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.

AIM: To investigate the effects of antitumor drug paclitaxel(PTX)on the proliferation, apoptosis, cell cycle, cell morphology, and related protein expression of Müller cells, and to evaluate its potential toxicity to the retina.METHODS:Müller cells were cultured in vitro and divided into two groups: control group(normal medium)and PTX group. Retinal Müller cells were treated with different concentrations of PTX(0.005, 0.05, 0.5 and 5mg/L)for varying durations(12, 24, 36, 48 and 72h). The CCK8 method was used to assess the effects of different concentrations of PTX and treatment duration on the proliferation Müller cells. Flow cytometry was employed to investigate the impact of different concentrations of PTX on Müller cells apoptosis and cell cycle arrest. Immunofluorescence was used to observe morphological changes in Müller cells. The effects of PTX on the expression of apoptosis-related proteins and aquaporins were analyzed by Western blot and qRT-PCR.RESULTS: PTX exhibits the ability to inhibit the proliferation of Müller cells when cultured in vitro. The efficacy of this inhibition was found to be dependent on both the concentration of the drug and the duration of the stimulation. Higher concentrations of the drug and longer stimulation times resulted in a weaker ability of the cells to proliferate. Additionally, PTX also induces apoptosis in Müller cells, with increased drug concentrations and longer stimulation times leading to higher apoptosis rates. Flow cytometry analysis demonstrates that PTX arrests Müller cells in the G2-M phase of the cell cycle. Moreover, there is a distinct change in cell morphology, with a shift from the typical appearance characterized by clear and slender fibrous structures to a rounder morphology, accompanied by a significant decrease in cell numbers. Further, our findings reveal that there is a transient increase in the expression of cytoinflammatory factors following drug treatment compared to the control group. However, discontinuation of drug stimulation can alleviate this heightened expression. In treated cells, the expression of the CA XIV protein is upregulated compared to the control group, while the expression of vascular endothelial growth factor(VEGF)is downregulated(P<0.05). Additionally, the levels of inflammatory factors in the PTX group are significantly higher than those in the control group(P<0.05), suggesting that PTX has the potential to disrupt the retinal barrier function.CONCLUSION: PTX affects the proliferation and apoptosis of Müller cells, with the effects dependent on stimulation duration and drug concentration. In addition, PTX blocks the Müller cell cycle at the G2-M phase and alters cell morphology, leading to a transient upregulation of inflammatory factors and affecting the integrity of the retinal barrier. These findings indicate the potential toxicity of the antitumor drug PTX to the retina.

Objective:To investigate the influence of different characteristics of implant-supported fixed dental prostheses on the incidence of peri-implant disease.Methods:Prospective cohort was established for patients who received implant-supported fixed dental prostheses at the Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University between June 2014 and September 2015. Several patient-related factors, implant prostheses factors, and oral hygiene maintenance factors were collected. The Log-rank test was used to compare the peri-implant disease rates of various factors, and the Cox proportional hazards model was used to conduct multivariate study on single factor significant factors to analyze the impact on the incidence of peri-implant disease.Results:A total of 214 subjects and 351 implants were included in the cohort, the follow-up period was (11.0±3.5) months. Finally, 43.0% (92/214) of patients and 37.3% (131/351) of implants developed peri-implant diseases. The incidence of peri-implant mucositis and peri-implantitis was 41.1% (88/214) and 4.2% (9/214) at the subject level,and 34.2% (120/351) and 3.1% (11/351) at the implant level. Among the factors associated with the implant prosthesis, single factor Log-rank analysis showed that prostheses retention methods, proximal contact of the prostheses, occlusion situation were statistical significance ( P<0.05). Multivariate analysis using Cox proportional hazards model showed that screw retention (hazard ratio=2.38, 95% CI: 1.42-3.99), proximal contact loss of the prostheses (hazard ratio=2.36, 95% CI: 1.31-4.27) were independent risk factors for peri-implant disease ( P<0.05). Conclusions:Factors such as prostheses retention mode and proximal contact characteristics have important influence on the health status of the implant.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).
Administration, Inhalation ; Adult ; China ; Coronavirus Infections ; diagnosis ; drug therapy ; mortality ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Follow-Up Studies ; Humans ; Integrative Medicine ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnosis ; drug therapy ; mortality ; Risk Assessment ; Severe Acute Respiratory Syndrome ; diagnosis ; drug therapy ; mortality ; Severity of Illness Index ; Survival Rate

ObjectiveTo investigate the serum level of ceruloplasmin in patients with different stages and etiologies of liver diseases. MethodsA total of 1077 patients with liver diseases who were hospitalized in Department of Hepatology, The First Hospital of Jilin University, from January 2012 to January 2018 were enrolled, and the serum level of ceruloplasmin was analyzed for the patients with different liver diseases. The Kruskal-Wallis H test was used to compare the level of ceruloplasmin between the patients with virus-related liver diseases with different liver functional states, and a Spearman correlation analysis was used to investigate the correlation of ceruloplasmin with other biomarkers. ResultsIn the Wilson’s disease group, 97.6% (41/42) of the patients had a serum ceruloplasmin level of ＜0.2 g/L and 881% (37/42) had a level of ＜0.1 g/L. In the non-Wilson’s disease group, 24.3% (251/1035) of the patients had a ceruloplasmin level of ＜0.2 g/L and 0.2% had a level of ＜0.1 g/L. There was a significant difference in the serum level of ceruloplasmin between the patients with virus-related liver diseases with different liver functional states, and the patients with chronic viral hepatitis, severe viral hepatitis, and viral hepatitis cirrhosis had a significantly lower level than those with acute viral hepatitis and virus-related liver cancer (P=0005, P＜0.001, P=0.001, P=0.027, P＜0.001, and P=0.001). In the patients without Wilson’s disease, serum ceruloplasmin was positively correlated with albumin and prealbumin (r=0.068 and 0.091, both P＜0.05) and was negatively correlated with prothrombin time (r=-0.297, P＜0.05). ConclusionCeruloplasmin often decreases significantly in patients with Wilson’s disease, with a slight reduction in patients with other types of liver diseases. For these patients, it should be determined whether the reduction in ceruloplasmin is caused by hepatocyte injury or the presence of Wilson’s disease.

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using "back-to-back" manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription "Keguan Yihao", immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.
Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/pharmacology* ; Betacoronavirus ; COVID-19 ; China ; Coronavirus Infections/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Pandemics ; Peptidyl-Dipeptidase A/chemistry* ; Pneumonia, Viral/drug therapy* ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry* ; COVID-19 Drug Treatment

Objective To analyze the distribution characteristics and influencing factors of X-ray diagnostic imaging in Shandong province,and to estimate the application frequency of X-ray diagnostic imaging in the province,and provide data support for X-ray equipment.Methods A random sampliug method was used to extract 32 medical institutions as respondents from 10 prefecture-level cities in Shandong province.The basic information of medical institutions and the age,sex,examination and procedure of the subjects were analyzed.The distribution of the X-ray application was analyzed and estimated by using a multiple linear regression model.Results Totally 14 694 085 subjects were surveyed,and the proportion of male and female in the sample was not completely uniform.A total of 2 099 155 X-ray diagnostic information was collected in 2016,and the frequency of conventional radiography was the highest,accounting for 59.49％.The next was CT examination,accounting for 28.34％.The frequency of the two examinations showed an increasing trend with the age of subjects.For the total frequency of conventional diagnostic radiography and CT examination,the tertiary hospitals accounted for the highest proportion of the total,up to 52.13％,while the secondary hospitals accounted for the relatively low proportion of 30.09％,and the primary hospitals the lowest with 17.77％.The chest radiography had the highest proportion in conventional radiography accounting for 32.79％ of the total frequency of X-ray diagnostic imaging,and the head procedure had the highest proportion in CT examination,accounting for 10.07％ of the total frequency of X-ray diagnostic imaging.The fluoroscopy,mammography and dental radiography were mainly concentrated in the tertiary hospitals,and the primary hospitals had mainly radiography.Multiple linear regression models showed that the frequency of application of conventional X-ray diagnostic imaging (including radiography,fluoroscopy,dental radiography and mammography) was positively correlated with equipment quantity,number of outpatient and emergency patients,and tertiary hospitals (t=4.334,3.615,2.339,P＜ 0.05).CT examination was positively correlated with equipment quantity and the number of inpatient (t =2.167,2.595,P＜0.05).The frequency of conventional X-ray diagnostic imaging and CT examination in Shandong province were estimated about 491.17 examinations per 1 000 population and 258.17 examinations per 1 000 population respectively.Conclusions The frequency of X-ray exposure in Shandong province increased significantly compared with that during the " 9th Five-Year Plan" period.All relevant departments should take effective measures to strengthen medical radiation protection and reduce radiation risk.

OBJECTIVE: Ideal cardiovascular health (CVH) could predict a lower risk of developing cardiovascular diseases. This study was conducted to investigate the association between ideal CVH and subclinical atherosclerosis in a population cohort of Chinese adults aged ⪖ 40 years. METHODS: This study was designed as a cross-sectional analysis of 8,395 participants who had complete data at baseline and a prospective analysis of 4,879 participants who had complete data at 4.3 years of follow-up. Ideal CVH metrics were defined according to the American Heart Association. Subclinical atherosclerosis was evaluated by plaques in carotid arteries, carotid intima-media thickness (CIMT), brachial-ankle pulse wave velocity (baPWV), and urinary albumin-to-creatinine ratio (UACR). RESULTS: Both the prevalence and incidence of atherosclerosis measures were found to be decreased with increasing numbers of ideal CVH metrics at baseline (all P values for trend < 0.01). The levels of CIMT and UACR at follow-up showed an inverse and significant association with the numbers of ideal CVH metrics at baseline (both P values for trend < 0.05) but a borderline significant association with baPWV (P for trend = 0.0505). Taking participants with 0-1 ideal metric as reference, we found that participants with 5-6 ideal metrics had significantly lower risks of developing carotid plaques (odds ratio, OR = 0.46; 95% confidence interval, CI 0.27-0.79), increased CIMT (OR = 0.60; 95% CI 0.42-0.84), and increased baPWV (OR = 0.57; 95% CI 0.34-0.97) after full adjustments. A significant interactive effect of age and CVH was detected on CIMT and baPWV progression (both P values for interaction < 0.05). CONCLUSION The numbers of ideal CVH metrics showed a significant and inverse association with the risk of developing subclinical atherosclerosis in middle-aged and elderly Chinese adults, whereas its dose-response effect was attenuated in individuals aged ≥ 60 years and partially weakened in male participants.
Aged ; Atherosclerosis ; epidemiology ; China ; epidemiology ; Cross-Sectional Studies ; Female ; Health Status ; Humans ; Male ; Middle Aged ; Prospective Studies

Objective: To evaluate the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily and dasabuvir (DSV) 250 mg twice daily combined with ribavirin in adult patients of Mainland China with chronic HCV genotype 1b infection and compensated cirrhosis. Methods: An open-label, multicenter, phase 3 clinical trial study was conducted in mainland China, Taiwan, and South Korea. Adult patients with compensated cirrhosis (Metavir score =F4) who were newly diagnosed and treated for hepatitis C virus genotype 1b infection with ombitasvir/paritaprevir/ritonavir and dasabuvir combined with ribavirin for 12 weeks were included. Assessed SVR rate of patients obtained at 12 and 24 weeks after drug withdrawal. Efficacy and safety were evaluated in patients who received at least one time study drugs. Results: A total of 63 patients from mainland China were enrolled, 62 of whom (98.4%) had a baseline Child-Pugh score of 5 points. The overall rate of SVR12 and SVR24 in patients was 100% (95% CI: 94.3% to 100.0%). Most of the adverse events that occurred were mild. The incidence of common (≥10%) adverse events and laboratory abnormalities included elevated total bilirubin (36.5%), weakness (19.0%), elevated unconjugated bilirubin (19.0%) and conjugated bilirubin (17.5%), and anemia (14.3%). Three cases (4.8%) of patients experienced Grade ≥ 3 adverse events that were considered by the investigators to be unrelated to the study drug. None patients had adverse events leading to premature drug withdrawal. Conclusion Mainland Chinese patients with chronic HCV genotype 1b infection and compensated cirrhosis who were treated with OBV/PTV/r plus DSV combined with RBV for 12 weeks achieved 100 % SVR at 12 and 24 weeks after drug withdrawal. Tolerability and safety were good, and majority of adverse events were mild.

Objective: To evaluate the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily combined with dasabuvir 250mg, twice daily in non-cirrhotic Chinese adult patients with newly diagnosed and treated chronic HCV genotype 1b infection. Methods: A randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial was conducted in mainland China, Korea, and Taiwan.Safety and efficacy of OBV/PTV/r plus DSV administered for 12 weeks were evaluated in a newly diagnosed and treated (interferon alpha /pegylated interferon alpha) and ribavirin non-cirrhotic adults with chronic HCVgenotype 1b infection. Patients randomly received OBV/PTV/r plus DSV for 12 weeks (Group A), or placebo for 12 weeks (Group B) followed by an open-label phase of OBV/PTV/r plus DSV for 12 weeks. Sustained response (SVR12) rate obtained at 12 weeks and (SVR24) 24 weeks after discontinuation of treatment, and the incidence of adverse events and laboratory abnormalities after double-blind and open-label phase treatment were assessed. Results: A total of 410 cases of Chinese patients were included and randomly assigned to group A and B (with 205 cases in each group) in a 1:1 ratio. The rates of SVR12 and SVR24 were 99% (95% CI: 94.8% - 99.8%) in the newly diagnosed patients in group A (205 patients) and the rates of SVR12 and SVR24 were 100% in treated patients (95% CI: 96.3% - 100%). Different baseline characteristics had no effect on SVR12 and SVR24 rates. Most of the adverse events occurred were mild, asymptomatic, and≥ 3 laboratory abnormalities during treatment were rare, including elevation of alanine aminotransferase (2 cases in double-blind stage A group), aspartate aminotransferase (Double-blind stage A (3 cases) and total bilirubin (1 case in open-label phase B group); however, those mild adverse events could be recovered after drug withdrawal or discontinuation. only1 person discontinued drugs due to adverse events (Group B, open-label phase). Conclusion The 12 weeks treatment course of OBV/PTV/r combined with DSV produced 99% ~ 100% rates of SVR12 and SVR24 in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection, and the tolerance and safety were good.