ObjectiveThe nucleolar protein PES1 (Pescadillo homolog 1) plays critical roles in ribosome biogenesis and cell cycle regulation, yet its involvement in cellular senescence remains poorly understood. This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role. MethodsInitially, we assessed PES1 expression patterns in two distinct senescence models: replicative senescent mouse embryonic fibroblasts (MEFs) and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells. Subsequently, PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types. Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays, respectively. The expression of senescence-associated proteins (p53, p21, and Rb) and SASP factors (IL-6, IL-1β, and IL-8) were analyzed by Western blot or qPCR. Furthermore, Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology. ResultsPES1 expression was significantly downregulated in senescent MEFs and HepG2 cells. PES1 knockdown resulted in decreased EdU-positive cells and increased SA‑β‑gal-positive cells, indicating proliferation inhibition and senescence induction. Mechanistically, PES1 suppression activated the p53-p21 pathway without affecting Rb expression, while upregulating IL-6, IL-1β, and IL-8 production. Notably, PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress, as evidenced by aberrant nucleolar morphology. ConclusionOur findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent (but Rb-independent) cellular senescence, highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.

Urinary incontinence is a common complication following robot-assisted radical prostatectomy (RARP). Urethral length has been identified as a factor affecting postoperative continence recovery. In this meta-analysis, we examined the association between use of the maximal urethral length preservation (MULP) technique and postoperative urinary continence in patients undergoing RARP. We conducted a comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library up to December 31, 2023. The quality of the literature was assessed using the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed to synthesize data and calculate the odds ratio (OR) from eligible studies on continence and MULP. Six studies involving 1869 patients met the eligibility criteria. MULP was positively associated with both early continence (1 month after RARP; Z = 3.62, P = 0.003, OR = 3.10, 95% confidence interval [CI]: 1.68-5.73) and late continence (12 months after RARP; Z = 2.34, P = 0.019, OR = 2.10, 95% CI: 1.13-3.90). Oncological outcomes indicated that MULP did not increase the overall positive surgical margin rate or the positive surgical margin status at the prostate apex (both P > 0.05). In conclusion, the use of the MULP technique in RARP significantly improved both early and late postoperative continence outcomes without compromising oncological outcomes.
Humans ; Prostatectomy/adverse effects* ; Robotic Surgical Procedures/methods* ; Male ; Urethra/surgery* ; Urinary Incontinence/prevention & control* ; Postoperative Complications/etiology* ; Prostatic Neoplasms/surgery* ; Organ Sparing Treatments/methods*

OBJECTIVE: Salt-processed Psoraleae Fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, due to improper clinical use or misuse, resulting in liver damage. In this study, network pharmacology was employed to analyze the mechanism of cholestatic liver damage. An adeno-associated virus overexpressing SULT1E1 (rAAV8-SULT1E1) was constructed and the hepatotoxicity of SPF, psoralen, and isopsoralen was determined. METHODS: By utilizing three databases inclding TCMSP, TCMID, and BATMAN- TCM, the targets of the three databases were summarized, and a total of 45 psoralen compounds were included. Network pharmacology analysis was then performed. The adenoviral vectors were injected into the tail vein of C57BL6 mice to elucidate the role of SULT1E1 in SPF-induced cholestasis-mediated hepatotoxicity in vivo. SPF (10 g/kg), psoralen, and isopsoralen (50 mg/kg each) were intragastrically administered to mice for 30 d. B-ultrasound and samples were collected and examined for follow-up experiments. RESULTS: A total of 854 targets were predicted for 45 active components, with 151 cholestasis-mediated hepatotoxicity-related disease targets obtained for SPF. A total of 126 pathways were enriched based on KEGG pathway analysis, with the "estrogen signaling pathway" identified as one of the top 20 pathways. In terms of pathological hepatic changes, treated mice had visually swollen hepatocytes, dilated bile ducts, and elevated serum biochemical markers, which were more prominent in mice treated with isopsoralen than in those treated with other compounds. Notably, the overexpression of SULT1E1 could reverse liver damage in each treatment group. B-ultrasound was used to observe the size of the gallbladder in vivo. The size of the gallbladder was found to significantly increase on day 30 after treatment in the SPF-, psoralen-, and isopsoralen-treated groups, especially the SPF group. Compared with the expression levels in the negative control group (rAAV8-empty + con), the expression levels of FXR, Mrp2, Bsep, SULT1E1, SULT2A1, Ntcp, and Nrf2 decreased, whereas those of CYP7a1 and IL-6 increased in the SPF-, psoralen-, and isopsoralen-treated groups. CONCLUSION The overexpression of SULT1E1 could alleviate the decreased or increased expression of indicators, indicating that SULT1E1 is an important target gene for SPF-induced liver damage. The severity of liver damage was significantly lower in the rAAV8-SULT1E1 groups than in the rAAV8-empty groups.

Objective:To analyze the positive detection rate, main genotypes of β-thalassemia in western region of Guangxi Zhuang Autonomous Region (referred to as Guangxi).Methods:Retrospective analysis of 26 189 individuals who underwent gene testing for thalassemia at the Affiliated Hospital of Youjiang Medical University for Nationalities from January 2013 to December 2019. Using the crossing breakpoint PCR (Gap-PCR) and reverse dot blot (RDB) techniques to detect Chinese common type of 7 kinds of α-thalassemia and 17 kinds of β-thalassemia genotypes, high-throughput sequencing(Sanger) was performed for suspected rare β-thalassemia. Gap-PCR was used for suspected deletion β-thalassemia types.Results:β-thalassemia was diagnosed in 4 495 (17.16%) of 26 189 samples. A total of 6 177 alleles of 20 types of β-thalassemia were detected, mainly CD17 (2 712 cases, 43.90%) and CD41-42 (2 240 cases, 36.26%), including 7 rare alleles: Gγ +( Aγδβ) 0, SEA-HPFH, Hb New York, Hb G-Taipei, Hb Hezhou, Hb G-Coushatta and IVS-Ⅱ-81. There were 3 903 case (86.83%) heterozygous, 273 case (6.07%) double heterozygous, and 319 case (7.10%) homozygous among 4 495 β-thalassaemia subjects. A total of 48 genotypes were detected. The two most common genotypes were CD17/β N (1 890 cases, 42.05%) and CD41-42/β N (1 212 cases, 26.96%), accounted for 69.01% (3 102/4 495). Seven rare genotypes were detected: Gγ +( Aγδβ) 0/β N in 3 cases, Hb New York/β N in 3 cases, Hb G-Taipei/β N in 2 cases, SEA-HPFH/β N, Hb Hezhou/β N, Hb G-Coushatta/β N and IVS-Ⅱ-81/β N in 1 case each. A total of 1 041 cases (3.97%, 1 041/26 189) of 116 types of αβ-thalassemia were detected, mainly -- SEA/αα composite CD17/β N (144 cases, 13.83%), followed by -α 3.7/αα composite CD17/β N (112 cases, 10.76%). Conclusions:Western region of Guangxi is a high prevalence area of β-thalassemia, CD17/β N and CD41-42/β N are the main genotypes. The variation spectrum of β-thalassemia is complex and diverse, with rich genotype.

Neurodevelopmental disorders in children have become a significant global public health concern,impacting child health worldwide.In China,the current intervention model for high-risk infants involves early diagnosis and early treatment.However,in recent years,overseas studies have explored novel preventive early intervention strategies for neurodevelopmental disorders in high-risk infants,achieving promising results.This article provides a comprehensive review of the optimal timing,methods,and intervention models of the preventive early intervention strategies for neurodevelopmental disorders in high-risk infants.The aim is to enhance the awareness and knowledge of healthcare professionals regarding preventive early intervention strategies for neurodevelopmental disorders in high-risk infants,facilitate clinical research and application of such interventions in China,and ultimately reduce the incidence of neurodevelopmental disorders in this high-risk population.[Chinese Journal of Contemporary Pediatrics,2024,26(3):297-301]

The incidence and disability rate of neurodevelopmental disorders in children are high,making it a significant public health issue affecting children's health globally. Neurodevelopmental disorders are particularly common in children with congenital heart disease (CHD),with clinical characteristics varying by type of CHD,surgical approach,age stage,and the presence of different complications or comorbidities. In recent years,based on the intervention model of "early diagnosis and early treatment," foreign studies have begun to explore new techniques for preventive early intervention in high-risk children with neurodevelopmental disorders,achieving promising results. This paper reviews the clinical characteristics of neurodevelopmental disorders associated with CHD,aiming to provide a theoretical basis for implementing new preventive early intervention techniques for children with CHD,thereby further reducing the incidence of neurodevelopmental disorders associated with CHD.

Objective:To investigate the risk factors affecting the completion of postoperative adjuvant chemotherapy in elderly patients with progressive gastric cancer.Methods:Clinicopathological data of patients diagnosed with gastric adenocarcinoma and treated with radical surgery at our hospital between January 2017 and December 2018 were retrospectively collected, and 96 patients were finally included in the study according to the inclusion and exclusion criteria.Patients were divided into a completed chemotherapy group and an uncompleted chemotherapy group depending on whether they had completed 6 cycles of adjuvant chemotherapy after surgery.The optimal cut-off value was derived from the receiver operating characteristic(ROC)curve, and the Youden Index was calculated.Relevant factors that might affect the completion of postoperative adjuvant chemotherapy in elderly patients with progressive gastric cancer were included in univariate and multivariate Logistic regression analyses to identify independent risk factors affecting the completion of postoperative adjuvant chemotherapy in gastric cancer patients.The Kaplan-Meier(K-M)method was used to plot the survival curves for the groups, and the log-rank test was used to compare the survival rates between the groups.Results:A total of 96 patients, aged 60-89 years, with a mean age of(70.3±7.0)years, were included.Sixteen patients completed postoperative adjuvant chemotherapy, while 80 patients did not.The following analysis was performed on clinicopathological data of patients in the two groups.Univariate Logistic regression analysis showed that patient age ≥70 years( OR=8.135, 95% CI: 1.735-38.153, P=0.008)or a preoperative prognostic nutritional index(PNI)score <49.5( OR=4.765, 95% CI: 1.549-14.656, P=0.006)affected the completion of postoperative adjuvant chemotherapy.The risk factors that might affect the completion of postoperative adjuvant chemotherapy in elderly gastric cancer patients were analyzed using multivariate Logistic regression and the results showed that age ≥70 years( OR=9.815, 95% CI: 1.947-49.485, P=0.006)and a preoperative PNI score <49.5( OR=5.895, 95% CI: 1.711-20.305, P=0.005)were independent risk factors hindering the completion of postoperative adjuvant chemotherapy. Conclusions:Age ≥70 years and PNI<49.5 are independent risk factors for the completion of postoperative adjuvant chemotherapy.Failure to complete postoperative adjuvant chemotherapy is associated with a poor prognosis.PNI is a valid predictor for whether postoperative adjuvant chemotherapy will be completed and helps to screen chemotherapy patients who need nutritional intervention.

Objective To evaluate the predictive value of a combined model based on clinical and radiomics features for the invasiveness of lung adenocarcinoma manifesting as ground glass nodule(GGN).Methods Clinical data of patients with GGN-type lung adenocarcinoma who underwent chest CT and were confirmed by surgical pathology at some hospital from January to December 2019 were analyzed retrospectively,and the extraction of imaging histological features was performed using Python-based open resource Pyradiomics.A clinical model was constructed based on independent risk factors obtained from univariate and multivariate analyses,a radiomics model was built using the screened radiomics features,and a combined model was established with the predictive values of the clinical models and radiomics scores(Radscore).The predictive performance of the three models in the training and test sets was assessed using ROC curves,the statistical significance of the differences in the ROC curves of the three models for predicting GGN-type lung adenocarcinoma was assessed using the Delong test,and the net benefits of the models were analyzed using clinical decision curves.Results Logistic multifactor analysis showed that age(P=0.020 2)and vascular characteristics(P=0.002 2)were the independent predictors of the degree of the invasiveness of lung adenocarcinoma.The AUCs of the radiomics model,clinical model and combined model were 0.876,0.867 and 0.904 on the training set,and 0.828,0.828 and 0.864 on the test set,respectively.The difference between the ROC curves of the combined model and the clinical and radiomics models was not statistically significant(P>0.05)on the test set.Clinical decision curves showed a higher clinical benefit when using the combined model to predict the invasiveness under most conditions of threshold probability.Conclusion The combined model based on clinical and radiomics features enhances the predictive performance for the invasiveness of GGN-type lung adenocarcinoma.

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.
Male ; Humans ; Middle Aged ; Atorvastatin/therapeutic use* ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Hypercholesterolemia/drug therapy* ; Cholesterol, LDL/therapeutic use* ; Anticholesteremic Agents/therapeutic use* ; Treatment Outcome ; Triglycerides ; Apolipoproteins B/therapeutic use* ; Double-Blind Method ; Pyrroles/therapeutic use*

OBJECTIVE: To evaluate the decompensation effectiveness and alveolar bone remodeling of mandibular anterior teeth after preoperative orthodontic treatment in high-angle patients with skeletal class Ⅱ malocclusion using lateral cephalogram and cone-beam computed tomography (CBCT). METHODS: Thirty high-angle patients with skeletal class Ⅱ malocclusion who had received preoperative orthodontic treatment and orthognathic surgery in Peking University School and Hospital of Stomatology between Ja-nuary 2017 and August 2022 and had taken lateral cephalogram and CBCT before and after preoperative orthodontic treatment were selected. Items were measured with lateral cephalogram including: The lower central incisor (L1)-Frankfort plane angle (L1-FH), the L1-mandibular plane angle (L1-MP), the L1-nasion-supramental angle (L1-NB) and the vertical distance from the incisal edge of lower central incisor to NB line (L1-NB distance), etc. The incidence of dehiscence/fenestration and the length of dehiscence at labial side (d-La) and lingual side (d-Li) were measured using CBCT. Pearson correlation analysis was used to evaluate the correlation between the changes of d-Li of L1 and age, duration of preoperative orthodontic treatment and the cephalometric measurements before preoperative orthodontic treatment to screen out risk factors affecting the periodontal risk of preoperative orthodontic treatment in high-angle patients with skeletal class Ⅱ malocclusions. RESULTS: After preoperative orthodontic treatment, L1-FH, L1-MP, L1-NB and L1-NB distances changed by 11.56°±5.62°, -11.13°±5.53°, -11.57°±5.43° and (-4.99±1.89) mm, respectively, and the differences were all statistically significant (P < 0.05). Among the 180 measured mandibular anterior teeth, 45 cases with labial dehiscence/fenestration before preoperative orthodontic treatment (T0) had no longer labial dehiscence/fenestration after preope-rative orthodontic treatment (T1); 142 cases without lingual dehiscence/fenestration at T0 had lingual dehiscence/fenestration at T1. After preoperative orthodontic treatment, the d-La of lower lateral incisors (L2), lower canines (L3) and lower anterior teeth (L1+L2+L3) decreased by (0.95±2.22) mm, (1.20±3.23) mm and (0.68±2.50) mm, respectively, and the differences were statistically significant (P < 0.05); the d-Li of L1, L2, L3 and L1+L2+L3 increased by (4.43±1.94) mm, (4.53±2.35) mm, (3.19±2.80) mm and (4.05±2.46) mm, respectively, and the differences were statistically significant (P < 0.05). The increase of d-Li of L1 was positively correlated with L1-FH (r=0.373, P=0.042). CONCLUSION This study showed that high-angle patients with skeletal class Ⅱ ma-locclusion could achieve ideal decompensation effect of mandibular anterior teeth after preoperative orthodontic treatment with bilateral mandibular first premolars extracted, but the lingual periodontal risk of mandibular anterior teeth was increased. This risk could be correlated to L1-FH before preoperative orthodontic treatment, which should be paid more attention in the design of orthodontic-orthognathic surgical treatment.
Humans ; Malocclusion, Angle Class III ; Malocclusion, Angle Class II/surgery* ; Facial Bones ; Incisor ; Orthognathic Surgical Procedures ; Cone-Beam Computed Tomography ; Mandible