BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

OBJECTIVES: Multiple myeloma (MM) is a highly heterogeneous hematologic malignancy, with disease progression driven by cytogenetic abnormalities and a complex bone marrow microenvironment. This study aims to construct a prognostic model for MM based on transcriptomic data and lipid metabolism related genes (LRGs), and to identify potential drug targets for high-risk patients to support clinical decision-making. METHODS: In this study, 2 transcriptomic datasets covering 985 newly diagnosed MM patients were retrieved from the Gene Expression Omnibus (GEO) database. Univariate Cox regression and 101 machine learning algorithms were used for gene selection. An LRG-based prognostic model was constructed using Stepwise Cox (both directions) and random survival forest (RSF) algorithms. The association between the prognostic score and clinical events was evaluated, and model performance was assessed using time-dependent receiver operating characteristic (ROC) curves and the C-index. The added predictive value of combining prognostic scores with clinical variables and staging systems was also analyzed. Differentially expressed genes between high- and low-risk groups were identified using limma and clusterProfiler and subjected to pathway enrichment analysis. Drug sensitivity analysis was conducted using the Genomics of Drug Sensitivity in Cancer (GDSC) database and oncoPredict to identify potential therapeutic targets for high-risk patients. The functional role of key LRGs in the model was validated via in vitro cell experiments. RESULTS: An LRG-based prognostic model (LRG17) was successfully developed using transcriptomic data and machine learning. The model demonstrated robust predictive performance, with area under the curve (AUC) values of 0.962, 0.912, and 0.842 for 3-, 5-, and 7-year survival, respectively. Patients were stratified into high- and low-risk groups, with high-risk patients showing significantly shorter overall survival (OS) and event-free survival (EFS) (both P<0.001) and worse clinical profiles (e.g., lower albumin, higher β2-microglobulin and lactate dehydrogenase levels). Enrichment analysis revealed that high-risk patients were significantly enriched for pathways related to chromosome segregation and mitosis, whereas low-risk patients were enriched for immune response and immune cell activation pathways. Drug screening suggested that AURKA inhibitor BMS-754807 and FGFR3 inhibitor I-BET-762 may be more effective in high-risk patients. Functional assays demonstrated that silencing of key LRG PLA2G4A significantly inhibited cell viability and induced apoptosis. CONCLUSIONS LRGs serve as promising biomarkers for prognosis prediction and risk stratification in MM. The overexpression of chromosomal instability-related and high-risk genetic event-associated genes in high-risk patients may explain their poorer outcomes. Given the observed resistance to bortezomib and lenalidomide in high-risk patients, combination therapies involving BMS-754807 or I-BET-762 may represent effective alternatives.
Humans ; Multiple Myeloma/mortality* ; Prognosis ; Lipid Metabolism/genetics* ; Transcriptome ; Machine Learning ; Male ; Female ; Gene Expression Profiling ; Algorithms

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Arachidonic acid can be transformed into a variety of metabolites that trigger an inflammatory response through cyclooxygenase, lipoxygenase, cytochrome P450 enzymes, and other metabolic pathways. Moreover, it plays a key role in the occurrence and development of inflammatory diseases. In recent years, multi-target drugs based on the arachidonic acid metabolic pathway have become an important direction of anti-inflammatory drug research. This article summarizes the opportunities and challenges of arachidonic acid metabolic pathways as well as their interference in the development of anti-inflammatory drugs, reviews the research progress of multi-target drug design, synthesis, and anti-inflammatory activity based on the arachidonic acid metabolic pathway, and discusses the difficulties and prospects of multi-target drugs based on metabolic pathways in anti-inflammatory drug development, aiming to provide some reference and inspiration for the study of multi-target anti-inflammatory drugs based on the arachidonic acid metabolic pathway.

Objective To explore the relationship between baseline urinary protein levels and the onset of chronic obstructive pulmonary disease (COPD). Methods A questionnaire survey, blood and urine sample collection, physical examination, and pulmonary function test were conducted among permanent residents over 40 years old in Pudong New Area, Shanghai. The subjects were divided into four groups based on the baseline urine albumin-to-creatinine ratio (ACR) quartiles (0~1.65 mg/g, 1.65~4.89 mg/g, 4.89~10.78 mg/g, and ≥10.78 mg/g). Cox regression analysis was used to explore the relationship between ACR levels and the incidence of COPD in middle-aged and elderly people. Results Among the 3 105 subjects, the median follow-up time was 3.212 years (P25~P75：3.102~3.473). 116 new cases of COPD were observed, with an incidence density of 10.423 per 1000 person-years. The incidence densities for COPD at four ACR levels were 7.922 per 1 000 person-years, 8.300 per 1 000 person-years , 11.419 per 1 000 person-years, and 13.843 per 1 000 person-years, respectively. Cox regression analysis revealed that as the ACR level increased, there was a rising trend in the incidence rate of COPD (χ²=4.396, P=0.036). After adjusting for gender, age, education level, occupational exposure to dust, history of childhood pneumonia, smoking, family history of COPD, central obesity, and hypertension, the risk of developing COPD was 2.499 times higher (95% CI: 1.460~4.276) for ACR levels ≥10.78 mg/g compared to the reference group with a baseline ACR level of 0~1.65 mg/g. Conclusion Elevated ACR levels in middle-aged and elderly population may increase the risk of COPD, and early monitoring of urine protein levels is beneficial for COPD prevention.

Objective To explore the value of multi-sequence MRI radiomics for predicting clinical stage of cervical squamous cell carcinoma(CSCC).Methods Totally 190 patients with single CSCC confirmed by pathology were retrospectively collected.Among them,67 cases with International Federation of Gynecology and Obstetrics(FIGO)stage ⅠB—ⅡA were classified into early stage group,while 123 cases with FIGO ⅡB—ⅢC were enrolled in middle-late stage group.The patients were divided into training set(n=114,including 40 cases in early stage subgroup and 74 cases in middle-late stage subgroup)and test set(n=76,including 27 cases in early stage subgroup and 49 cases in middle-late stage subgroup)at the ratio of 6∶4.Single factor and logistic analyses were used to screen clinical relevant factors,and a clinical model was constructed.The best radiomics features of lesions were extracted and selected based on pre-treatment pelvic MR T2WI,diffusion-weighted imaging(DWI),dynamic contrast enhancement(DCE)-T1WI and all the three,respectively,and the radiomics models were constructed,including T2WI,DWI,DCE-TWI and combined sequences models,then a clinical-radiomics model was established based on clinical model and combined sequences model.The predictive efficacy of each model was evaluated by receiver operating characteristic curves,and the area under the curves(AUC)were calculated.The integrated discrimination improvement(IDI)index was also calculated to compare the diagnostic efficacy of each model in training set,and decision curve analysis(DCA)was used to evaluate their clinical value.Results Squamous cell carcinoma associated antigen in middle-late stage subgroup was higher than that in early stage subgroup in both training and test sets(both P＜0.05),which was used to establish the clinical model.The AUC of clinical,T2WI,DWI,DCE-TWI,combined sequences and clinical-radiomics models for predicting clinical stage of CSCC was 0.66,0.71,0.78,0.81,0.88 and 0.89 in training set,respectively,which was 0.62,0.64,0.72,0.73,0.77 and 0.76 in test set,respectively.In training set,the predictive efficacy of clinical-radiomics model was higher than that of combined sequences model(IDI=0.19,P＜0.05),both higher than that of the rest models(IDI=0.19-0.47,all P＜0.05).When the thresholds were 0.02-1.00 and 0.05-1.00,combined sequences and clinical-radiomics models had higher clinical net benefits in training set.Conclusion Multi-sequence MRI radiomics could effectively predict clinical stage of CSCC,and combining clinical data could improve its diagnostic efficacy.

Objective To compare the cleaning abilities of ProTaper Gold(PTG)and TF-Adaptive(TFA).Methods Forty single-abstracted premolars were randomly divided into PTG and TFA groups.The debris and smear layer of the root coronal 1/3,middle 1/3 and apical 1/3 in the two groups were observed using scanning electron microscope(SEM).The cleaning abilities of the PTG and TFA rotary systems were scored according to the scoring standard developed by YAMASHITA.The scores of the two groups were compared and then analyzed.Results There was no significant difference found in the scores of the smear layer and debris at the root coronal 1/3 and the middle 1/3.The scores of the debris and smear layer at the apical 1/3 in the group PTG were higher than those in the TFA group(P<0.05).Conclusion PTG and TFA can effectively remove the root canal smear layer and debris at the root coronal 1/3,and the middle 1/3.However,at the apical 1/3,the cleaning efficiency of TFA is better than that of PTG.

Objective:To explore the relationship between the expression of long chain non coding ribonucleic acid (LncRNA) small nucleolar RNA host gene 1 (LncRNA SNHG1) and microRNA (miR)-143-3p in nasopharyngeal squamous cell carcinoma (HSCC) tissue and clinical pathological features and prognosis.Methods:A prospective selection was made from 97 HSCC patients admitted to the Handan Central Hospital from March 2016 to March 2018. Surgical resection of HSCC tissue and normal mucosa tissue adjacent to cancer were taken, and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of LncRNA SNHG1 and miR-143-3p. The patient′s survival status was followed up after leaving the hospital. We compared the differences in the expression of LncRNA SNlHG1 and miR-143-3p in HSCC tissues with different clinical pathological parameters, analyzed the correlation between LncRNA SNHG1 and miR-143-3p expression, and the relationship between LncRNA SNHG1 and miR-143-3p expression and the prognosis of HSCC patients.Results:The expression of LncRNA SNHG1 in HSCC tissue was higher than that in normal mucosa tissue adjacent to cancer ( P<0.05), and the expression of miR-143-3p was lower than that in normal mucosa tissue adjacent to cancer ( P<0.05). The expression of LncRNA SNHG1 in cancer tissues of HSCC patients with tumor node metastasis (TNM) stage Ⅲ, low to medium differentiation, and lymph node metastasis was higher than that of HSCC patients with TNM stage Ⅰ-Ⅱ, high differentiation, and no lymph node metastasis (all P<0.05), and the expression of miR-143-3p was lower than that of HSCC patients with TNM stage Ⅰ-Ⅱ, high differentiation, and no lymph node metastasis (all P<0.05). The expression of LncRNA SNHG1 in HSCC tissues is negatively correlated with the expression of miR-143-3p ( r=-0.522, P<0.05). The 5-year cumulative survival rate of HSCC patients with high expression of LncRNA SNHG1 was lower than that of HSCC patients with low expression of LncRNA SNHG1 ( P<0.05), and the 5-year cumulative survival rate of HSCC patients with low expression of miR-143-3p was lower than that of HSCC patients with high expression of miR-143-3p ( P<0.05). Multivariate Cox regression analysis showed that TNM stage Ⅲ and high expression of LncRNA SNHG1 were risk factors for poor prognosis in HSCC patients (all P<0.05), while high expression of miR-143-3p was a protective factor ( P<0.05). Conclusions:The expression of LncRNA SNHG1 is upregulated and miR-143-3p is downregulated in HSCC tissues, with a negative correlation between the two, which is related to the malignant pathological characteristics and poor prognosis of HSCC.

Objective:To evaluate the diagnostic efficacy and practicality of the Jaundice color card (JCard) as a screening tool for neonatal jaundice.Methods:Following the standards for reporting of diagnostic accuracy studies (STARD) statement, a multicenter prospective study was conducted in 9 hospitals in China from October 2019 to September 2021. A total of 845 newborns who were admitted to the hospital or outpatient department for liver function testing due to their own diseases. The inclusion criteria were a gestational age of ≥35 weeks, a birth weight of ≥2 000 g, and an age of ≤28 days. The neonate′s parents used the JCard to measure jaundice at the neonate′s cheek. Within 2 hours of the JCard measurement, transcutaneous bilirubin (TcB) was measured with a JH20-1B device and total serum bilirubin (TSB) was detected. The Pearson′s correlation analysis, Bland-Altman plots and the receiver operating characteristic (ROC) curve were used for statistic analysis.Results:Out of the 854 newborns, 445 were male and 409 were female; 46 were born at 35-36 weeks of gestational age and 808 were born at ≥37 weeks of gestational age. Additionally, 432 cases were aged 0-3 days, 236 cases were aged 4-7 days, and 186 cases were aged 8-28 days. The TSB level was (227.4±89.6) μmol/L, with a range of 23.7-717.0 μmol/L. The JCard level was (221.4±77.0) μmol/L and the TcB level was (252.5±76.0) μmol/L. Both the JCard and TcB values showed good correlation ( r=0.77 and 0.80, respectively) and agreements (96.0% (820/854) and 95.2% (813/854) of samples fell within the 95% limits of agreement, respectively) with TSB. The JCard value of 12 had a sensitivity of 0.93 and specificity of 0.75 for identifying a TSB ≥205.2?μmol/L, and a sensitivity of 1.00 and specificity of 0.35 for identifying a TSB ≥342.0?μmol/L. The TcB value of 205.2?μmol/L had a sensitivity of 0.97 and specificity of 0.60 for identifying TSB levels of 205.2 μmol/L, and a sensitivity of 1.00 and specificity of 0.26 for identifying TSB levels of 342.0 μmol/L. The areas under the ROC curve (AUC) of JCard for identifying TSB levels of 153.9, 205.2, 256.5, and 342.0 μmol/L were 0.96, 0.92, 0.83, and 0.83, respectively. The AUC of TcB were 0.94, 0.91, 0.86, and 0.87, respectively. There were both no significant differences between the AUC of JCard and TcB in identifying TSB levels of 153.9 and 205.2 μmol/L (both P>0.05). However, the AUC of JCard were both lower than those of TcB in identifying TSB levels of 256.5 and 342.0 μmol/L (both P<0.05). Conclusions:JCard can be used to classify different levels of bilirubin, but its diagnostic efficacy decreases with increasing bilirubin levels. When TSB level are ≤205.2 μmol/L, its diagnostic efficacy is equivalent to that of the JH20-1B. To prevent the misdiagnosis of severe jaundice, it is recommended that parents use a low JCard score, such as 12, to identify severe hyperbilirubinemia (TSB ≥342.0 μmol/L).

Objective:To translate Evidence-based Practice-knowledge, attitude, application, anticipated future use (EBP-KAPF) scale into Chinese, and evaluate its reliability and validity.Methods:The Chinese version of the EBP-KAPF scale was determined through translation, adaptation, recall, review and pre-investigation. From July to August 2022, 250 clinicians from 28 provinces (autonomous regions and municipalities directly under the Central Government) were selected by using the convenience sampling method. A self-made questionnaire was used to investigate the EBP-KAPF scale in Chinese to investigate the EBM ability of clinicians, including the basic information of the respondents, the learning and use of Evidence-based medicine courses and related software. The item analysis, validity and reliability evaluation of the Chinese version of the EBP-KAPF scale were performed.Results:The Chinese version of the EBP-KAPF scale included 26 items in four dimensions: knowledge mastery, attitude, personal application and future use. A total of 265 questionnaires were sent out (including self-made questionnaires and the Chinese version of the EBP-KAPF scale), and 250 effective questionnaires were obtained, with a total effective rate of 94.3%. The total score of the Chinese version of the EBP-KAPF scale was (102.85±17.48) points, and the scores of knowledge mastery, attitude, personal application and future use sub-scales were (27.22±4.47), (13.56±7.70), (20.07±6.78), and (42.00±9.00) points, respectively. Except for item 16, all items were correlated with the total score of the scale, and the correlation coefficient ranged from 0.456 to 0.828. After item 16 was deleted, the determination values of the remaining 25 items ranged from 4.287 to 18.262 ( P<0.001). After item was removed one by one, the Cronbach′s α coefficient of the scale ranged from 0.870 to 0.888. After item 16 was removed, the Chinese version of the 25-item EBP-KAPF scale had good content validity, structural validity and discriminant validity. The content validity index (I-CVI) at the item level ranged from 0.875 to 1.000, and the content validity index at the overall agreement scale level was 0.615. The average S-CVI values were 0.952, and the probability of correction ( K*) values were 0.87 to 1.00. The results of confirmatory factor analysis showed that the structure fit was good [comparative fit index (CFI)=0.962, Tucker-Lewis index (TLI)=0.957, root mean square error of approximation (RMSEA)=0.060, χ2/ df=1.889]. Discriminant validity analysis showed that there were statistically significant differences in the EBP-KAPF scores among clinicians of different ages, evidence-based medicine course learning and related software use ( P<0.05). After item 16 was removed, the Cronbach′s α coefficient of the Chinese version of the EBP-KAPF scale was 0.893, and the Guttman half coefficients of each dimension were 0.915, 0.901, 0.812 and 0.906, respectively. The correlation coefficients were 0.902-0.982, 0.507-0.953, 0.517-0.744 and 0.632-0.986, respectively. Conclusion:The Chinese version of the EBP-KAPF scale is simple, easy to understand, unambiguous, and has good validity and reliability.