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IRF3-p300 axis controls global acetylation and mitotic progression
No full textAccurate mitotic progression depends on precisely regulated post-translational modifications, including lysine acetylation, but the upstream mechanisms governing acetylation during mitosis remain unclear. Here, we identify the IRF3-p300 axis as a major regulator of global protein acetylation during mitosis. We show that p300 serves as the major lysine acetyltransferase active during mitosis, and its enzymatic activity is essential for proper cell division. Notably, p300 activation during mitosis requires phosphorylation and dimerization of IRF3, a transcription factor known for its role in innate immunity. IRF3 interacts with and activates p300, and depletion of either IRF3 or p300 reduces global mitotic protein acetylation and delays mitotic progression. These defects are rescued by wild-type IRF3 or p300, but not by phosphorylation- or dimerization-deficient IRF3 mutants or catalytically inactive p300. Mass spectrometry analysis reveals that the mitotic acetylome is substantially altered upon loss of IRF3 or p300, with widely overlapping subsets of non-histone proteins-many involved in RNA biogenesis and processing-being affected. These findings reveal a non-canonical role for IRF3 as an upstream activator of p300 and establish the IRF3-p300 axis as a key signaling pathway that ensures proper mitotic progression through global regulation of protein acetylation
Cytoplasmic delivery of antibodies through grafting a functional single complementarity-determining region loop
No full textThe mouse 3D8 anti-DNA antibody can enter cells and localize in the cytoplasm, primarily facilitated by the complementarity-determining region 1 of the variable light chain (CDR L1) domain. In this study, we grafted the CDR L1 loop from 3D8 onto non-cell-penetrating IgG antibodies to investigate whether these IgGs could acquire cytoplasmic localization ability while retaining antigen-binding activity. One of three IgGs was successfully delivered into the cytoplasm while maintaining antigen-binding activity. In silico protein modeling suggests that this capability is linked to structural similarity between CDR L1 in the grafted Ab and that in 3D8. This study proposes a strategy to confer cell-penetrating capability by incorporating a specific CDR loop into an antibody backbone while retaining affinity
Artificial intelligence applied to electrocardiogram to rule out acute myocardial infarction: the ROMIAE multicentre study
No full textBACKGROUND AND AIMS: Emerging evidence supports artificial intelligence-enhanced electrocardiogram (AI-ECG) for detecting acute myocardial infarction (AMI), but real-world validation is needed. The aim of this study was to evaluate the performance of AI-ECG in detecting AMI in the emergency department (ED). METHODS: The Rule-Out acute Myocardial Infarction using Artificial intelligence Electrocardiogram analysis (ROMIAE) study is a prospective cohort study conducted in the Republic of Korea from March 2022 to October 2023, involving 18 university-level teaching hospitals. Adult patients presenting to the ED within 24 h of symptom onset concerning for AMI were assessed. Exposure included AI-ECG score, HEART score, GRACE 2.0 score, high-sensitivity troponin level, and Physician AMI score. The primary outcome was diagnosis of AMI during index admission, and the secondary outcome was 30 day major adverse cardiovascular event (MACE). RESULTS: The study population comprised 8493 adults, of whom 1586 (18.6%) were diagnosed with AMI. The area under the receiver operating characteristic curve for AI-ECG was 0.878 (95% CI, 0.868-0.888), comparable with the HEART score (0.877; 95% CI, 0.869-0.886) and superior to the GRACE 2.0 score, high-sensitivity troponin level, and Physician AMI score. For predicting 30 day MACE, AI-ECG (area under the receiver operating characteristic, 0.866; 95% CI, 0.856-0.877) performed comparably with the HEART score (0.858; 95% CI, 0.848-0.868). The integration of the AI-ECG improved risk stratification and AMI discrimination, with a net reclassification improvement of 19.6% (95% CI, 17.38-21.89) and a C-index of 0.926 (95% CI, 0.919-0.933), compared with the HEART score alone. CONCLUSIONS: In this multicentre prospective study, the AI-ECG demonstrated diagnostic accuracy and predictive power for AMI and 30 day MACE, which was similar to or better than that of traditional risk stratification methods and ED physicians
Association of COX-2 Selectivity in Pain Medication Use with Endometriosis Incidence: Retrospective Cohort Study
No full textPURPOSE: This retrospective cohort study aimed to investigate the association between the use of pain medications with varying cyclooxygenase-2 (COX-2) selectivity and the incidence of endometriosis (EMS) in women. MATERIALS AND METHODS: Medical records from January 1, 1994, to December 31, 2022, were retrospectively analyzed. The cohort included 33406 patients diagnosed with any pain-related condition who were prescribed either selective COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients were followed for up to 5 years from the cohort entry date. The incidence of EMS was compared between the two medication groups using Cox proportional hazards models, adjusting for confounding factors such as age, past drug use, and prior diagnosis. RESULTS: The incidence rates of EMS were 3.00 per 1000 person-years in the COX-2 inhibitor group and 3.97 per 1000 person-years in the NSAIDs group. After adjustment for confounders, the hazard ratio for EMS incidence in the COX-2 inhibitor group compared to the NSAIDs group was 0.77 [95% confidence interval (CI), 0.63 to 0.93; p<0.01], indicating a significantly lower risk in the COX-2 inhibitor group. Subgroup analysis revealed that this association was particularly significant in younger women aged 20-44 years, with a hazard ratio of 0.71 (95% CI, 0.54 to 0.95; p<0.05) in this age group. CONCLUSION: The findings suggest that COX-2 inhibitors may reduce the incidence of EMS compared to traditional NSAIDs, highlighting their potential as a strategic option for managing EMS, particularly among younger women. Further prospective studies are needed to confirm these findings
Radiological Outcomes and Approach-Related Complications in Oblique Lateral Interbody Fusion at the Upper Lumbar Level
No full textBackground/Objectives: Despite recent advances in minimally invasive extrapleural lateral approaches, oblique lateral interbody fusion (OLIF) at the upper lumbar level is often difficult and limited to optimal reconstruction. We aimed to compare the radiological outcomes and approach-related complications of OLIF between the upper (L1-2 or L2-3) and lower (L3-4 or L4-5) levels. Methods: This study is a retrospective review of OLIF in the upper (n = 63) and lower (n = 60) lumbar level groups. Radiological parameters included the anterior/posterior disc height, coronal/sagittal disc angle, cage position, cage subsidence, and fusion rate at a postoperative 1-year follow-up. Approach-related complications including pleural/peritoneal lacerations, neurovascular injury, and other organ injuries were examined. Results: The baseline radiological parameters were similar between the two groups (all p > 0.05). At 1-year postoperatively, the anterior disc height (ADH) was significantly greater in the lower-level group (p = 0.031), while no significant differences were observed in the posterior disc height, coronal/sagittal disc angle, cage anterior position, or cage subsidence rate (all p > 0.05). The fusion rates were 97.9% and 95.0% at the upper and lower lumbar levels, respectively (p = 0.146). During OLIF at the upper lumbar level, chest tube insertion due to pleural laceration was observed in 11 (17.5%) cases. One case (1.2%) of segmental artery injury and two cases (3.2%) of pseudo-hernia were attributed to iliohypogastric nerve injury. Conclusions: Although the extrapleural approach in OLIF at the upper lumbar level is often limited, the radiological outcomes were comparable to those of OLIF at the lower lumbar level
COVID-19 infection in patients with end-stage kidney disease undergoing renal replacement therapies in Korea
No full textBACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic has placed patients with end-stage kidney disease (ESKD) at heightened risk owing to their vulnerability to infections. Our study focused on patients with ESKD, examining COVID-19 incidence, hospitalization, and mortality in relation to their renal replacement therapy (RRT) type and identifying factors influencing COVID-19 hospitalization. METHODS: We conducted a retrospective cohort study using health insurance claims data from the Health Insurance Review and Assessment Service for patients with ESKD between July 2017 and June 2022. COVID-19 data for the general population were sourced from the Korea Disease Control and Prevention Agency. RESULTS: Patients undergoing hemodialysis (HD) constituted 90.7% of the cohort, followed by kidney transplantation (KT) recipients and peritoneal dialysis (PD). After adjusting for every 10,000 individuals, KT recipients exhibited the highest COVID-19 incidence, followed by those undergoing HD and PD, whereas the general population showed a higher infection rate of 43.64. Patients undergoing HD had the highest hospitalization rates, followed by KT recipients and those undergoing PD. The mortality rate per 10,000 individuals was highest in HD, followed by PD, the general population, and KT. Multivariate analysis indicated that age, RRT duration, residence in a nursing hospital, and comorbidities were associated with COVID-19 hospitalization. CONCLUSION: Among RRT modalities, KT recipients displayed the highest COVID-19 incidence, whereas those undergoing HD exhibited the highest hospitalization and mortality rates. This study contributes to our understanding of infectious diseases in patients on RRT and aids in preparedness for future infectious disease outbreaks
Deferoxamine prevents dexamethasone-induced muscle atrophy by reducing MuRF1 and atrogin-1
No full textINTRODUCTION: Muscle atrophy, commonly triggered by glucocorticoids such as dexamethasone (DEX), involves increased protein degradation via the ubiquitin-proteasome system. Recent findings suggest that iron imbalance can also induce muscle atrophy. However, there have been no reports indicating that DEX causes intracellular iron imbalance leading to muscle atrophy. This study evaluated whether DEX causes iron imbalance-mediated muscle atrophy and whether deferoxamine (DFO), an iron chelator, can protect against DEX-induced muscle atrophy, exploring the underlying mechanisms in vitro and in vivo. METHOD: Differentiated C2C12 myotubes were exposed to DEX, with or without DFO, to evaluate morphological changes, expression of muscle-specific ubiquitin ligases (atrogin-1 and MuRF1), and related signaling pathways via quantitative reverse transcription polymerase chain reaction, Western blotting, and immunocytochemistry. Intracellular iron accumulation was quantified using fluorescence imaging. Additionally, C57BL/6J mice were administered intraperitoneal injections of DEX, with or without DFO, every other day for 12 days. Muscle function was assessed by grip strength, and muscle mass and fiber size were measured histologically. RESULTS: DEX significantly induced muscle atrophy in C2C12 myotubes, elevating intracellular iron and upregulating atrogin-1 and MuRF1 via increased nuclear translocation of FOXO3a and expression of KLF15. DFO treatment prevented these effects by restoring the iron balance, enhancing AKT phosphorylation, inhibiting FOXO3a nuclear translocation, and reducing KLF15 expression. Consistently, animal experiments demonstrated that DFO administration effectively preserved grip strength, tibialis anterior muscle mass, and muscle fiber size in DEX-treated mice. Furthermore, DFO treatment restored insulin-like growth factor 1 and myostatin expression levels altered by DEX. DISCUSSION: DFO effectively ameliorates DEX-induced muscle atrophy by modulating the AKT/FOXO3a and KLF15 signaling pathways and restoring the intracellular iron balance. These findings highlight DFO as a potential therapeutic agent for glucocorticoid-induced muscle atrophy
Targeting neutrophil-driven inflammation in adult-onset still’s disease: molecular insights from gene expression profiles
No full textBACKGROUND: The rarity and heterogeneity of adult-onset Still's disease (AOSD) pose significant challenges in understanding its precise pathogenic mechanisms, developing effective treatment options, and establishing therapeutic strategies. A comprehensive analysis of gene expression profiles could help to bridge the knowledge gaps in those areas. METHODS: A blood transcriptomic dataset comprising 31 patients with AOSD and 22 healthy controls was fetched. Cellular and molecular features were identified by analyzing differentially expressed genes (DEGs) and functional enrichment. Optimal molecular targets for neutrophil activation were identified using kernel-based diffusion scoring techniques. RESULTS: Blood molecular signatures indicate that neutrophil degranulation is the most enriched pathological process in AOSD. Neutrophil degranulation correlated significantly with the expression of Fcgamma receptors, IL-1 receptors, and chemokine receptors and their signaling activities. IL-1 inhibitors and IL-6 inhibitors did not exhibit a diffusion score favorable for directly deactivating neutrophil degranulation, but agents targeting CXCR1/CXCR2, C5AR1, neutrophil elastase, SRC, and SYK demonstrated significant diffusion scores for neutrophil degranulation. In particular, CXCR1, CXCR2, and C5AR1 were the DEGs predominantly expressed in neutrophils and closely associated with neutrophil degranulation in a context-specific functional analysis. CONCLUSIONS: Neutrophil activation is a key pathological module in AOSD. Therapeutic approaches aimed at neutrophils could offer a promising opportunity to regulate the inflammatory response in AOSD
Clinical Impact of TP53 Mutations in Patients with Head and Neck Cancer Who Were Treated with Targeted Therapies or Immunotherapy
No full textPURPOSE: Tumor suppressor p53 (TP53) mutations are common in head and neck squamous cell carcinoma (HNSCC). We evaluated their clinical impact in patients treated with targeted agents or immunotherapy in the KCSG HN15-16 TRIUMPH trial. MATERIALS AND METHODS: We analyzed clinical characteristics and outcomes of patients with TP53 mutations in the TRIUMPH trial, a multicenter, biomarker-driven umbrella trial in Korea. Patients were assigned to treatment groups based on genomic profiles: group 1, alpelisib; group 2, poziotinib; group 3, nintedanib; and group 4, abemaciclib. If there was no identifiable target, the patients were allocated to group 5 (durvalumab+/-tremelimumab). RESULTS: TP53 mutations were detected in 116/179 patients (64.8%), more frequently in human papillomavirus-negative and non-oropharyngeal cancers. Patients with TP53 mutations exhibited shorter progression-free survival than TP53 wild-type in all the patients (1.7 vs. 3.8 months, p=0.002) and in those who received targeted treatments (2.5 vs. 7.3 months, p=0.009). Furthermore, TP53 mutations were strongly associated with poor overall survival than TP53 wild-type in all the patients (11.1 vs. 28.8 months, p=0.005) and in group 5 (8.1 vs. 33.0 months, p=0.001). CONCLUSION: TP53 mutations were associated with aggressive clinical characteristics and poor survival, particularly in HNSCC patients treated with immunotherapy
Refining oxygen management through rigorous Oxygen Reserve Index (ORi) monitoring in patients undergoing general anesthesia: a randomized controlled trial: ORi to avoid excessive hyperoxia
No full textOptimizing oxygenation for patients necessitates a delicate balance between sufficient oxygen delivery and mitigating the potential hazards of hyperoxemia. We hypothesized that integrating Oxygen Reserve Index (ORi) monitoring would effectively reduce intraoperative hyperoxemia compared to reliance solely on pulse oximetry. This single-center randomized controlled trial included multiple trauma patients with ASA class 3 or higher undergoing general anesthesia. FiO(2) adjustments to 0.5 started at T0 with arterial blood gas analysis (ABGA) every 30-minutes. Patients were randomized into Group O (ORi monitoring) and Group N (pulse oximetry). In Group O, FiO(2) was reduced if ORi > 0.05; unchanged if ORi was 0-0.05. Group N decreased FiO(2) if SpO(2) was 100%, unchanged if SpO(2) was < 99%, and increased FiO(2) by 0.05 until SpO(2) reached 95% or above. 54 participants were randomized, and 51 analyzed. Group O demonstrated a significantly higher percentage of normoxemia (80 /= 120mmHg and >/= 150mmHg at 0.06 and 0.22, respectively. Simultaneous ORi and pulse oximetry reduce intraoperative hyperoxemia through safe and meticulous protocol adherence in patients