoter-luciferase constructs, the promoter region 538-234 bp of the transcription start site containing the binding sites for activator protein 1 (AP-1) was shown to be responsible for the increased transcriptional activity by HMGB1. In addition, the binding activity of AP-1 was increased in HMGB1-stimulated cells, highlighting the pivotal role of AP-1 on OPN expression in HMGB1-stimulated VSMCs. An examination of the vascular effects of Ech A showed that the increased AP-1 binding/promoter activities and OPN expression induced by HMGB1 were attenuated in cells pretreated with Ech A (3 or 10 μM). Similarly, Ech A inhibited HMGB1-induced VSMC migration in a concentration-dependent manner. These findings suggest that Ech A inhibits VSMC migration by suppressing OPN expression.Hence, Ech A is suggested as a potential therapeutic strategy for vascular remodeling in the injured vasculatures.

Purpose: This study aimed to explore the effects of both the presence and size of posterior subependymal germinal matrix hemorrhage (PS-GMH), considered a mild form of hemorrhage, on the neurodevelopmental outcomes of extremely preterm infants. Methods: A retrospective analysis was conducted on 221 extremely preterm infants, assessing their initial and term-equivalent age (TEA) cranial ultrasound (cUS) examinations from 2016 to 2021. Infants were classified based on the presence and size (small/large) of PS-GMH. Neurodevelopmental outcomes at corrected ages of 18-24 months were analyzed in 135 infants. Results: PS-GMH was identified in 86.9% (192/221) of the infants, with 13.5% (26/192) exhibiting large PS-GMH. Among the 135 infants who were followed up, those with PS-GMH were found to have younger gestational ages (P<0.001) and a higher incidence of maternal chorioamnionitis (P=0.016) than those without PS-GMH. Significant differences were observed in the incidence of grade II intraventricular hemorrhage (IVH) on initial cUS (P=0.003) and ventriculomegaly at TEA cUS (P=0.026) across the groups with no PS-GMH, small PS-GMH, and large PS-GMH. The large PS-GMH group exhibited a higher occurrence of grade II IVH than the small PS-GMH group (P=0.006). However, ventriculomegaly incidence did not significantly vary with PS-GMH status. Neurodevelopmental outcomes were also not significantly different across PS-GMH statuses. The adjusted odds ratios for any neurodevelopmental impairment, compared to the no PS-GMH group, were 1.70 (95% confidence interval [CI], 0.40 to 7.26; P=0.471) for all PS-GMH, 1.61 (95% CI, 0.37 to 6.93; P=0.526) for small PS-GMH, and 3.84 (95% CI, 0.62 to 24.00; P=0.150) for large PS-GMH. Conclusion PS-GMH was frequently observed in extremely preterm infants; however, it did not independently predict adverse neurodevelopmental outcomes.

Purpose: This study aimed to evaluate the prognosis of the not evaluated (NE) group by comparing it with the lost to follow-up (LTFU) group among patients with multidrug/rifampin-resistant tuberculosis (MDR/RR-TB). Materials and Methods: This was a retrospective longitudinal follow-up study using an integrated database constructed by data linkage of the three national databases. This database included 7226 cases of MDR/RR-TB notified between 2011 and 2017 in South Korea. Results: Among the 7226 MDR/RR-TB cases, 730 (10.1%) were classified as LTFU group, and 353 (4.9%) as NE group. When comparing NE group with LTFU group, there were no significant differences in the all-cause mortality rate (18.1% vs. 13.8%, p=0.065), median time to death [404 days (interquartile range, IQR 46–850) vs. 443 days (IQR 185–1157), p=0.140], and retreatment rate (26.9% vs.22.2%, p=0.090). After adjusting for potential confounders, the adjusted hazard ratio (aHR) for all-cause mortality (aHR 1.11; 95% confidence interval 0.80-1.53; p=0.531) in NE group was not significantly different than that in LTFU group. Among retreated cases, NE group had a higher treatment success rate (57.9% vs 43.8%, p=0.029) and a lower LTFU rate (11.6% vs 38.3%, p<0.001) compared to LTFU group. Conclusion NE group had an unfavorable outcome comparable to LTFU group, suggesting undetected cases of LTFU or deaths during the referral process. Establishing an efficient patient referral system would contribute to reducing the incidence of NE cases.

Parkinson’s disease (PD) is a movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have shown that necroptosis is involved in the development of inflammatory and neurodegenerative diseases. Receptor-interacting protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) play key roles in necroptosis, with MLKL being the final executor of necroptosis. Necrosulfonamide (NSA) is a specific inhibitor of MLKL, and its therapeutic effects in various inflammatory and neurological disorders have been previously reported. However, its role in PD has not yet been clearly demonstrated. In this study, we examined the effects of NSA in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. NSA reduced dopaminergic cell death and restored the expression of neurotrophic factors, such as BDNF, GDNF, and PGC-1α, in the SN region of MPTP mice. In addition, NSA inhibited microglial/ astrocyte activation and the expression of proinflammatory markers, such as iNOS, TNF-α, IL-1β, and IL-6. NSA also reduced oxidative stress markers, such as 8-OHdG and 4-HNE, while enhancing Nrf2-driven antioxidant enzymes, including HO-1, catalase, MnSOD, GCLC, and GCLM. We found that NSA inhibited MLKL phosphorylation in dopaminergic neurons and microglia, which may have reduced neuronal cell death and inflammation. Therefore, NSA-mediated suppression of dopaminergic neuronal cell death, inflammation, and oxidative stress may have therapeutic potential in PD.

Tofacitinib, which is used to treat rheumatoid arthritis (RA), is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, CYP3A1/2 and CYP2C11. Acetaminophen (APAP), which is frequently used for pain relief in patients with RA, can induce acute liver injury (ALI) when taken in excess, profoundly affecting drug metabolism. Resveratrol (RVT) is a polyphenolic compound with hepatoprotective properties. This study investigated the protective effects of RVT against APAP-induced ALI in rats, and explored its influence on the pharmacokinetics of tofacitinib. In ALI rats, both intravenous and oral administration of tofacitinib resulted in a significant (207% and 181%) increase in the area under the plasma concentration-time curve (AUC), primarily driven by a substantial reduction (66.1%) in non-renal clearance (CLNR) compared to that in control (CON) rats. Notably, RVT administration in ALI rats provided effective liver protection, partially restoring liver function, as evidenced by normalized glutamate oxaloacetate transaminase levels and the pharmacokinetic parameters, AUC and CLNR, closer to those observed in untreated CON rats (117% and 81.9%, respectively). These findings highlight the importance of considering the potential interactions between RVT or polyphenol-rich natural products and medications in patients with ALI in clinical practice.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability, and homologous recombination deficiency scores, which were essential for clinical decision-making. Conclusion TE-WGS is a comprehensive approach in personalized oncology, matching TSO500’s key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

The common data model (CDM) has found widespread application in healthcare studies, but its utilization in cancer research has been limited. This article describes the development and implementation strategy for Cancer Clinical Library Databases (CCLDs), which are standardized cancer-specific databases established under the Korea-Clinical Data Utilization Network for Research Excellence (K-CURE) project by the Korean Ministry of Health and Welfare. Fifteen leading hospitals and fourteen academic associations in Korea are engaged in constructing CCLDs for 10 primary cancer types. For each cancer type-specific CCLD, cancer data experts determine key clinical data items essential for cancer research, standardize these items across cancer types, and create a standardized schema. Comprehensive clinical records covering diagnosis, treatment, and outcomes, with annual updates, are collected for each cancer patient in the target population, and quality control is based on six-sigma standards. To protect patient privacy, CCLDs follow stringent data security guidelines by pseudonymizing personal identification information and operating within a closed analysis environment. Researchers can apply for access to CCLD data through the K-CURE portal, which is subject to Institutional Review Board and Data Review Board approval. The CCLD is considered a pioneering standardized cancer-specific database, significantly representing Korea’s cancer data. It is expected to overcome limitations of previous CDMs and provide a valuable resource for multicenter cancer research in Korea.

Background: Immunocompromised patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection often have prolonged viral shedding, and some are clinically suspected of reinfection with different SARSCoV-2 variants. However, data on this issue are limited. This study investigated the SARS-CoV-2 variants in serially collected respiratory samples from immunocompromised patients with prolonged viral shedding for over 12 weeks or relapsed viral shedding after at least 2 weeks of viral clearance. Materials and Methods: From February 2022 to September 2023, we prospectively enrolled immunocompromised patients with coronavirus disease 2019 who had hematologic malignancies or had undergone transplantation and were admitted to a tertiary hospital. Weekly saliva or nasopharyngeal swabs were collected from enrolled patients for at least 12 weeks after diagnosis. Genomic RNA polymerase chain reaction (PCR) was performed on samples, and those testing positive underwent viral culture to isolate the live virus. Spike gene full sequencing via Sanger sequencing and real-time reverse transcription-PCR for detecting mutation genes were conducted to identify SARSCoV-2 variants. Results: Among 116 enrolled patients, 20 with prolonged or relapsed viral shedding were screened to identify the variants. Of these 20 patients, 7 (35%) exhibited evidence of re-infection; one of 8 patients with prolonged viral shedding and 6 of 12 with relapsed viral shedding were reinfected with SARS-CoV-2. Conclusion Our data suggest that approximately one-third of immunocompromised patients with persistent or relapsed viral shedding had reinfection with different variants of SARS-CoV-2.

Background: and Purpose Treatments for neuromyelitis optica spectrum disorder (NMOSD) such as eculizumab, ravulizumab, satralizumab, and inebilizumab have significantly advanced relapse prevention, but they remain expensive. Rituximab is an off-label yet popular alternative that offers a cost-effective solution, but its real-world efficacy needs better quantification for guiding the application of newer approved NMOSD treatments (ANTs). This study aimed to determine real-world rituximab failure rates to anticipate the demand for ANTs and aid in resource allocation. Methods: We conducted a nationwide retrospective study involving 605 aquaporin-4-antibody-positive NMOSD patients from 22 centers in South Korea that assessed the efficacy and safety of rituximab over a median follow-up of 47 months. Results: The 605 patients treated with rituximab included 525 (87%) who received continuous therapy throughout the follow-up period (median=47 months, interquartile range=15–87 months). During this period, 117 patients (19%) experienced at least 1 relapse. Notably, 68 of these patients (11% of the total cohort) experienced multiple relapses or at least 1 severe relapse.Additionally, 2% of the patients discontinued rituximab due to adverse events, which included severe infusion reactions, neutropenia, and infections. Conclusions This study has confirmed the efficacy of rituximab in treating NMOSD, as evidenced by an 87% continuation rate among patients over a 4-year follow-up period. Nevertheless, the occurrence of at least one relapse in 19% of the cohort, including 11% who experienced multiple or severe relapses, and a 2% discontinuation rate due to adverse events highlight the urgent need for alternative therapeutic options.

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.