Ovarian cancer is the most lethal malignancy affecting the female reproductive system. Pharmacological inhibitors targeting CDK4/6 have demonstrated promising efficacy across various cancer types. However, their clinical benefits in ovarian cancer patients fall short of expectations, with only a subset of patients experiencing these advantageous effects. This study aims to provide further clinical and biological evidence for antineoplastic effects of a CDK4/6 inhibitor (TQB4616) in ovarian cancer and explore underlying mechanisms involved. Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616. Potential key genes related to TQB3616 sensitivity were identified through RNA-seq analysis, and TRIM4 was selected as a candidate gene for further investigation. Subsequently, co-immunoprecipitation and GST pull-down assays confirmed that TRIM4 binds to hnRNPDL and promotes its ubiquitination through RING and B-box domains. RIP assay demonstrated that hnRNPDL binded to CDKN2C isoform 2 and suppressed its expression by alternative splicing. Finally, in vivo studies confirmed that the addition of siTRIM4 significantly improved the effectiveness of TQB3616. Overall, our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment. TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.
Humans ; Female ; Ovarian Neoplasms/pathology* ; Animals ; Tripartite Motif Proteins/genetics* ; Mice ; Cyclin-Dependent Kinase 4/antagonists & inhibitors* ; Cell Line, Tumor ; Cyclin-Dependent Kinase 6/antagonists & inhibitors* ; Protein Kinase Inhibitors/pharmacology* ; Ubiquitin/metabolism* ; Xenograft Model Antitumor Assays ; Ubiquitination ; Antineoplastic Agents/pharmacology*

Objective To assess early clinical safety and efficacy of transfemoral transcatheter aortic valve replacement (TF-TAVR) for pure aortic regurgitation (PAR). Methods The clinical data of PAR patients who underwent TAVR in Wuhan Asia Heart Hospital and Wuhan Asia General Hospital from January 2018 to October 2022 were retrospectively analyzed. Patients were divided into a TF-TAVR group and a transapical transcatheter aortic valve replacement (TA-TAVR) group. The clinical data of the patients were analyzed. Results A total of 54 patients were enrolled, including 34 males and 20 females with an average age of 74.43±6.87 years. The preoperative N-terminal pro-B-type natriuretic peptide level was lower [808.50 (143.50, 2 937.00) pg/mL vs. 2 245.00 (486.30, 7 177.50) pg/mL, P=0.015], and the left ventricular end-diastolic diameter (56.00±6.92 mm vs. 63.07±10.23 mm, P=0.005) and sinus junction diameter (32.47±4.41 mm vs. 37.65±8.08 mm, P=0.007) were smaller in the TF-TAVR group. There was no death in the two groups during the hospitalization. Only 1 new death within postoperative 1 month in the TF-TAVR group (cerebral hemorrhage). A total of 2 new deaths in the TF-TAVR group (1 patient of sudden cardiac death and 1 of multiple organ failure), and there was no death in the TA-TAVR group within postoperative 3 months. There was 1 new death in the TA-TAVR group (details unknown), and there was no death in the TF-TAVR group within postoperative 6 months. There was no statistical difference between the two groups in the all-cause mortality and the cumulative survival rate during the follow-up period (P>0.05). The incidence of high atrioventricular block was 36.0% in the TF-TAVR group and 10.3% in the TA-TAVR group (P=0.024). There were no significant differences between the two groups in the perivalvular leakage (≥moderate), valve in valve, a second valve implantation, valve migration, cerebrovascular events, major vascular complications, complete left bundle branch block, new permanent pacemaker implantation or transferring to surgery (P>0.05). However, the incidence rates of complete left bundle branch block and new permanent pacemaker implantation were higher in the TF-TAVR group, accounting for 56.0% and 40.0%, respectively. Conclusion TF-TAVR is a safe and feasible treatment for PAR patients, which is comparable to TA-TAVR in the early postoperative safety and efficacy.

Objective To compare the role and importance of fibular fixation in tibiofibular fractures by Meta-analysis.Methods The literature related to the comparison of the efficacy of fixation of the fibula with or without fixation on the treatment of tibiofibular fractures was searched through the databases of China Knowledge Network,Wipu,Wanfang,The Cochrane Li-brary,Web of science and Pubmed,and statistical analysis was performed using RevMan 5.3 software.The rates of malrotation,rotational deformity,internal/external deformity,anterior/posterior deformity,non-union,infection,secondary surgery and op-erative time were compared between the fibula fixation and non-fixation groups.Results A total of 11 publications were includ-ed,six randomised controlled trials and five case-control trials,eight of which were of high quality.A total of 813 cases were in-cluded,of which 383 were treated with fibula fixation and 430 with unfixed fibulae.Meta-analysis results showed that fixation of the fibulae in the treatment of tibiofibular fractures reduced the rates of postoperative rotational deformity[RR=0.22,95％CI(0.10,0.45),P＜0.000 1]and internal/external deformity[RR=0.34,95％CI(0.14,0.84),P=0.02]and promoted fracture heal-ing[RR=0.76,95％CI(0.58,0.99),P=0.04].In contrast,the rates of poor reduction[RR=0.48,95％CI(0.10,2.33),P=0.36],anterior/posterior deformity[RR=1.50,95％CI(0.76,2.96),P=0.24],infection[RR=1.43,95％CI(0.76,2.72),P=0.27],sec-ondary surgery[RR=1.32,95％CI(0.82,2.11),P=0.25],and operative time[MD=10.21,95％CI(-17.79,38.21),P=0.47]were not statistically significant(P＞0.05)for comparison.Conclusion Simultaneous fixation of the tibia and fibula is clinically more effective in the treatment of tibiofibular fractures.

BACKGROUND:Bioactive glass is a multifunctional synthetic composite material that releases active ions slowly and exhibits certain biological activities after affinity with tissues.Their versatility stems from the versatility of their preparation processes and components,allowing them to be applied in different clinical scenarios. OBJECTIVE:To review the main application forms,application fields of bioactive glass,as well as the influence of doping different elements on its function. METHODS:A literature search was conducted across WanFang Medical Database,CNKI Database,PubMed Database,and Web of Science Database,using the search terms"bioactive glass,slow-release ions,bone tissue engineering,composite scaffold,tissue regeneration and repair,biomedical engineering"in Chinese and English.The timeframe was limited from 2000 to 2023.Finally,88 articles were included for review. RESULTS AND CONCLUSION:(1)In terms of application forms,bioactive glass can be fabricated as coatings,particles,bone cements,and scaffolds according to needs.Coatings have the potential to enhance the biological activity of implants,yet they are susceptible to instability as a result of degradation.Particles offer a viable solution for the repair of irregular bone defects;however,particles produced through traditional methods often possess limited functionality.Bone cement provides the benefits of minimal invasiveness and injectability,yet its application is restricted to smaller bone defects.Scaffolds exhibit excellent mechanical properties and are commonly used for larger-sized bone defects,yet they have limited toughness.(2)In terms of applications,bioactive glass can be used in a variety of tissue regeneration and repair and disease treatment fields,including dentistry,orthopedics,soft tissue engineering,and cancer.(3)In terms of element doping,the addition of specific elements to bioactive glass not only improves its mechanical properties but also endows it with special biological functions such as bioactivity,degradability,and antibacterial properties.(4)Biologically active glass is a versatile material that can be used in different forms and functions by adjusting the preparation process and element doping to meet various clinical needs in bone tissue engineering and is widely used in the field of biomedical engineering.

A ratiometric fluorescent probe([Eu(Hpfdap)3(CTMR-Phen-N)])was designed and synthesized for detection of singlet oxygen(1O2)with dimethyl anthracyl-containing β-diketone compound 1,1,1,2-pentafluoro-5-(9',10'-dimethyl-2'-anthracene)-3,5-pentanedione(Hpfdap)as recognition ligand and 5-amino-1,10-phenanthroline conjugated with Rhodamine as auxiliary ligand(CTMR-Phen-N).The results of spectral analysis showed that the europium(Ⅲ)complex had almost no fluorescence due to the presence of anthracene ring in the probe.After reaction with 1O2,the anthracene ring was oxidized to endoperoxide,and the fluorescence of the europium(Ⅲ)complex at 614 nm was restored,followed by the increase of quantum yield from 1.60%to 25.16%.The fluorescence intensity of Rhodamine at 575 nm remained unchanged before and after the reaction with 1O2.Therefore,the ratio of fluorescence intensity at 614 nm and 575 nm could be used to measure 1O2 by the developed rationmetric fluorescence method.The probe showed good selectivity for 1O2,and the detection limit(S/N=3)was as low as 3 μmol/L.The fluorescence imaging results demonstrated that the probe had low cytotoxicity and good membrane permeability,and could be applied to fluorescence imaging of 1O2 in Hela cells.

Objective:To explore the pregnancy outcome and postpartum clinical phenotype of LCR22B/C~D central 22q11.2 deletion syndrome.Methods:For fetuses diagnosed with central 22q11.2 deletion by chromosomal microarray analysis (CMA) at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January 2019 to April 2022, their prenatal imaging, parental CMA verification, pregnancy outcomes and postpartum clinical phenotype were analyzed.Results:Eight cases of central 22q11.2 deletion syndrome were included, including six cases with LCR22B~D 22q11.2 deletions and two with LCR22C~D 22q11.2 deletions. Among the six cases with LCR22B~D type 22q11.2 deletions, three had shown cardiovascular malformations (right aortic arch, ventricular septal defect, mild tricuspid regurgitation), one had shown urinary defect (right kidney heterotopia). Two cases with LCR22C~D 22q11.2 deletions showed nonspecific ultrasonographic findings, including oligohydramnios with growth restriction and nuchal skin thickening. The CMA verification showed that six cases were inherited from their parents, and five couples had chosen to continue with the pregnancy. Postpartum follow-up showed that the physical and intellectual development of all children were normal. One couple had opted to terminate the pregnancy considering the ectopic fetal right kidney. Two remaining cases had decided to terminate their pregnancies without parental verification.Conclusion:The central 22q11.2 deletion syndrome of the LCR22B/C~D type is different from the classical types. Its genetic information mainly comes from parents. Prenatal imaging has mainly shown cardiovascular and urinary abnormalities. Postnatal growth and intellectual development have been normal. Therefore, the couples should be provided with suffice prenatal genetic counseling.

Objective:To analyze ultrasonographic manifestations and genetic etiology of nine fetuses with 7q11.23 duplication syndrome.Methods:Ultrasonographic finding, pregnancy outcome and follow-up of nine fetuses detected at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January 2017 to December 2021 were retrospectively analyzed.Results:The fetuses were found to harbor a duplication in the 7q11.23 region by chromosomal microarray analysis (CMA). Among these, five had shown ventriculomegaly, including four syndromic and one non-syndromic. For the remainders, one had ventricular septal defect and mild tricuspid regurgitation, one had echogenic intracardiac focus, whilst another two were normal. Five couples had accepted parental verification, and the results confirmed that the 7q11.23 duplication carried by their fetuses were de novo in origin. Following genetic counseling, seven couples had opted to terminate their pregnancies. Two fetuses were delivered at full term, and follow-up had found no abnormalities. Conclusion:Prenatal ultrasonographic manifestations of fetuses with 7q11.23 duplication syndrome are variable. CMA can provide assistance for their diagnosis and genetic counseling.

Objective:To explore the correlation between grip strength promotion and improvement of body composition and metabolic disorders in health examination population of different genders.Methods:In this retrospective cohort study, clinical data of 600 people who received health examination and grip strength check-up two times or more in the Medical Examination Center of Peking University Third Hospital from January 2018 to November 2022 were selected. The general data, physical examination, biochemical parameters, body composition and grip strength results were collected. After the first physical examination, the grip strength test was conducted, appropriate resistance strength exercises were given based on individual evaluation results. A health lecture was held, and the information related to health exercise was pushed through WeChat official account every week. The grip strength test was completed at the same time at the second physical examination, and the difference between the two test results was calculated before and after the second physical examination. The generalized estimation equation was used to analyze the correlation between the improvement of grip strength and the improvement of body composition and metabolic disorders in different gender health-check population.Results:In man and women, the body mass index [(25.50±3.66) vs (25.33±3.74) kg/m 2, (22.41±3.55) vs (22.25±3.46) kg/m 2] and grip strength [(42.71±7.30) vs (41.77±7.36) kg, (25.28±5.30) vs (23.98±4.87) kg] at the second health check-up were all significantly higher than those at the first time, and the diastolic blood pressure [(72.79±10.30) vs (74.47±9.85) mmHg (1 mmHg=0.133 kPa), (66.93±8.90) vs (68.92±9.42) mmHg] and serum homocysteine [(17.96±14.09) vs (19.27±14.26) μmol/L, (9.47±3.91) vs (10.26±3.90) μmol/L] were all significantly lower than those at the first time (all P<0.05). Among man, the low-density lipoprotein cholesterol (LDL-C) at the second physical examination was significantly lower than that at the first time [(2.94±0.78) vs (3.00±0.69) mmol/L] (all P<0.05). Among women, the systolic blood pressure and uric acid at the second health check-up were both significantly lower than those at the first time [(109.34±12.85) vs (110.54±12.32) mmHg, (276.91±62.46) vs (287.16±68.78) μmol/L], and the waist-hip ratio was significant higher (85.8%±5.1% vs 85.4%±5.0%) (all P<0.05). In males, the decreased aspartate aminotransferase ( OR=0.932, 95% CI: 0.888-0.978) and the increased skeletal muscle index ( OR=75.370, 95% CI: 29.012-195.806) were both positively correlated with the elevation of grip strength (all P<0.05); and in females, the decreased homocysteine ( OR=0.876, 95% CI: 0.782-0.982) and glycosylated hemoglobin ( OR=0.423, 95% CI: 0.222-0.805) and increased skeletal muscle index ( OR=22.918, 95% CI: 11.114-47.256) were all positively correlated with the elevation of grip strength (all P<0.05). Conclusion:There is a positive correlation between the improvement of grip strength and the improvement trend of body composition and metabolic disorders in in health examination population of different genders.

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.

Objective To study the diagnosis,treatment,and complications of hypophosphatemic rickets(HR)in children,explore effectiveness evaluation indicators for the disease,and understand the pattern in height growth among these patients.Methods A retrospective analysis of the initial clinical data and five-year follow-up data of 85 children with HR treated at Children's Hospital of Nanjing Medical University from January 2008 to December 2022.Results Among the 85 children with HR,there were 46 males(54%)and 39 females(46%).The age at initial diagnosis ranged from 6 months to 13 years and 9 months,with a median age of 2.75 years.The average height standard deviation score was-2.0±1.1.At initial diagnosis,children exhibited reduced blood phosphate levels and elevated alkaline phosphatase(ALP),with 99%(84/85)presenting with lower limb deformities.The positive rate for PHEX gene mutations was 93%(55/59).One year post-treatment,there was a significant reduction in ALP levels and the gap between the lower limbs(P<0.05).The fastest height growth occurred in the first year after treatment,at 8.23 cm/year,with a peak height velocity(PHV)phase lasting about two years during puberty.The height increased by 9-20 cm in male children during the PHV stage and 10-15 cm in female children.Major complications included nephrocalcinosis and hyperparathyroidism.The incidence rate of nephrocalcinosis in the first year after treatment was 55%(22/40),which increased with the duration of the disease(P<0.001);an increased urinary phosphate/creatinine ratio was positively associated with a higher risk of nephrocalcinosis(OR=1.740,P<0.001).The incidence of hyperparathyroidism in the first year after treatment was 64%(27/42).Conclusions For children presenting with lower limb deformities,short stature,and slow growth,early testing for blood levels of phosphate,calcium,and ALP,along with imaging examinations of the lower limbs,can aid in the early diagnosis of HR.Genetic testing may be utilized for definitive confirmation when necessary.ALP combined with improvements in skeletal deformities and annual height growth can serve as indicators of therapeutic effectiveness for HR.Compared to normal children,children with HR demonstrate a lower height increase during the PHV phase,necessitating close follow-up and timely adjustment of treatment plans