Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

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 investigate the occurrence of chronic postsurgical pain (CPSP) among patients with preoperative COVID-19, and further analyze the risk factors for CPSP.  Methods  This study was a ambispective cohort study, with subjects from a completed cohort study with follow-up. We included the clinical data of the patients with preoperative COVID-19 who underwent surgery at Peking Union Medical College Hospital from December 1, 2022 to February 28, 2023. Follow-up was conducted up to 6 months postoperatively, with the primary outcome being CPSP. Multivariate Logistic regression analysis was used to analyze the correlation between COVID-19-related exposure indicators and CPSP.  Results  A total of 4117 surgical patients were included, all of whom had preoperative COVID-19. Among them, 4002 cases had mild symptoms during the acute phase, 62 cases had severe symptoms, and 53 cases were critically ill. At 6th month postoperatively, 1298 cases (31.53%) had long COVID-19 syndrome, and the incidence of CPSP was 5.59% (95% CI: 4.88%-6.28%). After adjusting for confounding factors including age, gender, comorbidities, anesthesia method, and type of surgery, multivariate Logistic regression analysis revealed that critically ill COVID-19 during the acute phase (aOR=3.35, 95% CI: 1.48-7.62, P < 0.001) and presence of long COVID-19 syndrome postoperatively (aOR=2.50, 95% CI: 1.90-3.29, P < 0.001) were associated with CPSP.  Conclusions  It is clear for the first time that critically ill COVID-19 during the acute phase and the presence of long COVID-19 syndrome postoperatively are the risk factors for CPSP among patients with preoperative COVID-19.

Objective To explore the effect of proprioceptive neuromuscular facilitation(PNF)on the knee abduction torque and vastus medialis-medial gastrocnemius(VM-MG)co-contraction index during walking among the old patients with medial compartment knee osteoarthritis. Methods From March to May,2022,32 old patients with medial compartment knee osteoarthritis in communities in Ji'nan were enrolled and randomly allocated to control group(n=16)and training group(n=16).The training group received PNF and the control group received home-based exercise,for six weeks.The knee abduction torque and VM-MG co-contraction index were measured using an infrared motion capture system synchronized with 3D force plate and electromyography system before and after treatment. Results Three cases in the control group and two cases in the training group dropped off.The first and the second peaks of knee abduction torque,and the VM-MG co-contraction index improved in the training group after treatment(|t|>2.460,P<0.05),and the first and the second peaks of knee abduction torque were better in the training group than in the control group(|t|>2.454,P<0.05). Conclusion PNF may optimize the load distribution between the medial and lateral compartments of the knee in patients with knee osteoarthritis.

With the rapid development of artificial intelligence technology,small molecule generation models have emerged as a significant research direction in the field of drug discovery.These models,including Generative Adversarial Networks(GANs),Variational Autoencoders(VAEs),and diffusion models,have proven to possess remarkable capabilities in optimizing drug properties and generating complex molecular structures.This article comprehensively analyzes the application of the aforementioned advanced technologies in the drug discovery process,demonstrating how they supplement and enhance traditional drug design methods.At the same time,it addresses the challenges facing current methods in terms of data quality,model complexity,computational cost,and generalization ability,with a prospect of future research directions.

Malignant tumors in children are one of the most important diseases that threaten the health and quality of life of children and are the second most common cause of death in children.With the continuous improvement and progress of treatment technology, the long-term survival rate of children with tumor has been significantly improved, but both the disease itself and the treatment can impair the immune function of children, which makes them vulnerable to various infectious diseases and secondary serious complications, and even become a source of infection, endangering the health of others. Vaccination is the most cost-effective measure to prevent infectious diseases. For children with normal immune functions, the benefits of vaccination usually outweigh the disadvantages. However, there is a lack of detailed data on the vaccination situation, efficacy and safety of vaccine use for such immunocompromised tumor survivors, and there are no authoritative and uniform vaccination recommendations. This article reviewed and summarized the literature and consensus of some domestic and foreign scholars on current status of post-treatment vaccination status, efficacy and safety of vaccination for children with tumors after treatment, with the aim of providing a reference for the practice in this field in China.

Objective:To clarify the potential correlation between biological changes of meninges in periodontitis mice and cognitive impairment by analyzing the biological changes of meninges in periodontitis mice using single-cell RNA sequencing.Methods:Thirty C57BL/6 mice were divided into two groups by using random number table method (15 mice in each group). Mice in the control group were locally administered 2% carboxyl methyl cellulose (CMC) without Porphyromonas gingivalis (Pg) on both buccal sides. A mixture of Pg W83 and 2% CMC was applied on both buccal sides in the experimental group mice three times a week, lasting for 16 weeks in total. The absorption of alveolar bone, locomotor activity and cognitive function, the activation of microglia and astrocytes in the cortex were observed and assessed. The mRNA expression levels of Occludin in meninges and brain were detected in two groups. Single-cell RNA sequencing data of meninges were processed by uniform manifold approximation and projection (UMAP). Differential genes expressions of endothelial cells were processed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. In addition, real-time fluorescence quantitative PCR (RT-qPCR) was used to verify the expressions of transcription activating factor 3 (Atf3) and apolpoprotein L domain-containing 1 (Apold 1). Results:Methylene blue staining found the distances of buccal and palatal cement-enamel junction-alveolar bone crest in experimental mice [(185.60±17.60), (206.90±13.37) μm] increased significantly compared with the control group [(135.33±9.57), (163.05±14.98) μm] ( t=5.02, P=0.002; t=4.37, P=0.005). Open field experiment showed the total distance and average speed of mice in the experimental group [(971.88±164.57) cm, (3.25±0.55) cm/s] were not statistically significant compared with the control group [(914.24±278.81) cm, (3.05±0.93) cm/s] ( t=0.65, P=0.525; t=0.65, P=0.520). The recognition index of the experimental group [(48.02±16.92) %] was lower than the control group [(66.27±17.90) %] ( t=2.40, P=0.027) by novel object recognition tests. Compared with the control group [(63.56±11.88) %], the alternation of experimental group [(50.99±14.17) %] was significantly decreased in Y maze tests ( t=2.33, P=0.030). Immunohistochemistry results showed microglia and astrocytes were activated in the cortex of experimental mice. Compared with the control group (1.02±0.25, 1.04±0.31), the relative mRNA expressions of Occludin decreased significantly in the meninges and brain of periodontitis mice, respectively (0.61±0.10, 0.64±0.20) ( t=3.47, P=0.010; t=2.66, P=0.024). By single-cell RNA sequencing, meninges cells were divided into 11 types, such as endothelial cells, fibroblasts, immune cells and so on. Endothelial cells were the main cell types in meninges [the control group: 26.47% (1 589/6 004), the experimental group: 26.26% (807/3 073)]. Compared with the control group [5.56% (334/6 004)], the percentage of granulocytes increased in the periodontitis mice [11.65% (358/3 073)]. Using clustering analysis to further focus on endothelial cells, GO enrichment analysis revealed differential genes were mainly related to angiogenesis, cell adhesion, apoptosis and so on. KEGG enrichment analysis revealed that differential genes were related to signaling pathways of interleukin-17, relaxin and so on. The relative mRNA expressions of Atf3 and Apold1 in meninges of periodontitis mice (0.42±0.24, 0.54±0.27) were significantly lower than the control group (1.03±0.26, 1.02±0.23) ( t=3.88, P=0.005; t=3.02, P=0.017). Conclusions:The mice chronically infected with Pg W83 occurred memory impairment, neuroinflammation and changes of barrier function. In the meninges of periodontitis mice, there were infiltration of immune cells and down-regulation expressions of Atf3 and Apold1 by single-cell RNA sequencing. Meningeal immunity and changes of barrier function may play an important role in the cognitive impairment caused by periodontitis.

Objective:To explore the repair strategy of chest radiation ulcer after radical mastectomy for breast cancer and its clinical effect.Methods:The study was a retrospective observational study. From September 2020 to September 2023, 27 female patients (aged 37-83 years) with chest radiation ulcers after radical mastectomy for breast cancer who met the inclusion criteria were admitted to Beijing Jishuitan Hospital Affiliated to Capital Medical University, of which 7 patients developed significant pain in the chest region. Various examinations were completed to accurately assess the presence of tumors and depth of radiation ulcers. After tumor recurrence was ruled out, the ulcer wounds were thoroughly debrided (the wound size after debridement was 8 cm×7 cm to 18 cm×18 cm). At the same time, pathological examination of the wound tissue and bacterial culture of the wound tissue/exudate samples were performed. The wound repair surgery was performed at the same time after debridement or one week after vacuum sealing drainage (VSD) treatment. Based on the location and size of the wound, the age and overall condition of the patient, as well as the principle of minimizing damage to the donor site, the most suitable tissue flap was selected to repair the wound. The donor site wound was transplanted with a split-thickness skin graft or sutured together. The level and tissue structure of radiation injury, and the type and size of transplanted tissue flap were recorded. The results of postoperative pathological examination of wound tissue and bacterial culture of wound tissue/exudate samples, pain relief, survival of tissue flap, and wound healing were recorded. During the follow-up, the shape of the tissue flap, whether the ulcer recurred, the wound healing of the donor site, and whether the abdominal wall hernia occurred in the donor site of the rectus abdominis myocutaneous flap were observed.Results:Radiation injury involved ribs and costal cartilage in 21 cases, ribs, sternum, and clavicle in 4 cases, and clavicle and subclavian artery in 2 cases. Twelve patients were transplanted with rectus abdominis myocutaneous flap, eight patients with latissimus dorsi myocutaneous flap, three patients with internal thoracic artery perforator flap, three patients with superior epigastric artery perforator flap, and one patient with free deep inferior epigastric perforator flap. The size of tissue flap was 14 cm×8 cm to 20 cm×20 cm. After surgery, no tumor component was found in the pathological examination of wound tissue; 25 patients were positive and 2 patients were negative in bacterial culture results of wound tissue/exudate samples; the pain of 7 patients was completely relieved. The tissue flaps of 25 patients survived completely after surgery, and the wounds healed. Two patients had partial necrosis at the tip of the rectus abdominis myocutaneous flap, which healed after debridement and tissue flap repair. The patients were followed up for 6 months to 2 years. The appearance of the tissue flaps was good, and no ulcer recurred. The linear scar was left on the donor site, and no abdominal wall hernia occurred in the donor site of the rectus abdominis myocutaneous flap.Conclusions:Thorough debridement and VSD treatment after accurate assessment of the extent of damage, and the selection of appropriate tissue flap to repair the wound based on the patient's general condition, the wound characteristics, and the principle of minimizing damage to the donor site are good repair strategies for the chest radiation ulcers after radical mastectomy for breast cancer. By using the strategies, the wounds could be closed as soon as possible, preventing ulcer recurrence and having a good prognosis.

Objective:To explore the clinical effects of chimeric perforator flaps in repairing wounds with bone or internal fixation exposure and wounds with osteomyelitis.Methods:This study was a retrospective observational study. From January 2018 to December 2022, 20 patients with wounds with bone or internal fixation exposure and wounds with osteomyelitis who met the inclusion criteria were admitted to Beijing Jishuitan Hospital Affiliated to Capital Medical University, including 19 males and 1 female, aged from 21 to 73 years. Among the 21 wounds, there were 5 wounds with bone exposure, 12 wounds with osteomyelitis, and 4 wounds with internal fixation exposure. After the debridement in the first stage, the wound area was 6 cm×3 cm to 22 cm×10 cm. Then vacuum sealing drainage was carried out for 5 to 7 days. In the second stage, the wounds were covered with pedicled chimeric medial sural artery perforator flap, pedicled chimeric posterior tibialis artery perforator flap, free chimeric perforator flap pedicled with descending branch of lateral circumflex femoral artery, free chimeric medial sural artery perforator flap or free chimeric deep circumflex iliac artery perforator flap with incision area of 7 cm×5 cm to 25 cm×12 cm. The chimeric muscle flap was used to fill and cover irregular deep cavities. The wounds in the flap donor sites were sutured directly or repaired with medium-thickness skin grafts from the thigh. The survival of flap and the healing of wound in flap donor site were observed after operation. The recurrence of infection was followed up.Results:Among the 18 free chimeric perforator flaps, 16 flaps survived successfully; one flap experienced a venous crisis on the day of surgery and survived completely after emergency exploration and re-anastomosis; another one flap had partial distal necrosis, which healed after dressing changes. All the wounds in the flap donor sites healed evenly. All 3 pedicled chimeric perforator flaps survived; one of them developed sub-flap infection but healed after debridement and bone cement placement. The wound in the donor site of 1 flap developed incision dehiscence, which healed successfully after redebridement and suturing. The donor site wounds of the rest 2 flaps healed well. During 3 to 12 months of follow-up, the patients with wounds with bone or internal fixation exposure showed no signs of abnormal exudation or infection, and no infection recurrence was observed in patients with wounds with osteomyelitis.Conclusions:The application of chimeric perforator flaps is effective in covering wounds, filling dead spaces, and controlling infection in wounds with bone or internal fixation exposure and wounds with osteomyelitis. Moreover, this method minimizes the damage to the donor site.

Objective This study aims to investigate the current status of burnout among anesthesi-ology residents,and to explore its influencing factors and potential interventions.Methods A total of 2 651 practicing anesthesiology residents from 218 hospitals nationwide were included in this study.Demographic characteristics,occupational features,and psychological resilience scores(Connor-Davidson resilience scale)were collected using a questionnaire distributed electronically.The Maslach burnout inventory-human service survey(MBI-HSS)was used to assess burnout.A comparison between groups with and without occu-pational burnout was conducted.Multiple logistic regression analysis was used to identify risk factors for burnout among anesthesiology residents.Results Out of the expected 2 651 questionnaires,1 990 valid responses were received(response rate 77.7%).The prevalence of burnout among the residents was 53.4%(1 063/1 990).Compared with residents without occupational burnout,those with burnout had a signifi-cantly higher proportion of females,working in tertiary hospitals,unmarried individuals,frequency of en-countering challenging patients,participating in on-call duty,and research tasks,and had a significantly lon-ger weekly working hours(P＜0.05).Multivariate logistic regression analysis indicated that female(OR = 1.58,95%CI 1.28-1.97,P＜0.01),longer working hours(OR = 1.62,95%CI 1.45-1.81,P＜0.01),and higher frequency of encountering challenging patients(OR = 1.11,95%CI 1.11-1.40,P＜0.01)were risk factors for occupational burnout.High levels of psychological resilience was protective factor against burnout(OR = 0.86,95%CI 0.84-0.88,P＜0.01).Conclusion The occurrence of burnout among anesthesiology residents is high.It is crucial to focus on and design practical preventive measures to en-hance psychological resilience,ensuring healthy physical and mental development of the resident community.