Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
G-Quadruplexes ; Cellular Senescence ; Ribosomes/genetics* ; Humans ; Animals ; Mice ; DEAD-box RNA Helicases/genetics* ; Protein Biosynthesis ; RNA/chemistry* ; Neoplasm Proteins

OBJECTIVE: The relationship between fish consumption and stroke is inconsistent, and it is uncertain whether this association varies across predicted stroke risks. METHODS: A cohort study comprising 95,800 participants from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project was conducted. A standardized questionnaire was used to collect data on fish consumption. Participants were stratified into low- and moderate-to-high-risk categories based on their 10-year stroke risk prediction scores. Hazard ratios ( HRs) and 95% confidence intervals ( CIs) were estimated using Cox proportional hazard models and additive interaction by relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). RESULTS: During 703,869 person-years of follow-up, 2,773 incident stroke events were identified. Higher fish consumption was associated with a lower risk of stroke, particularly among moderate-to-high-risk individuals ( HR = 0.53, 95% CI: 0.47-0.60) than among low-risk individuals ( HR = 0.64, 95% CI: 0.49-0.85). A significant additive interaction between fish consumption and predicted stroke risk was observed (RERI = 4.08, 95% CI: 2.80-5.36; SI = 1.64, 95% CI: 1.42-1.89; AP = 0.36, 95% CI: 0.28-0.43). CONCLUSION Higher fish consumption was associated with a lower risk of stroke, and this beneficial association was more pronounced in individuals with moderate-to-high stroke risk.
Humans ; China/epidemiology* ; Male ; Female ; Stroke/etiology* ; Middle Aged ; Prospective Studies ; Incidence ; Aged ; Animals ; Fishes ; Risk Factors ; Diet ; Seafood ; Adult ; Cohort Studies

As an indispensable trace element in the human body,copper plays an important role in various physiological and biochemical reactions.The dyshomeostasis of copper leads to the disorder of copper metabolism and the occurrence of related diseases.Cuproptosis,a newly proposed regulatory cell death mode,is different from the known apoptosis,pyroptosis,necroptosis,and ferroptosis.Recent studies have found that the dyshomeostasis of copper has been observed in a variety of cancers.Therefore,targeting copper for disease treatment may become a new strategy and a new idea.This article systematically summarizes the fundamental properties of copper,copper dyshomeostasis-related diseases (Menkes syndrome,Wilson's disease,and cancer) and their treatment,and reviews the research progress in cuproptosis.
Humans ; Copper/metabolism* ; Homeostasis ; Neoplasms/metabolism* ; Hepatolenticular Degeneration/metabolism* ; Menkes Kinky Hair Syndrome/metabolism*

Objective To analyze the efficacy of bevacizumab combined with paclitaxel+carboplatin in the treatment of recurrent/metastatic cervical cancer,and to explore the influence on survival prognosis of patients.Methods Patients with recurrent/metastatic cervical cancer were divided into control group and treatment group according to different treatment methods.The control group received paclitaxel combined with carboplatin chemotherapy regimen(intravenous infusion of 170 mg·m-2 paclitaxel and carboplatin(AUC=5 mg·mL-1·min)for 3 weeks as a course of chemotherapy),and the treatment group was given bevacizumab on the basis of control group,intravenous infusion of 15 mg·kg-1 bevacizumab,once every 3 weeks.Both groups were treated for 3 cycles of treatment by taking 3 weeks as 1 treatment cycle.The clinical efficacy,levels of serum tumor markers,quality of life,survival prognosis and occurrence of drug-related adverse reactions during treatment were compared between the two groups.Results There were 41 cases in treatment group and 48 cases in control group.After treatment,the overall response rate(ORR)of treatment group and control group were 31.71％(13 cases/41 cases)and 14.58％(7 cases/48 cases),with no statistical significance(P＞0.05).After treatment,the disease control rate(DCR)in control group and treatment group were 62.50％(30 cases/48 cases)and 82.93％(34 cases/41 cases);the squamous cell carcinoma antigen(SCCA)levels were(3.58±0.73)and(2.52±0.57)ng·mL-1;carbohydrate antigen 19-9(CA19-9)levels were(23.60±4.29)and(19.19±3.72)U·mL-1;carbohydrate antigen 15-3(CA15-3)levels were(27.13±5.36)and(22.86±3.94)U·mL-1;carbohydrate antigen 125(CA125)levels were(39.24±6.88)and(26.47±5.09)U·mL-1;the overall improvement rates of quality of life were 41.67％(20 cases/48 cases)and 73.17％(30 cases/41 cases),the progression-free survival times were 8.67 months(95％CI:7.82-9.53)and 10.25 months(95％CI:9.68-10.81),the total survival times were 9.96 months(95％CI:9.13-10.79)and 11.47 months(95％CI:11.00-11.93),all with significant difference(all P＜0.05).There were no statistically significant differences in the incidence of nausea and vomiting,leukopenia,thrombocytopenia and liver-kidney function impairment between both groups(all P＞0.05).Conclusion Bevacizumab combined with chemotherapy has significant efficacy in the treatment of recurrent/metastatic cervical cancer,and it can reduce the levels of serum tumor markers,enhance the quality of life,and improve the survival prognosis,and it has good safety.

Objective To evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Objective:To retrospectively analyze the clinical and pathologic characteristics, response to treatment, survival, and prognosis of patients with primary large B-cell lymphoma of the central nervous system (PCNSLBCL) .Methods:Clinical and pathologic data of 70 patients with PCNSLBCL admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from December 2010 to November 2022 were collected for retrospective analysis. Survival analysis was performed using the Kaplan-Meier method and log-rank test, and prognosis analysis was conducted using the Cox proportional hazards model.Results:Among 70 patients with PCNSLBCL, complete remission (CRs) were achieved in 49 (70.0% ) and partial remission in 4 (5.7% ) after the first-line induction therapy; the overall remission rate was 75.7%. The 2-year progression-free survival (PFS) rate was 55.8% and the median progression-free survival (mPFS) time was 35.9 months, whereas the 2-year overall survival (OS) rate was 79.1% with a median OS time not reached. After CR induced by first-line therapy, cumulative incidence of relapse (CIR) was lower in patients who had received auto-HSCT than in those who had not received consolidation therapy ( P=0.032), whose 2-year PFS rate was 54.4% and mPFS time was 35.9 months; comparatively, the 2-year PFS rate in patients having received oral maintenance of small molecule drugs reached 84.4% with a mPFS time of 79.5 months ( P=0.038). Multivariant analysis demonstrated that Class 3 in the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model is an independent adverse prognostic factor of OS in patients with PCNSLBCL ( HR=3.127, 95% CI 1.057-9.253, P=0.039) . Conclusions:In patients with PCNSLBCL achieving CR after the first-line induction therapy, auto-HSCT as consolidation therapy would lead to a decreased CIR, and PFS time could be prolonged by oral maintenance of small molecule drugs. Class 3 MSKCC prognostic model is independently associated with poorer OS.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

OBJECTIVE: To determine the feasibility of conducting a full-scale randomized controlled trial (RCT) and investigate the basic information and safety of acupuncture for patients with chronic spontaneous urticaria (CSU). METHODS: A total of 80 participants with CSU from July 2018 to July 2019 were randomly assigned to receive active acupuncture (n=41) on a fixed prescription of acupoints or sham acupuncture (n=39) with superficial acupuncture on non-acupuncture points through the completely randomized design. Patients in both groups received 5 sessions per week for 2 weeks, and participants were followed for a further 2 weeks. Feasibility was assessed by recruitment and randomization rates, retention of participants, treatment protocol adherence, and the incidence of adverse events (AEs). The clinical primary outcome was the changes from baseline weekly urticaria activity scores (UAS7) after treatment at 2 weeks. Secondary outcomes included the Visual Analogue Scale (VAS) score of itching intensity, Dermatology Life Quality Index (DLQI), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA). RESULTS: A total of 80 participants were enrolled. The recruitment rate of 24.02%, randomization rate of 100%, a loss rate of 6.25%, and no obvious AEs were observed in either group. The decrease from baseline in the mean UAS7 total score at week 2 in the active acupuncture group was -8.63 (95%CI, -11.78 to -5.49) and -6.21 (95%CI, -9.43 to -2.98) in the sham acupuncture group for a between-group difference of -2.42 (95% CI, -6.93 to 2.07). The change in the DLQI, VAS of itching intensity, HAMA, and HAMD were a slightly better improvement trend in the active acupuncture group than the sham acupuncture group, but the between-group difference was not significant. CONCLUSIONS Active acupuncture had a better improvement trend in alleviating symptoms, improving quality of life and regulating the mood of anxiety and depression in patients with CSU than sham acupuncture. (Registration Nos. AMCTR-ICR-18000190 and ChiCTR2100054776).

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*