PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.

Stabilization of stalled replication forks is a prominent mechanism of PARP (Poly(ADP-ribose) Polymerase) inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF (p300/CBP-associated) as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11 and EXO1. A H4K8ac binding domain within MRE11/EXO1 is required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks, resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR (ataxia telangiectasia and Rad3-related), which phosphorylates PCAF on serine 264 (S264) to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses.

Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity.

Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability as well as therapeutic targets in cancer. Here, we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using several cell-based assays and proteomic interaction network analysis. Applying these approaches, we identify 24 of the 42 BRD proteins as promoters of DNA repair and/or genome integrity. We identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allowing direct acetylation by PCAF, and repair of DSBs by homologous recombination. We also discovered the bromo-and-extra-terminal (BET) BRD proteins, BRD2 and BRD4, as negative regulators of transcription-associated RNA-DNA hybrids (R-loops) as inhibition of BRD2 or BRD4 increased R-loop formation, which generated DSBs. These breaks were reliant on topoisomerase II, and BRD2 directly bound and activated topoisomerase I, a known restrainer of R-loops. Thus, comprehensive interactome and functional profiling of BRD proteins revealed new homologous recombination and genome stability pathways, providing a framework to understand genome maintenance by BRD proteins and the effects of their pharmacological inhibition.

PCAF promotes R-loop resolution via histone acetylation.

R-loops cause genome instability, disrupting normal cellular functions. Histone acetylation, particularly by p300/CBP-associated factor (PCAF), is essential for maintaining genome stability and regulating cellular processes. Understanding how R-loop formation and resolution are regulated is important because dysregulation of these processes can lead to multiple diseases, including cancer. This study explores the role of PCAF in maintaining genome stability, specifically for R-loop resolution. We found that PCAF depletion promotes the generation of R-loop structures, especially during ongoing transcription, thereby compromising genome stability. Mechanistically, we found that PCAF facilitates histone H4K8 acetylation, leading to recruitment of the a double-strand break repair protein (MRE11) and exonuclease 1 (EXO1) to R-loop sites. These in turn recruit Fanconi anemia (FA) proteins, including FANCM and BLM, to resolve the R-loop structure. Our findings suggest that PCAF, histone acetylation, and FA proteins collaborate to resolve R-loops and ensure genome stability. This study therefore provides novel mechanistic insights into the dynamics of R-loops as well as the role of PCAF in preserving genome stability. These results may help develop therapeutic strategies to target diseases associated with genome instability.

R-loops are harmful DNA-RNA hybrid structures that cause genome instability, disrupting normal cell functions. This study explored the role of the protein PCAF in resolving R-loops to maintain genome stability. The researchers found that depleting PCAF leads to increased R-loop formation, especially during transcription, compromising the genome. Mechanistically, PCAF facilitates histone acetylation, recruiting proteins like MRE11, EXO1, FANCM and BLM to R-loop sites. These proteins collaborate to resolve R-loop structures. The findings suggest that PCAF, histone acetylation, and these repair proteins work together to untangle R-loops and preserve genome integrity. Understanding this process provides insights into R-loop dynamics and PCAF's role in genome maintenance, potentially leading to therapeutic strategies for diseases associated with genome instability, such as cancer.

PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors.

PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

Assessing risk stratification in long-term outcomes of rectal neuroendocrine tumors following endoscopic resection: a multicenter retrospective study.

OBJECTIVES: While endoscopic resection of rectal neuroendocrine tumors (NETs) has significantly increased, long-term data on risk factors for recurrence are still lacking. Our aim is to analyze the long-term outcomes of patients with rectal NETs after endoscopic resection through risk stratification. METHODS: In this multicenter retrospective study, we included patients who underwent endoscopic resection of rectal NETs from 2009 to 2018 and were followed for ≥12 months at five university hospitals. We classified the patients into three risk groups according to the clinicopathological status of the rectal neuroendocrine tumors: low, indeterminate, and high. The high-risk group was defined if the tumors have any of the followings: size ≥ 10 mm, lymphovascular invasion, muscularis propria or deeper invasion, positive resection margins, or mitotic count ≥2/10. RESULTS: A total of 346 patients were included, with 144 (41.6%), 121 (35.0%), and 81 (23.4%) classified into the low-, indeterminate-, and high-risk groups, respectively. Among the high-risk group, seven patients (8.6%) received salvage treatment 28 (27-67) days after the initial endoscopic resection, with no reported extracolonic recurrence. Throughout the follow-up period, 1.1% (4/346) of patients experienced extracolonic recurrences at 56.5 (54-73) months after the initial endoscopic resection. Three of these patients (75%) were in the high-risk group and did not undergo salvage treatment. The risk of extracolonic recurrence was significantly higher in the high-risk group compared to the other groups (p = 0.039). CONCLUSION: Physicians should be concerned about the possibility of metastasis during long-term follow-up of high-risk patients and consider salvage treatment.

The combination of osimertinib with Raf inhibitor overcomes osimertinib resistance induced by KRAS amplification in EGFR-mutated lung cancer cells.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)1 tyrosine kinase inhibitor (TKI) approved for the treatment of EGFR-positive patients exhibiting a T790 M resistance mutation after treatment with an earlier generation of EGFR TKIs. However, resistance to osimertinib inevitably develops despite its efficacy, and the resistance mechanisms are complex and not fully understood. We established cell lines with acquired resistance to osimertinib from gefitinib- or erlotinib-resistant NSCLC cells using a dose-escalation method, and found that they had upregulated levels of phosphorylated ERK1/2. Targeted next-generation sequencing of 143 genes was performed, and interestingly, amplification of KRAS was observed in osimertinib-resistant cells. Transfection of siRNA against the KRAS gene notably reduced the activation of ERK1/2 and AKT and significantly enhanced the induction of apoptosis by osimertinib treatment in osimertinib-resistant cells. LY3009120, a RAF inhibitor, showed a significant synergistic effect with osimertinib on apoptotic cell death in osimertinib-resistant cells. Combined treatment with osimertinib and LY3009120 also demonstrated remarkable synergistic anti-tumor activity in mouse xenografts of these cells. This could be a potential new treatment option for KRAS amplification-induced osimertinib failure.

Comparative Morphology of Island and Inland Agastache rugosa and Their Gastroprotective Effects in EtOH/HCl-Induced Gastric Mucosal Gastritis.

Agastache rugosa Kuntze (Lamiaceae; Labiatae), a medicinal and functional herb used to treat gastrointestinal diseases, grows well both on islands and inland areas in South Korea. Thus, we aimed to reveal the morphological and micromorphological differences between A. rugosa grown on island and inland areas and their pharmacological effects on gastritis in an animal model by combining morphological and mass spectrophotometric analyses. Morphological analysis showed that island A. rugosa had slightly smaller plants and leaves than inland plants; however, the density of all types of trichomes on the leaves, petioles, and stems of island A. rugosa was significantly higher than that of inland plants. The essential oil component analysis revealed that pulegone levels were substantially higher in island A. rugosa than in inland A. rugosa. Despite the differences between island and inland A. rugosa, treatment with both island and inland A. rugosa reduced gastric damages by more than 40% compared to the gastritis induction group. In addition, expression of inflammatory protein was reduced by about 30% by treatment of island and inland A. rugosa. The present study demonstrates quantitative differences in morphology and volatile components between island and inland plants; significant differences were not observed between the gastritis-inhibitory effects of island and inland A. rugosa, and the efficacy of island A. rugosa was found to be similar to that of A. rugosa grown in inland areas.

Alliums as Potential Antioxidants and Anticancer Agents.

The genus Allium plants, including onions, garlic, leeks, chives, and shallots, have long been recognized for their potential health benefits, particularly in oxidative and cancer prevention. Among them, onions and garlic have been extensively studied, unveiling promising biological activities that are indicative of their potential as potent antioxidant and anticancer agents. Research has revealed a rich repository of bioactive compounds in Allium species, highlighting their antioxidative properties and diverse mechanisms that target cancer cells. Compounds such as allicin, flavonoids, and organosulfur compounds (OSCs) exhibit notable antioxidant and anticancer properties, affecting apoptosis induction, cell cycle arrest, and the inhibition of tumor proliferation. Moreover, their antioxidant and anti-inflammatory attributes enhance their potential in cancer therapy. Studies exploring other Allium species beyond onions and garlic have revealed similar biological activities, suggesting a broad spectrum of natural products that could serve as promising candidates for developing novel anticancer treatments. Understanding the multifaceted potential of Allium plants will pave the way for innovative strategies in oxidative and cancer treatment and prevention, offering new avenues for pharmaceutical research and dietary interventions. Therefore, in this review, we compile an extensive analysis of the diversity of various Allium species, emphasizing their remarkable potential as effective agents.

Five Dimensions of Needs for Help: The Efficacy of a Technology-Based Intervention Among Asian American Breast Cancer Survivors.

Cancer survivors including Asian American breast cancer survivors have reported their high needs for help during their survivorship process. With the COVID-19 pandemic, the necessity of technology-based programs to address their needs for help without face-to-face interactions has been highlighted. The purpose of this randomized intervention study was to determine the efficacy of a technology-based program in reducing various types of needs for help among this specific population. This was a randomized clinical trial with repeated measures. A total of 199 participants were included in the data analysis. The recruitment settings included both online and offline communities/groups for Asian Americans. The needs for help were assessed using the Support Care Needs Survey-34 Short Form (SCNS) subscales measuring psychological, information, physical, support, and communication needs. Data analysis was conducted through an intent-to-treat approach. In the mixed effect models, psychological needs, information needs, physical needs, and communication needs decreased over time (P < .001). However, there were no significant group * time effects. Social support significantly mediated the effects of a technology-based intervention on psychological, information, and support needs at the pre-test and the post-1 month. This study supported significant decreases in the needs for help of Asian American breast cancer survivors by a technology-based intervention. Further studies are needed with other racial/ethnic groups of cancer survivors to confirm the efficacy of a technology-based intervention in reducing cancer survivors' needs for help during their survivorship process.

Recruitment and Retention Issues in a Technology-Based Intervention Among Korean American Midlife Women With Depressive Symptoms'.

The number of health technology-based intervention studies has grown significantly. However, issues in the recruitment and retention for such studies, especially of Asian Americans, have rarely been discussed. The purpose of this paper was to discuss issues in the recruitment and retention of a specific group of Asian Americans-Korean American midlife women with depressive symptoms-into a technology-based intervention study using computers and mobile devices with a measurement device and to provide directions for future participant recruitment and retention in technology-based intervention studies. The written memos of research team members and the written records of research team meetings were analyzed using a content analysis. The issues in the recruitment and retention process included (1) low recruitment and retention rates; (2) the perceived long intervention period; (3) strict inclusion/exclusion criteria; (4) concerns related to the use of a measurement device; and (5) the perceived adequacy of monetary incentives. Based on the issues identified in the study, several suggestions are made for future recruitment and retention of racial/ethnic minorities in technology-based intervention studies (eg, appropriate intervention period, innovative and creative motivation strategies, acceptable measurement scales and devices, and adequate monetary reimbursement).

Anti-Leukemic Effects of Idesia polycarpa Maxim Branch on Human B-Cell Acute Lymphoblastic Leukemia Cells.

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL.

USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing.

Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

WSB1 promotes tumor metastasis by inducing pVHL degradation.

The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.

Clinical and Mechanistic Implications of R-Loops in Human Leukemias.

Genetic mutations or environmental agents are major contributors to leukemia and are associated with genomic instability. R-loops are three-stranded nucleic acid structures consisting of an RNA-DNA hybrid and a non-template single-stranded DNA. These structures regulate various cellular processes, including transcription, replication, and DSB repair. However, unregulated R-loop formation can cause DNA damage and genomic instability, which are potential drivers of cancer including leukemia. In this review, we discuss the current understanding of aberrant R-loop formation and how it influences genomic instability and leukemia development. We also consider the possibility of R-loops as therapeutic targets for cancer treatment.

scAAV2-Mediated Expression of Thioredoxin 2 and C3 Transferase Prevents Retinal Ganglion Cell Death and Lowers Intraocular Pressure in a Mouse Model of Glaucoma.

Elevated intraocular pressure (IOP) in glaucoma causes retinal ganglion cell (RGC) loss and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. In this paper, we aimed to develop a novel gene therapy for glaucoma using an AAV2-based thioredoxin 2 (Trx2)-exoenzyme C3 transferase (C3) fusion protein expression vector (scAAV2-Trx2-C3). We evaluated the therapeutic effects of this vector in vitro and in vivo using dexamethasone (DEX)-induced glaucoma models. We found that scAAV2-Trx2-C3-treated HeLa cells had significantly reduced GTP-bound active RhoA and increased phosphor-cofilin Ser3 protein expression levels. scAAV2-Trx2-C3 was also shown to inhibit oxidative stress, fibronectin expression, and alpha-SMA expression in DEX-treated HeLa cells. NeuN immunostaining and TUNEL assay in mouse retinal tissues was performed to evaluate its neuroprotective effect upon RGCs, whereas changes in mouse IOP were monitored via rebound tonometer. The present study showed that scAAV2-Trx2-C3 can protect RGCs from degeneration and reduce IOP in a DEX-induced mouse model of glaucoma, while immunohistochemistry revealed that the expression of fibronectin and alpha-SMA was decreased after the transduction of scAAV2-Trx2-C3 in murine eye tissues. Our results suggest that AAV2-Trx2-C3 modulates the outflow resistance of the trabecular meshwork, protects retinal and other ocular tissues from oxidative damage, and may lead to the development of a gene therapeutic for glaucoma.

Knowledge, attitudes, and perceptions associated with HPV vaccination among female Korean and Chinese university students.

BACKGROUND: Human papillomavirus (HPV) vaccination is a form of primary prevention for cervical cancer. The HPV vaccination rate of female university students is not high in Korea and China. Therefore, the purpose of this study was to identify and compare the factors associated with intention to receive HPV vaccination between Korean and Chinese female university students. METHODS: The participants were 273 Korean and 317 Chinese female university students who had not been vaccinated for HPV, and data were collected using a self-reported questionnaire about attitudes toward HPV vaccination, HPV knowledge, perceptions of HPV infection, and intention to receive HPV vaccine. RESULTS: There were no significant differences between the Korean and Chinese female university students in HPV knowledge, attitudes, perceptions, and vaccination intention. The factors influencing the intention of HPV vaccination in Korean students were a positive attitude toward the HPV vaccine and a high HPV knowledge score. For Chinese students, sexual experience, awareness of genital warts, a positive attitude toward the HPV vaccine, a high HPV knowledge scores, a perception of the seriousness of HPV infection, and negative emotions regarding HPV infection were significant factors. CONCLUSIONS: It is important to improve attitudes and knowledge about HPV and the HPV vaccine in order to enhance HPV vaccination both in Korea and China. Perceived seriousness and negative emotions regarding HPV infection should be used as a framework to develop subject-tailored interventions in China.

Dieckol Isolated from Eisenia bicyclis Ameliorates Wrinkling and Improves Skin Hydration via MAPK/AP-1 and TGF-ß/Smad Signaling Pathways in UVB-Irradiated Hairless Mice.

Repetitive exposure to ultraviolet B (UVB) is one of the main causes of skin photoaging. We previously reported that dieckol isolated from Eisenia bicyclis extract has potential anti-photoaging effects in UVB-irradiated Hs68 cells. Here, we aimed to evaluate the anti-photoaging activity of dieckol in a UVB-irradiated hairless mouse model. In this study, hairless mice were exposed to UVB for eight weeks. At the same time, dieckol at two doses (5 or 10 mg/kg) was administered orally three times a week. We found that dieckol suppressed UVB-induced collagen degradation and matrix metalloproteinases (MMPs)-1, -3, and -9 expression by regulating transforming growth factor beta (TGF-ß)/Smad2/3 and mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) signaling. In addition, dieckol rescued the production of hyaluronic acid (HA) and effectively restored the mRNA expression of hyaluronan synthase (HAS)-1/-2 and hyaluronidase (HYAL)-1/-2 in UVB-irradiated hairless mice. We observed a significant reduction in transepidermal water loss (TEWL), epidermal/dermal thickness, and wrinkle formation in hairless mice administered dieckol. Based on these results, we suggest that dieckol, due to its anti-photoaging role, may be used as a nutricosmetic ingredient for improving skin health.

Predictors of Acceptance of Cosmetic Surgery in South Korean Women.

BACKGROUND: Examining the characteristics of the growing cosmetic surgery (CS) consumer population could help promote safer cosmetic procedure practices. We identified the predictors of acceptance of cosmetic surgery (ACS) among South Korean women aged 20-69 years. METHODS: An online survey was administered to 291 randomly sampled participants during August 30-September 6, 2021. An equal number of participants from each age group was selected. They completed a questionnaire concerning the general and CS-related characteristics, acceptance of cosmetic surgery scale, appearance satisfaction, self-esteem, and depression. The mean participants' age and body mass index were 44.12 (± 13.79) years and 22.15 (± 3.39) kg/m2, respectively. RESULTS: Approximately 90.0% of the participants had been exposed to a CS advertisement, with 96.2% having acquired information regarding the CS side effects and 52.6% considering CS in future. Eighty-eight (30.2%) participants had undergone CS. The most common surgical and non-surgical categories were eyelid surgery and botulinum toxin injection, respectively. The ACS increased with decreasing age (ß = - 0.12, p < .05), exposure to a CS advertisement (ß = 0.10, p < .05), consideration of undergoing CS in future (ß = 0.59, p < .001), and increasing depression scores (ß = 0.29, p < .001); collectively, these factors explained 43.0% of the variance (F = 25.21, p < .001). CONCLUSIONS: "Consideration of undergoing CS" was the strongest ACS predictor in the multiple regression analysis for the entire study population and according to CS history. Future studies should conduct an in-depth analysis based on the current CS trends, intention to undergo CS in future, and past CS experiences of South Korean women aged 20-69 years. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Hepatocyte-Specific Deficiency of DAX-1 Protects Mice from Acetaminophen-Induced Hepatotoxicity by Activating NRF2 Signaling.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.