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 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.

Objective:The effect and safety of etoposide combined with G-CSF were compared with those of cyclophosphamide combined with G-CSF in autologous peripheral blood mobilization in patients with multiple myeloma (MM) .Methods:Patients with MM who received autologous peripheral blood stem cell mobilization and collection in the Department of Hematology, Beijing Chaoyang Hospital Affiliated to Capital Medical University from January 1, 2020 to July 31, 2023 were included. A total of 134 patients were screened by propensity score matching technology according to a 1∶1 ratio. A total of 67 cases were each treated with ETO combined with G-CSF mobilization scheme (ETO group) and CTX combined with G-CSF mobilization scheme (CTX group). Their clinical data were retrospectively analyzed.Results:①Collection results: the ETO and CTX groups [2 (1-3) d vs 2 (1-5) d; P<0.001] and CD34 + cells [7.62×10 6 (2.26×10 6-37.20×10 6) /kg vs 2.73×10 6 (0.53×10 6-9.85×10 6) /kg; P<0.001] were collected. The success rate of collection was 100.0% (67/67) versus 76.1% (51/67) ( P<0.001). Excellent rate of collection was 82.1% (55/67) versus 20.9% (14/67; P<0.001). Two patients in the ETO group switched protocols after 1 day of collection, and 11 patients in the CTX group switched protocols after 1-2 days of collection. ②Adverse reactions: granular deficiency with fever (21.5%[14/65] vs. 10.7%[6/56]; P=0.110), requiring platelet transfusion [10.7% (7/65) vs 1.8% (1/56) ; P=0.047]. ③Until the end of follow-up, 63 cases in the ETO group and 54 cases in the CTX group have undergone autologous transplantation. The median number of CD34 + cells infused in the two groups was 4.62×10 6 (2.14×10 6-19.89×10 6) /kg versus 2.62×10 6 (1.12×10 6-5.31×10 6) /kg ( P<0.001), neutrophil implantation time was 11 (9-14) d versus 11 (10-14) d ( P=0.049), and platelet implantation time was 11 (0-19) d vs. 12 (0-34) d ( P=0.035). One case in the CTX group experienced delayed platelet implantation. Conclusion:The mobilization scheme of etoposide combined with G-CSF requires relatively platelet transfusion, but the collection days are shortened. The collection success rate, excellent rate, and the number of CD34 + cells obtained are high, and the neutrophil and platelet engraftment is accelerated after transplantation.

Objective:To explore the prognostic factors of primary plasma cell leukemia (pPCL) in the era of novel agents.Methods:The clinical data of 66 patients with pPCL treated at the Department of Haematology, Beijing Chao-Yang Hospital, Capital Medical University from 2011 to 2022 were retrospectively collected to analyze their prognostic factors.Results:Among the 66 patients with pPCL, the median age was 59 (range: 29-79) years. The median overall survival (OS) duration was 19.0 (95% CI 10.4-27.6) months, and the median progression-free survival (PFS) duration was 11.0 (95% CI 6.5-15.6) months. The median OS and PFS were significantly longer in patients with the best post-treatment response of very good partial remission (VGPR) or better than in patients with a response of partial remission (PR) or worse (median OS: 33.0 months vs 6.0 months, P<0.001; median PFS: 16.0 months vs 3.0 months, P<0.001). OS was significantly longer in patients who underwent autologous hematopoietic stem cell transplantation than in those who did not undergo transplantation (49.0 months vs 6.0 months, P=0.002), and there was a trend toward a longer PFS in patients who underwent transplantation than in those who did not undergo transplantation (19.0 months vs 8.0 months, P=0.299). The median OS and PFS were significantly longer in patients who received maintenance therapy than in those who did not receive maintenance therapy (median OS: 56.0 months vs 4.0 months, P<0.001; median PFS: 20.0 months vs 2.0 months, P<0.001). Multivariate analysis showed that hypercalcemia was an independent risk factor ( HR=3.204, 95% CI 1.068-9.610, P=0.038) for patients with pPCL, while receiving maintenance therapy ( HR=0.075, 95% CI 0.022-0.253, P<0.001) and post-treatment response of VGPR or better ( HR=0.175, 95% CI 0.048-0.638, P=0.008) were independent protective factors for patients with pPCL. Conclusions:In the era of novel agents, hypercalcemia, receiving maintenance therapy, and post-treatment response of VGPR or better are independent prognostic factors for pPCL.

Objective:To investigate the clinical features and prognosis of multiple myeloma(MM)patients who resisted to the combination of bortezomib,lenalidomide and dexamethasone(VRD). Methods:The clinical features and prognosis of 150 patients with newly diagnosed MM in Beijing Chaoyang Hospital who were treated with VRD from January 2015 to January 2020 were retrospectively analyzed by SPSS software. Results:Among a total of 150 MM patients,21 patients resisted to VRD,including 14 patients with primary refractory to VRD and 7 patients with early relapse.In the VRD-resistant group(n=21),the median age of patients was 58 years(37-70 years),and female patients were more common(61.9％);Durie-Salmon stage:17 patients were DS stage Ⅲ,4 patients were DS stage Ⅱ;44.4％of those patients were cytogenetic high risk.CD20 positive rate was higher in the VRD-resistant group(P=0.014).The overall survival(OS)of MM patients in the VRD-resistant group was significantly lower than that in the VRD-nonresistant group(34 months vs not achieved,P＜0.001).In the VRD-resistant group,the median OS of MM patients receiving autologous hematopoietic stem cell transplantation was significantly longer than that of non-transplant patients(34 months vs 16 months,P=0.038).Drug resistance and non-autologous transplantation are independent adverse prognostic factors for newly diagnosed MM patients receiving VRD induction chemotherapy.COX multivariate analysis showed that age＞65,cytogenetic high risk and non-autologous stem cell transplantation may be adverse prognostic factors for VRD-resistant MM patients. Conclusion:Positive CD20 was more common in MM patients with VRD resistence,which may indicate more aggressive biological characteristics in VRD-resistent MM patients.The VRD-resistent MM patients had poor prognosis,they can obtain disease remission from salvage chemotherapy including daratumumab,and the survival of them also can be improved after autologous stem cell transplantation.

Objective:To evaluate the prognostic value of CD56 expression in newly diagnosed MM (NDMM).Methods:A total of 332 NDMM patients were enrolled in Beijing Chaoyang Hospital, Capital Medical University from January 1, 2011 to January 1, 2021, with a median age of 60 years and a male to female ratio of 1.2∶1. CD56 expression on myeloma cells was detected by flow cytometry before induction therapy. Overall survival (OS) and progression-free survival (PFS) data were collected. In order to reduce the confounding factors, the propensity score matching technique was used to match CD56 positive versus negative patients at a ratio of 1∶1.Results:Among 332 patients, CD56 positivity rate was 65.1% (216/332). Patients with CD56 expression had significantly longer median OS (58.4 vs. 43.1 months, P=0.024) and PFS (28.7 vs. 24.1 months, P=0.013) than those with negative CD56. Univariate Cox proportional hazards regression analyses showed that CD56 expression was positively correlated with OS ( HR=0.644, 95 %CI 0.438-0.947, P=0.025) and a favorable prognostic factor for PFS ( HR=0.646, 95 %CI 0.457-0.913, P=0.013). The favorable effect of CD56 expression on PFS was confirmed in multivariate analysis ( HR=0.705, 95 %CI 0.497-0.998, P=0.049), but OS was not affected ( P>0.05).In the propensity score matching analysis, 194 patients with 97 in each group were identified. CD56 positivity consistently predicted longer PFS (34.2 vs.25.1 months, P=0.047), but not OS (63.4 vs.43.1 months, P=0.056). Conclusion:These results demonstrate that CD56 expression is a favorable prognostic factor for PFS of newly diagnosed MM patients.

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.

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2, also called IMP2) plays an essential role in the development and maturation of germ cells and embryos and is a candidate gene for goat litter size, based on a previous genome-wide selective sweep analysis. In this study, the mRNA expression level of IGF2BP2 was found to be significantly higher in a single-lamb group than in a multi-lamb group. Insertions/deletions (indels) within the goat IGF2BP2 gene, including P4-Ins-13bp and P5-Del-12bp, were verified in 918 Shaanbei White Cashmere (SBWC) female goats. The minor allelic frequencies (MAFs) of P4-Ins-13bp and P5-Del-12bp loci were 0.349 and 0.295, respectively. Analysis using the Chi-square (χ2) test showed that the genotype (χ2=14.479, P=0.006) distribution of P4-Ins-13bp was significantly different between the single-lamb and multi-lamb groups. Correlation analysis demonstrated that P4-Ins-13bp was significantly associated with goat litter size (P=0.022), and individual goats with the homozygous deletion/deletion (DD) genotype produced more litters than other goats. Therefore, considered as a potential molecular marker significantly related to lambing traits, the P4-Ins-13bp mutation of the goat IGF2BP2 gene can be used in goat breeding with practical molecular marker-assisted selection (MAS) to optimize female reproduction and improve economic efficiency in the goat industry.

Objective:To evaluate the effect of autologous stem cell transplantation (auto-HSCT) on treatment remission and survival of newly diagnosed multiple myeloma (MM) patients.Methods:A total of 243 new diagnosed MM patients (age ≤65 years) who had received auto-HSCT were selected, and 176 MM patients (age ≤65 years) who had not received auto-HSCT were selected as the control group to evaluate the effect of auto-HSCT on the remission and survival. To balance the distribution of prognostic factors between auto-HSCT and non-auto-HSCT patients, the propensity score matching technique was used to reduce the bias between groups in a 1∶1 scale, 64 in each group, and correlation analysis was performed.Results:A total of 128 patients (64 cases in each group) were screened by propensity score matching analysis. 64 patients received auto-HSCT after induction therapy. After auto-HSCT, 24 patients (37.5%) obtained sCR, 16 patients (25.0%) obtained CR, 15 patients (23.4%) obtained VGPR, and 9 patients (14.1%) obtained PR. The efficacy of patients with auto-HSCT was significantly better than that of non-auto-HSCT patients ( P=0.032) . Progression-free survival (PFS) and overall survival (OS) were significantly longer in auto-HSCT patients compared with non-auto-HSCT patients[PFS: 42.2 (95% CI 29.9-54.5) months vs 22.4 (95% CI 17.1-27.7) months, P=0.007; OS: 87.6 (95% CI 57.3-117.9) months vs 53.9 (95% CI 36.1-71.7) months, P=0.011]. Multivariate analysis confirmed that auto-HSCT had a favorable effect on OS ( HR=0.448, 95% CI 0.260-0.771, P=0.004) and PFS ( HR=0.446, 95% CI 0.280-0.778, P=0.003) . Conclusion:These results demonstrated that auto-HSCT was a favorable prognostic factor for newly diagnosed MM patients.