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Ferroptosis is a specific form of cell death characterized by excessive accumulation of cellular lipid peroxides. Ferroptosis is closely associated with various diseases, inhibition of which may help alleviate multi-organ injury caused by ischemia-reperfusion and enhance the anti-tumor effect by promoting the immunity of T cells. However, clinical approved drugs targeting ferroptosis process remain rare. In this study, we unexpectedly found that (R)-crizotinib, the first-generation ALK inhibitor, has potent inhibitory activity against ferroptosis across various cell lines. Moreover, its chiral molecule (S)-crizotinib, which was considered to share no common targets with (R)-crizotinib, also suppresses ferroptosis with an efficacy similar to that of (R)-crizotinib. We further demonstrated that both crizotinib enantiomers inhibit ferroptosis independently of their known targets, but through a common mechanism involving the targeting of AGPAT3-mediated synthesis of ether-linked polyunsaturated fatty acids (PE-O-PUFA), which are known to promote lipid-ROS generation and ferroptosis. In line with their activity in cell lines, (R)-crizotinib and (S)-crizotinib effectively mitigate renal ischemia-reperfusion injury in mice. Furthermore, the two compounds also inhibit lipid-ROS accumulation in CD8+ T cells in draining lymph nodes of B16-F10 subcutaneous xenograft mice, thereby promoting anti-tumor effects. Collectively, our study firstly reports a common activity shared by (R)-crizotinib and (S)-crizotinib in ferroptosis regulation. As a clinically approved drug, (R)-crizotinib has well-established pharmacokinetics and safety, which makes it a promising candidate for repurposing. Given the current lack of FDA-approved ferroptosis inhibitors, our findings suggest therapeutically repurposing (R)-crizotinib as well as its enantiomer (S)-crizotinib for treating ferroptosis-related diseases.
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Liquid crystal monomers (LCMs) are a new class of emerging pollutants with high octanol-water partition coefficients; however, their transformation behavior and associated risk to environments with high organic matter content has rarely been reported. In this study, we investigated the photodegradation kinetics, mechanism, and toxicity variation of 23 LCMs on leaf wax models (e.g., organic solvents methanol and n-hexane). The order of the photolysis rates of these LCMs were biphenylethyne LCMs > phenylbenzoate LCMs > diphenyl/terphenyl LCMs under simulated sunlight, while the phenylcyclohexane LCMs were resistant to photodegradation. The phenylbenzoate and biphenylethyne LCMs mainly undergo direct photolysis, while the diphenyl/terphenyl LCMs mainly undergo self-sensitized photolysis. The main photolysis pathways are the cleavage of ester bonds for phenylbenzoate LCMs, the addition, oxidation and cleavage of alkynyl groups for biphenylethyne LCMs, and the cleavage/oxidation of chains attached to phenyls and the benzene ring opening for diphenyl/terphenyls LCMs. Most photolysis products remained toxic to aquatic organisms to some degree. Additionally, two quantitative structure-activity relationship models for predicting kobs of LCMs in methanol and n-hexane were developed, and employed to predict kobs of 93 LCMs to fill the kobs data gap in systems mimicking leaf surfaces. These results can be helpful for evaluating the fate and risk of LCMs in environments with high content of organic phase.
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Cristais Líquidos , Fotólise , Relação Quantitativa Estrutura-Atividade , Cinética , Cristais Líquidos/química , Luz SolarRESUMO
Liquor-pairing food is a common dietary combination. Baijiu and peanuts are unquestionably a classic pairing in China. But no one has explained why. Its alteration in baijiu flavor was studied using multiple sensory evaluation, as well as nontargeted proton-transfer reaction mass spectrometry coupled with GC × GC-MS. Multiple statistical analyses were used to discover the changes in the retronasal aroma and its contribution to baijiu flavor. It showed that the consumption of peanuts enhances the burst intensity of ester aroma (0.814-1.00) and Jiao aroma (0.889-0.963) but decreases the aftertaste of baijiu (p < 0.05). Meanwhile, it increases the release intensity and advances the burst time of baijiu retronasal aroma (p < 0.05), suppressing its aftertaste through the retention effect of the food matrix, the changes in oral processing, and cross-modal interactions. Hydrophobicity, polarity, and chemical characteristics are key factors of the uneven impact of accompanying food to aroma compounds. Esters, especially ethyl caprylate (2103 ± 927 to 51.9 ± 4.05) is most impacted by peanuts and contributes most to baijiu flavor changes. Pyrazines from peanut enhance the Qu-aroma, grain aroma, and Chen aroma in baijiu flavor. Therefore, we revealed the chemical nature of baijiu-peanut combination and help to optimize baijiu consumption experience.
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Arachis , Cromatografia Gasosa-Espectrometria de Massas , Odorantes , Paladar , Humanos , Arachis/química , Odorantes/análise , Adulto , Feminino , Masculino , Adulto Jovem , China , Compostos Orgânicos Voláteis/química , Aromatizantes/química , Bebidas Alcoólicas/análise , Olfato , Pessoa de Meia-IdadeRESUMO
To maintain protein homeostasis, X-box binding protein 1 (XBP1) undergoes splicing following the activation of the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. Although targeting ER stress represents a promising therapeutic strategy, a comprehensive understanding of XBP1 at the cellular level and the link between XBP1 and the innate nervous system is lacking. Here, TCGA pancancer datasets from 33 cancer types, scRNA pancancer datasets from 454 patients and bulk RNA-seq datasets from 155 paired esophageal squamous cell carcinoma (ESCC) patients were analyzed. To cope with ER stress, plasma cells tend to activate XBP1 after undergoing bacterial infection and inflammatory signaling from the innate immune system. Patients with high XBP1 expression in their plasma cells have a higher tumor grade and worse survival. However, activation of the innate immune system with increased XBP1 expression in plasma cells correlates with an increased lymphocyte ratio, indicative of a more robust immune response. Moreover, XBP1 activation appears to initiate leukocyte migration at the transcriptional level. Our study revealed that the XBP1-induced UPR could mediate the crosstalk between optimal acquired humoral immune responses and innate immunity in ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Imunidade Inata , Plasmócitos , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box , Humanos , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Masculino , Feminino , Estresse do Retículo Endoplasmático/imunologia , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Idoso , PrognósticoRESUMO
Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.
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Elementos de DNA Transponíveis , Humanos , Elementos de DNA Transponíveis/genética , Engenharia Genética/métodos , Genoma Humano , Animais , Evolução MolecularRESUMO
Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network and transcriptional signatures of T cells and myeloid cells define distinct ESCC subtypes characterized by T cell exhaustion, and interleukin (IL) and interferon (IFN) signaling. Furthermore, this approach classifies ESCC patients into ICI responders and non-responders, as validated by whole tumor transcriptomes and liquid biopsy-based single-cell transcriptomes of anti-PD-1 ICI responders and non-responders. Our study stratifies ESCC patients based on TME transcriptional network, providing novel insights into tumor niche remodeling and potentially predicting ICI responses in ESCC patients.
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BACKGROUND: Medulloblastoma (MB) is one of the most common malignant brain tumors that mainly affect children. Various approaches have been used to model MB to facilitate investigating tumorigenesis. This study aims to compare the recapitulation of MB between subcutaneous patient-derived xenograft (sPDX), intracranial patient-derived xenograft (iPDX), and genetically engineered mouse models (GEMM) at the single-cell level. METHODS: We obtained primary human sonic hedgehog (SHH) and group 3 (G3) MB samples from six patients. For each patient specimen, we developed two sPDX and iPDX models, respectively. Three Patch+/- GEMM models were also included for sequencing. Single-cell RNA sequencing was performed to compare gene expression profiles, cellular composition, and functional pathway enrichment. Bulk RNA-seq deconvolution was performed to compare cellular composition across models and human samples. RESULTS: Our results showed that the sPDX tumor model demonstrated the highest correlation to the overall transcriptomic profiles of primary human tumors at the single-cell level within the SHH and G3 subgroups, followed by the GEMM model and iPDX. The GEMM tumor model was able to recapitulate all subpopulations of tumor microenvironment (TME) cells that can be clustered in human SHH tumors, including a higher proportion of tumor-associated astrocytes and immune cells, and an additional cluster of vascular endothelia when compared to human SHH tumors. CONCLUSIONS: This study was the first to compare experimental models for MB at the single-cell level, providing value insights into model selection for different research purposes. sPDX and iPDX are suitable for drug testing and personalized therapy screenings, whereas GEMM models are valuable for investigating the interaction between tumor and TME cells.
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Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.
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OBJECTIVE: Delayed cerebral ischemia (DCI)-induced cerebral infarction is a major cause of adverse neurological outcomes following aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to investigate the relationship between postoperative serum electrolyte levels and DCI in patients with aSAH. MATERIALS AND METHODS: We analyzed the data of patients with aSAH between 2015 and 2022. The patients were classified into two groups according to whether they experienced DCI. Electrolyte levels were categorized into three groups based on the normal ranges for electrolytes. Logistic regression models were used to study the relationship between electrolyte levels and DCI. Another logistic regression analysis was conducted to explore the relationship between the different severity levels of statistically significant indicators and DCI. A restrictive cubic spline model was adopted to assess the potential linear relationship between electrolytes and DCI. Subsequently, sensitivity analysis was performed to assess the impact of collinearity among ions. Finally, subgroup analysis was performed. RESULTS: This study included 1,099 patients. Patients with hyperchloremia were more prone to DCI than those with normal chloride levels. Subsequently, excluding the population with hypochloremia, both mild and severe hyperchloremia were found to be associated with an increased risk of DCI compared with normal chloride levels. Within the framework of a restrictive cubic spline, our findings revealed an increased incidence of DCI (P for nonlinear = 0.735) as chloride levels increased. Sensitivity analysis revealed that patients with severe hyperchloremia were more susceptible to DCI. CONCLUSIONS: This study found that patients with aSAH and postoperative hyperchloremia are more prone to developing DCI.
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Isquemia Encefálica , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico , Estudos Retrospectivos , Cloretos , Infarto Cerebral/etiologia , Infarto Cerebral/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiologiaRESUMO
BACKGROUND AND OBJECTIVE: Lysine and its pathway metabolites have been identified as novel biomarkers for metabolic and vascular diseases. The role of them in the identification of moyamoya disease (MMD) has not been elucidated. This study aimed to determine the association between lysine pathway metabolites and the presence of MMD. METHODS: We prospectively enrolled 360 MMD patients and 89 healthy controls from September 2020 to December 2021 in Beijing Tiantan Hospital. Serum levels of lysine, pipecolic acid and 2-aminoadipic acid were measured by liquid chromatography-mass spectrometry. We employed logistic regression and restricted cubic spline to explore the association between these metabolites and the presence of MMD. Stratified analyses were also conducted to test the robustness of results. RESULTS: We observed that lysine levels in MMD patients were significantly higher and pipecolic acid levels were significantly lower compared to HCs (both p < 0.001), while no difference was found in the level of 2-AAA between both groups. When comparing metabolites by quartiles, elevated lysine levels were linked to increased odds for MMD (the fourth quartile [Q4] vs the first quartile [Q1]: odds ratio, 3.48, 95%CI [1.39-8.75]), while reduced pipecolic acid levels correlated with higher odds (Q4 vs Q1: odds ratio, 0.08; 95 % CI [0.03-0.20]). The restricted cubic spline found a L-shaped relationship between pipecolic acid level and the presence of MMD, with a cutoff point at 2.52 µmol/L. Robust results were also observed across subgroups. CONCLUSION: Elevated lysine levels were correlated with increased odds of MMD presence, while lower pipecolic acid levels were associated with higher odds of the condition. These results suggest potential new biomarkers for the identification of MMD. CLINICAL TRIAL REGISTRY NUMBER: URL: https://www.chictr.org.cn/. Unique identifier: ChiCTR2200061889.
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Doença de Moyamoya , Humanos , Ácido 2-Aminoadípico , Biomarcadores , Lisina , Estudos Transversais , Estudos de Casos e ControlesRESUMO
BACKGROUND: This study aimed to investigate the effect of increased HER-2 expression on tumor-infiltrating lymphocytes (TILs) and determine its impact on the prognosis of colorectal cancer (CRC) patients; Methods: HER-2, CD4, CD8, CD19, LY6G, CD56, CD68, CD11b, and EpCam expression in CRC tissues and adjacent paracancerous tissues were assessed using multiplex fluorescence immunohistochemical staining. The correlation between HER-2 expression and the number of TILs in CRC tissues was analyzed. Kaplan-Meier and Cox proportional hazards models were used to analyze survival outcomes; Results: The expression of HER-2 in tumor tissues was higher than that in paracancerous tissues (1.31 ± 0.45 vs. 0.86 ± 0.20, p < 0.05). Additionally, there was an increase in the numbers of CD4+, CD8+, CD19+, and CD68+ cells in CRC tissues (14.11 ± 1.10 vs. 3.40 ± 0.18, p < 0.005; 0.16 ± 0.12 vs. 0.04 ± 0.04, p < 0.005; 0.71 ± 0.46 vs. 0.25 ± 0.13, p < 0.0005; 0.27 ± 0.24 vs. 0.03 ± 0.11, p < 0.05). An increase in HER-2 expression was positively correlated with an increase in CD4, CD8, and CD19 (p < 0.0001). In HER-2-positive CRC tissues, CD68 expression was increased (0.80 ± 0.55 vs. 0.25 ± 0.22, p < 0.05). In HER-2-upregulated CRC tissues, CD4, CD8, CD19, CD68, CD11b, Ly6G, and CD56 expressions were elevated (0.70 ± 0.37 vs. 0.32 ± 0.17, p = 0.03; 0.22 ± 0.13 vs. 0.09 ± 0.06, p = 0.03; 0.31 ± 0.19 vs. 0.12 ± 0.08, p = 0.02; 1.05 ± 0.62 vs. 0.43 ± 0.21, p < 0.01; 1.34 ± 0.81 vs. 0.53 ± 0.23, p < 0.01; 0.50 ± 0.31 vs. 0.19 ± 0.10, p < 0.01; 1.26 ± 0.74 vs. 0.52 ± 0.24, p < 0.01). Furthermore, increased HER-2 expression was an independent risk factor for recurrence-free survival (RFS) in patients (p < 0.01, HR = 3.421); Conclusions: The increased expression of HER-2 and its relationship with immune cells will provide new insights for immunotherapy in CRC patients.
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Background: To determine whether the neutrophil-to-lymphocyte ratio (NLR) can serve as a predictive indicator for acute appendicitis among pregnant females. Patients and Methods: A comprehensive search was conducted across multiple databases including PubMed, Embase, and Web of Science seeking to gather pertinent research on the NLR concerning pregnant individuals either suspected of or diagnosed with acute appendicitis. The NLR value and receiver operating characteristic (ROC) curve were utilized to assess the predictive value of the NLR in predicting acute appendicitis among pregnant patients. Results: Seven studies and 410 patients were included in the meta-analysis. The area under the curve (AUC) for identifying acute appendicitis in pregnant patients using the NLR was found to be 0.856 (95% confidence interval [CI], 0.833-0.879). Additionally, the NLR values for pregnant patients with acute appendicitis were significantly elevated, showing a mean difference (MD) of 0.80 (95% CI, 0.58-1.03; p < 0.001). Conclusions: The NLR can be considered a valuable and effective diagnostic tool for anticipating acute appendicitis in pregnant patients.
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Apendicite , Neutrófilos , Feminino , Humanos , Gravidez , Doença Aguda , Apendicite/diagnóstico , Linfócitos , Curva ROCRESUMO
BACKGROUND: Moyamoya disease (MMD) is a rare progressive vascular disease that leads to intracranial internal carotid artery stenosis and eventual occlusion. However, its pathogenesis remains unclear. The purpose of this study is to explore the role of abnormally expressed proteins in the pathogenesis of MMD. METHODS: Data-independent acquisition mass spectrometry identifies the differentially expressed proteins in MMD serum by detecting the serum from 60 patients with MMD and 20 health controls. The differentially expressed proteins were validated using enzyme linked immunosorbent assays. Immunofluorescence for superficial temporal artery and middle cerebral artery specimens was used to explore the morphological changes of vascular wall in MMD. In vitro experiments were used to explore the changes and mechanisms of differentially expressed proteins on endothelial cells. RESULTS: Proteomic analysis showed that a total of 14 726 peptides and 1555 proteins were quantified by mass spectrometry data. FLNA (filamin A) and ZYX (zyxin) proteins were significantly higher in MMD serum compared with those in health controls (Log2FC >2.9 and >2.8, respectively). Immunofluorescence revealed an intimal hyperplasia in superficial temporal artery and middle cerebral artery specimens of MMD. FLNA and ZYX proteins increased the proportion of endothelial cells in S phase and promoted their proliferation, angiogenesis, and cytoskeleton enlargement. Mechanistic studies revealed that AKT (serine/threonine kinase)/GSK-3ß (glycogen synthase kinase 3ß)/ß-catenin signaling pathway plays a major role in these FLNA- and ZYX-induced changes in endothelial cells. CONCLUSIONS: This study provides proteomic data on a large sample size of MMD. The differential expression of FLNA and ZYX in patient with MMD and following in vitro experiments suggest that these upregulated proteins are related to the pathology of cerebrovascular intimal hyperplasia in MMD and are involved in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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Doença de Moyamoya , Humanos , Doença de Moyamoya/patologia , Glicogênio Sintase Quinase 3 beta , Proteínas do Citoesqueleto , Células Endoteliais/metabolismo , Proteômica , Hiperplasia/patologia , Neovascularização PatológicaRESUMO
BACKGROUND: This study aimed to investigate the natural history of re-rupture in ruptured brain arteriovenous malformations (AVMs) and to provide comprehensive insights into its associated factors and prevention. METHODS: This study included 1712 eligible ruptured AVMs from a nationwide multicenter prospective collaboration registry between August 2011 and September 2021. The natural rupture risk before intervention and the annual rupture risk after intervention were both assessed. Cox proportional hazard regression models and Kaplan-Meier survival curves were used to explore independent factors associated with AVM re-rupture. The correlation between these factors and AVM re-rupture was verified in multiple independent cohorts, and the prevention effect of intervention timing and intervention strategies on AVM re-rupture was further analyzed. RESULTS: The annual re-rupture risk in ruptured AVMs was 7.6%, and the cumulative re-rupture risk in the first 1, 3, 5, and 10 years following the initial rupture were 10%, 25%, 37.5%, and 50%, respectively. Cox proportional hazard regression analysis confirmed adult patients, ventricular system involvement, and any deep venous drainage as independent factors associated with AVM re-rupture. The intervention was found to significantly reduce the risk of AVM re-rupture (annual rupture risk 11.34% vs 1.70%, p<0.001), especially in those who underwent surgical resection (annual rupture risk 0.13%). CONCLUSIONS: The risk of re-rupture in ruptured AVMs is high. Adult patients, ventricular system involvement, and any deep venous drainage are independent risk factors for re-rupture. Applying the results universally to all ruptured AVM cases may be biased. Intervention could effectively reduce the risk of re-rupture.
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Background: Stress-related gastrointestinal bleeding (SRGB) is one of the major complications after aneurysmal subarachnoid hemorrhage (aSAH), and it can present challenges in patient care and treatment. The aim of this study was to explore the clinical significance of the caudate Hounsfield unit (HU) value in the Alberta Stroke Program Early CT (ASPECT) score for predicting SRGB in patients with aSAH. Methods: We retrospectively analyzed the data of 531 aSAH patients admitted to our institution between 2019 and 2022. Potential predictors of SRGB were identified using multivariate Cox regression analysis. We used a restricted cubic spline (RCS) to evaluate whether there is a nonlinear relationship between the right caudate HU value and SRGB. MaxStat analysis (titled as maximally selected rank statistics) was performed to identify the optimal cutoff point for the right caudate HU value. Another Kaplan-Meier method with the log-rank test was used to analyze the right caudate HU value in predicting the occurrence of SRGB. Results: The incidence rate of SRGB was 17.9%. In the multivariate Cox regression analysis, the right caudate HU value was an independent predictor of SRGB [Hazard ratio (HR) = 0.913; 95% confidence interval (CI): 0.847-0.983, and p = 0.016]. The RCS indicated that the incidence of developing SRGB reduces with increasing right caudate HU values (nonlinear p = 0.78). The optimal cut-off value of the right caudate HU was 25.1. Conclusion: Among aSAH patients, lower right caudate HU values indicated a higher risk of developing SRGB. Our findings provide further evidence for the relationship between the gastrointestinal system and the brain.
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Indirect bypass surgery is an effective treatment for moyamoya disease (MMD), but the success of the surgery depends on the formation of spontaneous collateral vessels, which cannot be accurately predicted before surgery. Developing a prediction nomogram model for neoangiogenesis in patients after indirect revascularization surgery can aid surgeons in identifying suitable candidates for indirect revascularization surgery. This retrospective observational study enrolled patients with MMD who underwent indirect bypass surgery from a multicenter cohort between December 2010 and December 2018. Data including potential clinical and radiological predictors were obtained from hospital records. A nomogram was generated based on a multivariate logistic regression analysis identifying potential predictors of good neoangiogenesis. A total of 263 hemispheres of 241 patients (mean ± SD age 24.38 ± 15.78 years, range 1-61 years) were reviewed, including 168 (63.9%) hemispheres with good postoperative collateral formation and 95 (36.1%) with poor postoperative collateral formation. Based on multivariate analysis, a nomogram was formulated incorporating four predictors, including age at operation, abundance of ICA moyamoya vessels, onset type, and Suzuki stage. The C-index for this nomogram was 0.80. Calibration curve and decision-making analysis validated the fitness and clinical application value of this nomogram. The nomogram developed in this study exhibits high accuracy in predicting good neoangiogenesis after indirect revascularization surgery in MMD patients. This model can be very helpful for clinicians when making decisions about surgical strategies for MMD patients in clinical practice.
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As a member of alpha-coronaviruses, PEDV could lead to severe diarrhea and dehydration in newborn piglets. Given that lipid peroxides in the liver are key mediators of cell proliferation and death, the role and regulation of endogenous lipid peroxide metabolism in response to coronavirus infection need to be illuminated. The enzymatic activities of SOD, CAT, mitochondrial complex-I, complex-III, and complex-V, along with the glutathione and ATP contents, were significantly decreased in the liver of PEDV piglets. In contrast, the lipid peroxidation biomarkers, malondialdehyde, and ROS were markedly elevated. Moreover, we found that the peroxisome metabolism was inhibited by the PEDV infection using transcriptome analysis. These down-regulated anti-oxidative genes, including GPX4, CAT, SOD1, SOD2, GCLC, and SLC7A11, were further validated by qRT-PCR and immunoblotting. Because the nuclear receptor RORγ-driven MVA pathway is critical for LPO, we provided new evidence that RORγ also controlled the genes CAT and GPX4 involved in peroxisome metabolism in the PEDV piglets. We found that RORγ directly binds to these two genes using ChIP-seq and ChIP-qPCR analysis, where PEDV strongly repressed the binding enrichments. The occupancies of histone active marks such as H3K9/27ac and H3K4me1/2, together with active co-factor p300 and polymerase II at the locus of CAT and GPX4, were significantly decreased. Importantly, PEDV infection disrupted the physical association between RORγ and NRF2, facilitating the down-regulation of the CAT and GPX4 genes at the transcriptional levels. RORγ is a potential factor in modulating the CAT and GPX4 gene expressions in the liver of PEDV piglets by interacting with NRF2 and histone modifications.