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.

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and sociodemographic index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.
Humans ; Noncommunicable Diseases/epidemiology* ; Global Burden of Disease ; Disability-Adjusted Life Years ; Male ; Female ; Risk Factors ; Middle Aged ; Kidney Diseases/epidemiology* ; Bayes Theorem ; Adult ; Aged ; Global Health ; Quality-Adjusted Life Years

OBJECTIVE: To explore the predictive value of age, D-Dimer and fibrinogen (FIB) for non-thrombotic. METHODS: A retrospective analysis was conducted on a total of 1 384 coagulation test cases from January to August 2024 at Nanning No. 8 People's Hospital. Among them, the control group comprised 400 non-thrombotic cases with D-Dimer test results within the reference range. The thrombotic group comprised 57 clinically diagnosed thrombotic patients. The research group comprised 927 non-thrombotic cases with D-Dimer levels exceeding the reference range. The diagnosis treatment records, age information, plasma D-Dimer, and FIB test results of each group were collected. The changes and correlations of age, D-Dimer, and FIB indicators were compared and analyzed among the three groups. A new combination factor was generated by fitting a Logistic binary regression model. ROC curves were used to evaluate the predictive value of each index for non-thrombotic disease in both the research group and the thrombotic group. RESULTS: Compared with the control group, the thrombotic group and the research group had significantly higher age, D-Dimer, and FIB levels (P < 0.001). Further comparative analysis showed that the research group had significantly lower age and D-Dimer levels than the thrombotic group, the FIB level was significantly higher than that of the thrombotic group (P < 0.001). Spearman correlation analysis showed that the correlation coefficient between age and D-Dimer in the research group was higher than that in the control group and thrombotic group (P < 0.01), the thrombotic group had the highest negative correlation coefficient between FIB and D-Dimer (P < 0.01). The ROC curve analysis results showed that the AUC values of age, plasma D-dimer, and FIB independently predicted non-thromb diseases were 0.726, 0.735, and 0.611, respectively. A new combined factor was generated by fitting age, D-dimer, and FIB with a logistic binary regression model. The AUC value of the combined prediction of non-thrombotic diseases was the maximum at 0.832, which had high diagnostic value, and its sensitivity and specificity were 0.572 and 0.070. CONCLUSION Elevated D-dimer levels were associated with age, increased FIB, and a variety of non-thrombotic diseases, and combination of age, D-dimer, and FIB had a certain predictive value for non-thrombotic diseases, but the combined model had a low specificity, other information needs to be combined in the clinic to improve diagnostic accuracy.
Humans ; Fibrin Fibrinogen Degradation Products ; Retrospective Studies ; Fibrinogen ; Predictive Value of Tests ; Thrombosis ; Age Factors ; ROC Curve ; Male ; Female ; Middle Aged ; Adult

OBJECTIVE: To explore the application of targeted mRNA sequencing in fusion gene diagnosis of hematologic diseases. METHODS: Bone marrow or peripheral blood samples of 105 patients with abnormally elevated eosinophil proportions and 291 acute leukemia patients from January 2015 to June 2023 in the First Affiliated Hospital of Soochow University were analyzed and gene structural variants were detected by targeted mRNA sequencing. RESULTS: Among 105 patients with abnormally elevated eosinophil proportions, 6 cases were detected with gene structural variants, among which fusion gene testing results in 5 cases could serve as diagnostic indicators for myeloid neoplasms with eosinophilia. In addition, a IL3∷ETV6 fusion gene was detected in one patient with chronic eosinophilic leukemia, not otherwise specified. Among 119 patients with acute myeloid leukemia (AML), 38 cases were detected structural variants by targeted mRNA sequencing, accounting for 31.9%, which was significantly higher than 20.2% (24/119) detected by multiple quantitative PCR (P < 0.05). We also found one patient with AML had both NUP98∷PRRX2 and KCTD5∷JAK2 fusion genes. A total of 104 patients were detected structural variants by targeted mRNA sequencing in 172 cases with acute B-lymphoblastic leukemia who were tested negative by multiple quantitative PCR, with a detection rate of 60.5% (102/172). CONCLUSION Targeted mRNA sequencing can effectively detect fusion gene and has potential clinical application value in diagnosis and classificatation in hematologic diseases.
Humans ; Hematologic Diseases/diagnosis* ; RNA, Messenger/genetics* ; Oncogene Proteins, Fusion/genetics* ; Sequence Analysis, RNA ; Leukemia, Myeloid, Acute/diagnosis*

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.

Rice is the world's largest food crop, and its yield and quality are directly related to food security and human health. Grain size, as one of the important factors determining the rice yield, has been widely concerned by breeders and researchers for a long time. To decipher the regulatory mechanism of rice grain size, we obtained a multi-tiller, dwarf, and small-grain mutant htd1 by ethyl methanesulfonate (EMS) mutation from the Japonica rice cultivar 'Zhonghua 11' ('ZH11'). Genetic analysis indicated that the phenotype of htd1 was controlled by a single recessive gene. Using the mutation site map (Mutmap) method, we identified the candidate gene OsHTD1, which encoded a carotenoid cleavage dioxygenase involved in the biosynthesis of strigolactone (SL). The SL content in htd1 was significantly lower than that in 'ZH11'. Cytological analysis showed that the grain size of the mutant decreased due to the reductions in the length and width of glume cells. The function of htd1 was further verified by the CRISPR/cas9 gene editing technology. The plants with the gene knockout exhibited similar grain size to the mutant. In addition, gene expression analysis showed that the expression levels of multiple grain size-related genes in the mutant changed significantly, suggesting that HTD1 may interact with other genes regulating grain size. This study provides a new theoretical basis for research on the regulatory mechanism of rice grain size and potential genetic resources for breeding the rice cultivars with high yields.
Oryza/growth & development* ; Mutation ; Edible Grain/growth & development* ; Alleles ; Plant Proteins/genetics* ; Dioxygenases/genetics* ; Lactones/metabolism* ; Gene Expression Regulation, Plant ; Genes, Plant ; Gene Editing ; CRISPR-Cas Systems ; Phenotype

Objective To analyze the effect of tislelizumab combined with chemotherapy in the treatment of stage Ⅲb-Ⅳ non-small cell lung cancer(NSCLC)and its influence on T lymphocyte immunity and survival prognosis.Methods Patients with NSCLC were divided into control group and treatment group according to different treatment methods.The control group was treated with platinum-containing dual-drug combined chemotherapy regimen(PC regimen:intravenous drip of pemetrexed 500 mg·m-2 on the 1st day and intravenous drip of carboplatin with area under plasma concentration-time curve(AUC)=5 mg·mL-1·min-1 on the 1st day;TP regimen:intravenous drip of taxol 135 mg·m-2 on the 1st day,and intravenous drip of carboplatin with AUC=5 mg·mL-1·min-1 on the 1st day to 3rd day).The treatment group was given tislelizumab 200 mg intravenously once every 3 weeks on the basis of the control group.Both groups were treated for 2 cycles by taking 3 weeks as 1 treatment cycle.The clinical efficacy,serum tumor markers levels,T lymphocyte immune function,progression-free survival(PFS)and overall survival(OS)and occurrence of adverse drug reactions during treatment were compared between the two groups.Results There were 40 cases in control group and 40 cases in treatment group.After treatment,the total effective rates in control group and treatment group were 40.00％(16 cases/40 cases)and 62.50％(25 cases/40 cases),the disease control rates were 70.00％(28 cases/40 cases)and 90.00％(36 cases/40 cases),carcinoembryonic antigen(CEA)levels were(9.21±2.03)and(5.42±1.36)ng·mL-1,carbohydrate antigen 125(CA125)levels were(72.53±8.16)and(31.95±5.08)U·mL-1,carbohydrate antigen 19-9(CA19-9)levels were(25.79±3.31)and(10.38±2.04)U·mL-1,cytokeratin19 fragment antigen 21-1(CYFRA21-1)levels were(6.47±1.34)and(4.26±0.91)ng·mL-1,CD3+levels were(54.36±5.81)％and(61.85±4.96)％,CD4+levels were(31.28±2.93)％and(43.08±3.15)％,CD4+/CD8+were 1.43±0.40 and 1.91±0.46,survival rates were 47.37％(18 cases/38 cases)and 67.57％(25 cases/37 cases),PFS were 7.73 months(95％CI:6.42-9.03)and 9.75 months(95％CI:8.68-10.82),and OS were 8.96 months(95％CI:7.94-9.97)and 10.52 months(95％CI:9.78-11.27)respectively(all P＜0.05).There were no statistically significant differences in the incidence of gastrointestinal reactions,liver dysfunction,bone marrow suppression,hypothyroidism and non-infectious pneumonia between both groups(all P＞0.05).Conclusion Tislelizumab combined with chemotherapy has a good effect in the treatment of stage Ⅲb-Ⅳ NSCLC,and it can effectively reduce the levels of serum tumor markers,improve the T lymphocyte immune function,and prolong the survival time of patients,with good safety.

Objective Evaluate the performance of the encephalon state index(ESI)in depth of anesthesia monitoring during clinical surgery,compared with the bispectral index(BIS).Methods ESI and BIS data were collected from 60 patients in a single-center clinical trial to compare their efficacy in measuring the depth of anesthesia.Results Consistency analysis revealed mean differences and standard deviations of-0.18±5.42 and-0.11±6.51 between ESI and BIS for awake and anesthetized states,respectively.Correlation analysis showed a correlation coefficient of 0.92 throughout the operative period.Prediction probability analysis indicated that both ESI and BIS had prediction probabilities of 0.97,effectively predicting anesthesia status.Conclusion ESI and BIS show good equivalence in monitoring depth of anesthesia during clinical surgery,which meet the requirements of clinical anesthesia.

Objective:To investigate the clinical characteristics and treatment of patients with perianal necrotizing fasciitis.Methods:This study was a retrospective cohort study. Twenty patients with perianal necrotizing fasciitis who met the inclusion criteria were admitted to the Department of Burn and Plastic Surgery of the First Affiliated Hospital of Guangxi Medical University (hereinafter referred to as our department) from August 2013 to September 2023, including 19 males and 1 female, aged 24-74 (56±11) years. Based on the spreading route of perianal infection to the lower abdomen, the patients were divided into perianal-inguinal-lower abdominal wall group (12 cases) and perianal-pelvic cavity-retroperitoneal group (8 cases). The following clinical data were compared between the two groups of patients: general data, including gender, age, combined underlying diseases, blood glucose level and acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score when admitted to our department, and laboratory risk indicator for necrotizing fasciitis (LRINEC) score when admitted to our department and at 14 d after admitted to our department; infection indicators when admitted to our department, including C-reactive protein level, white blood cell count, lymphocyte count, procalcitonin level, and lactic acid level; clinical outcome-related indicators, including time from onset to definite infection range, number of surgery, treatment in intensive care unit (ICU), length of hospital stay, treatment outcome, and recurrence of necrotizing fasciitis during follow-up; detection of pathogen and bacterial drug resistance in wound necrotic tissue specimen when admitted to our department.Results:Compared with those in perianal-inguinal-lower abdominal wall group, the APACHE Ⅱ score and lactic acid level when admitted to our department and LRINEC score at 14 d after admitted to our department (with t values of -5.98, -5.01, and -2.86, respectively, P<0.05) and ICU treatment ratio ( P<0.05) were significantly increased, the time from onset to definite infection range was significantly prolonged ( Z=-3.75, P<0.05), and the number of surgery was significantly increased ( Z=2.80, P<0.05) in patients in perianal-pelvic cavity-retroperitoneal group. There were no statistically significant differences in other data between the two groups of patients ( P>0.05). Eighteen patients were cured, and no recurrence of perianal necrotizing fasciitis was observed during follow-up of 6 months in 18 cured patients. The main bacteria were Escherichia coliand Klebsiella pneumoniae, and the fungui were Aspergillus and Candida albicans detected in wound necrotic tissue specimens in two groups of patients when admitted to our department. The ratio of multiple drug resistance of bacteria in wound necrotic tissue specimens in perianal-pelvic cavity-retroperitoneal group of patients was significantly higher than that in perianal-inguinal-lower abdominal wall group ( P<0.05). Conclusions:Perianal necrotizing fasciitis can spread to the lower abdomen through two routes: the perianal-inguinal-lower abdominal wall route and the perianal-pelvic cavity-retroperitoneal route. The latter is more insidious in disease progression and more challenging in treatment. Establishing a mechanism of multi-disciplinary team diagnosis and treatment can achieve the goal of early diagnosis and precise treatment of perianal necrotizing fasciitis.