Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To observe the effects of moxibustion at Shenshu(BL23)and Zusanli(ST36)on Toll-like receptor 4(TLR4)-myeloid differentiation factor 88(Myd88)signaling pathway-mediated inflammatory factors in the synovial tissue of ankle joints of rats with rheumatoid arthritis(RA),and to explore the molecular and biological mechanisms underlying the anti-inflammatory and analgesic effects.Methods:A total of 24 male Sprague-Dawley(SD)rats were randomly divided into a normal group,a model group,and a moxibustion group,with 8 rats in each group.The RA model was established with exposure to wind,cold,and damp environmental factors,along with Freund's complete adjuvant.After three days of modeling,mild moxibustion was applied to bilateral Shenshu(BL23)and Zusanli(ST36)in the moxibustion group using moxa sticks of 0.9 cm in diameter for 30 min each time,once a day for 14 d.Structural changes in the synovial tissue and cells were then observed using hematoxylin-eosin staining and transmission electron microscopy,while immunohistochemistry analysis was used to detect tumor necrosis factor(TNF)-α,interleukin(IL)-17,IL-1β,and IL-6 levels.Moreover,the protein expression levels of Myd88,TLR4,and transient potential receptor vanilloid type 1(TRPV1)in the synovial tissue were detected using Western blotting,while their mRNA expression levels were detected using reverse transcription-polymerase chain reaction.Finally,the levels of IL-1β,IL-2,IL-6,IL-17A,and TNF-α in rat serum were detected using enzyme-linked immunosorbent assay.Results:Compared to the normal group,the model group exhibited notable pathological synovial tissue damage,along with significantly higher IL-1β,IL-6,and TNF-α levels(P<0.01)and a slightly higher IL-17 content(P>0.05).Furthermore,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly higher in the model group than in the normal group(P<0.01).Compared to the model group,the moxibustion group exhibited a lower degree of synovial tissue pathological damage,along with significantly lower IL-1β,IL-6,and TNF-α levels(P<0.05 or P<0.01)and a lower IL-17 content without statistical significance(P>0.05).Moreover,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels,and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly lower in the moxibustion group than in the model group(P<0.01 or P<0.05).Conclusion:Mild moxibustion at Shenshu(BL23)and Zusanli(ST36)can effectively inhibit TLR4-MyD88 signaling pathway-mediated inflammatory factor expression in the synovial tissue of ankle joints of RA rats.Furthermore,the effect of moxibustion on synovial tissue inflammation in RA rats may be attributed to TRPV1 channel activation.

Cardiovascular disease and cancer are the two leading chronic conditions contributing to global mortality. With the rising incidence of cancer, the prevalence of cancer therapy-related cardiovascular complications has also increased, driving the development of the emerging field of cardio-oncology. The advancement of precision medicine offers new opportunities for the individualized and targeted management of cardiovascular toxicities associated with cancer treatment. Artificial intelligence (AI) has the potential to overcome traditional limitations in medical data integration, dynamic monitoring, and interdisciplinary collaboration, thereby accelerating the application of precision medicine in cardio-oncology. By enabling personalized treatment and reducing cardiovascular complications in cancer patients, AI serves as a critical tool in this domain. This article provides an in-depth interpretation of the 鈥淎rtificial intelligence to enhance precision medicine in cardio-oncology: a scientific statement from the American Heart Association鈥?aiming to inform the integration of AI into precision medicine in China. The goal is to promote its application in the management of cardiovascular diseases related to cancer therapy and to achieve precision management in this context.

Objective:To observe the effects of moxibustion at Shenshu(BL23)and Zusanli(ST36)on Toll-like receptor 4(TLR4)-myeloid differentiation factor 88(Myd88)signaling pathway-mediated inflammatory factors in the synovial tissue of ankle joints of rats with rheumatoid arthritis(RA),and to explore the molecular and biological mechanisms underlying the anti-inflammatory and analgesic effects.Methods:A total of 24 male Sprague-Dawley(SD)rats were randomly divided into a normal group,a model group,and a moxibustion group,with 8 rats in each group.The RA model was established with exposure to wind,cold,and damp environmental factors,along with Freund's complete adjuvant.After three days of modeling,mild moxibustion was applied to bilateral Shenshu(BL23)and Zusanli(ST36)in the moxibustion group using moxa sticks of 0.9 cm in diameter for 30 min each time,once a day for 14 d.Structural changes in the synovial tissue and cells were then observed using hematoxylin-eosin staining and transmission electron microscopy,while immunohistochemistry analysis was used to detect tumor necrosis factor(TNF)-α,interleukin(IL)-17,IL-1β,and IL-6 levels.Moreover,the protein expression levels of Myd88,TLR4,and transient potential receptor vanilloid type 1(TRPV1)in the synovial tissue were detected using Western blotting,while their mRNA expression levels were detected using reverse transcription-polymerase chain reaction.Finally,the levels of IL-1β,IL-2,IL-6,IL-17A,and TNF-α in rat serum were detected using enzyme-linked immunosorbent assay.Results:Compared to the normal group,the model group exhibited notable pathological synovial tissue damage,along with significantly higher IL-1β,IL-6,and TNF-α levels(P<0.01)and a slightly higher IL-17 content(P>0.05).Furthermore,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly higher in the model group than in the normal group(P<0.01).Compared to the model group,the moxibustion group exhibited a lower degree of synovial tissue pathological damage,along with significantly lower IL-1β,IL-6,and TNF-α levels(P<0.05 or P<0.01)and a lower IL-17 content without statistical significance(P>0.05).Moreover,the Myd88,TLR4,and TRPV1 protein and mRNA expression levels,and serum IL-1β,IL-2,IL-6,IL-17A,and TNF-α levels were all significantly lower in the moxibustion group than in the model group(P<0.01 or P<0.05).Conclusion:Mild moxibustion at Shenshu(BL23)and Zusanli(ST36)can effectively inhibit TLR4-MyD88 signaling pathway-mediated inflammatory factor expression in the synovial tissue of ankle joints of RA rats.Furthermore,the effect of moxibustion on synovial tissue inflammation in RA rats may be attributed to TRPV1 channel activation.

Objective:To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China.Methods:This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival.Results:The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P<0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS ( HR=2.37, 95% CI 1.30-4.30; HR=4.50, 95% CI 2.35-9.01) and OS ( HR=4.20, 95% CI 1.50-11.80; HR=9.53, 95% CI 3.21-28.29). Conclusions:The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

Objective:To investigate the predictive value of albumin-to-fibrinogen ratio (AFR) for postoperative acute kidney injury (AKI) in infants with ventricular septal defect repair under cardiopulmonary bypass (CPB).Methods:A retrospective analysis was conducted on infants diagnosed with ventricular septal defect in Anhui Children's Hospital from January 2019 to July 2023. The infants were divided into AKI group and non-AKI group according to whether AKI occurred in hospital after operation. Demographic data, preoperative data, intraoperative data, postoperative data and laboratory results during CPB were collected. Multivariate Logistic regression analysis was used to find the factors of AKI after ventricular septal defect repair with CPB. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of AFR for postoperative AKI after ventricular septal defect repair with CPB.Results:A total of 215 children were collected, including 28 in AKI group and 187 in non-AKI group. There were no significant differences in age, gender, body weight, height, history of pneumonia and history of chronic heart failure between the two groups, but the left ventricular ejection fraction (LVEF) in the AKI group was significantly lower than that in the non-AKI group (0.526±0.028 vs. 0.538±0.030, P = 0.048). The duration of CPB (minutes: 74.1±12.1 vs. 65.8±11.3, P < 0.001), aortic cross-clamping (minutes: 41.7±9.7 vs. 37.2±9.4, P = 0.021) and hypothermic circulation arrest (21.4% vs. 8.6%, P = 0.047) in AKI group were significantly higher than those in non-AKI group, but there were no significant differences in the proportion of ultrafiltration and urine volume between the two groups. The length of intensive care unit (ICU) stay in AKI group was significantly longer than that in non-AKI group (days: 5.3±2.0 vs. 4.0±1.7, P < 0.001), but there were no significant differences in duration of mechanical ventilation and the proportion of postoperative hypotension between the two groups. During CPB, the levels of blood glucose (mmol/L: 9.4±1.3 vs. 8.8±0.8, P < 0.001), blood lactic acid (mmol/L: 2.2±0.3 vs. 2.0±0.3, P = 0.015) and serum creatinine (μmol/L: 79.7±11.5 vs. 74.4±10.9, P = 0.018) in AKI group were significantly higher than those in non-AKI group, while the AFR was significantly lower than that in non-AKI group (8.5±1.3 vs. 10.2±1.6, P < 0.001), but there were no significant differences in the levels of hemoglobin, blood urea nitrogen, alanine aminotransferase and aspartate aminotransferase between the two groups during CPB. Multivariate Logistic regression showed that AFR was a protective factor for AKI after ventricular septal defect repair with CPB [odds ratio ( OR) = 0.439, 95% confidence interval (95% CI) was 0.288-0.669, P < 0.001]. Blood glucose ( OR = 2.133, 95% CI was 1.239-3.672, P = 0.006) and blood lactic acid ( OR = 5.568, 95% CI was 1.102-28.149, P = 0.038) were risk factors for AKI after ventricular septal defect repair with CPB. ROC curve analysis showed that the area under the curve (AUC) of AFR in predicting AKI after ventricular septal defect repair with CPB was 0.804 (95% CI was 0.712-0.897, P < 0.001). When the optimal cut-off value was less than 9.05, the corresponding sensitivity was 75.0% and the specificity was 72.7%. Conclusions:Low AFR (≤9.05) during CPB is an independent risk factor for AKI after ventricular septal defect repair with CPB. AFR during CPB has a high predictive value for postoperative AKI after ventricular septal defect repair with CPB.

Purpose To investigate the clinical and patho-logical characteristics,molecular characteristics,treatment and prognosis of systemic ALK-negative anaplastic large cell lympho-ma(ALCL).Methods Retrospective analysis was conducted on the clinical pathology,immunophenotype,molecular charac-teristics,treatment and prognosis of 18 cases of systemic ALK-ALCL.HE,immunohistochemistry,FISH,and NGS tests were performed,and relevant literatures were reviewed.Results Systemic ALK-ALCL tended to occur in elderly men,often in the advanced stage,mainly in lymph node lesions.The extran-odal primary sites included the primary pancreas and primary thoracic vertebrae.Morphological examination showed 17 cases belong to common type,1 case belong to"Hodgkin like"type.CD30 was diffuse and strongly positive in tumor cells(＞75％),CD2(16/17),CD3(13/18),CD5(4/18),CD7(8/18),CD4(14/18),TIA-1(16/18),CD8(2/16),GATA-3(10/12),EMA(3/5),MUM1(12/12),CD43(6/6)and CD56(2/8)were positive to varying degrees.The Ki67 proliferation index of 30％to 90％,PD-L1(22C3)(TPS=0-100％),ALK,CD15,CD79α and CD20 were all negative.FISH detection:5 cases of TP63 deficiency and 2 cases of DUSP22 deficiency;NGS detection:16 cases of gene mutations occurred,with a fre-quency of 0-11 gene mutations and an average of 4.2 gene mu-tations;ALK-ALCL with TP63 rearrangement was more likely to occur in women,mostly in lymph nodes,late clinical staging,susceptibility to p53 gene abnormalities,low PD-L1 expression rate and high mortality rate.Conclusion Systemic ALK-ALCL with TP63 rearrangement is associated with many adverse factors,the clinical process is often invasive with poor progno-sis.

Objective:To investigate the clinical features of pediatric patients with intracranial primary non-germinomatous germ cell tumors (NGGCT) and evaluate the treatment outcomes and prognostic factors of NGGCT.Methods:Clinical data of 40 children with NGGCT who were treated with radiotherapy (RT) at our department between November 2008 and June 2019 were retrospectively analyzed. Ninety percent of them received craniospinal irradiation (CSI). All children received platinum-based chemotherapy. Survival analysis was conducted using the Kaplan-Meier estimate. The prognostic factors were analyzed by log-rank test.Results:The primary sites were pineal gland, sellar / suprasellar region and basal ganglia. The median age of onset was 108 months (20-204 months). The median follow-up time was 33 months (8-131 months), and the 3-year and 5-year overall survival (OS) rates were 82.0%. The 3-year and 5-year progression-free survival (PFS) rates were 78.6% and 73.0%. Univariate analysis showed that increased alpha-fetoprotein (AFP) ( P=0.02), age at first diagnosis>10 years ( P=0.006), metastasis at first diagnosis ( P<0.001), and the pathological type (choriocarcinoma, yolk sac tumor and / or embryonal carcinoma) ( P=0.036) were independent adverse prognostic factors. Conclusions:Increased AFP, age>10 years at first diagnosis, tumor metastasis and pathological type were independent adverse prognostic factors of NGGCT. The overall prognosis of NGGCT children is worse than that of their counterparts with germinoma, and multidisciplinary intensive therapy is needed to improve survival.

Objective To investigate the relationship between nucleotide excision repair cross-complementing (ERCC) gene polymorphisms [single nucleotide polymorphism (SNP) sites: rs11615, rs13181, rs238406, rs6498486, rs17655] and susceptibility to endemic arsenic poisoning. Methods The study recruited 848 subjects, including 348 cases and 500 controls, from populations exposed to high arsenic levels through drinking water in northwest China, and 3 - 5 ml venous blood was collected. The genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism techniques(PCR-RFLP). Logistic regression analysis was used to assess the association of genotypes with endemic arsenic poisoning. Results The polymorphisms of rs11615 (ERCC1), rs238406 (ERCC2), rs6498486 (ERCC4) and rs17655 (ERCC5) and endemic arsenic poisoning were not related(P > 0.05). Participants who carried the CC genotype or at least one C allele for the ERCC2 rs13181 had an increased risk of endemic arsenic poisoning[OR(95%CI)=1.63(1.13,2.34),1.64(1.14,2.34)]compared with wild type homozygous individuals. Conculsions There is no positive correlation between the polymorphisms of ERCC1 rs11615, ERCC2 rs238406, ERCC4 rs6498486, ERCC5 rs17655 and endemic arsenic poisoning. ERCC2 rs13181 polymorphism increases the risk of endemic arsenic poisoning.

BACKGROUND: Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice. METHODS: Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-α and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses. RESULTS: The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-α and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure. CONCLUSIONS Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure.
Animals ; Biomarkers ; metabolism ; Inflammation ; physiopathology ; Insulin Receptor Substrate Proteins ; genetics ; metabolism ; Insulin Resistance ; genetics ; immunology ; MAP Kinase Signaling System ; physiology ; Male ; Mice ; Mice, Inbred ICR ; Mitogen-Activated Protein Kinase 8 ; genetics ; metabolism ; Noise ; adverse effects ; Oxidative Stress ; physiology ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Random Allocation ; Time Factors