BACKGROUND:Ursolic acid can promote the directed differentiation of bone marrow mesenchymal stem cells into osteoblasts.However,there are few reports on whether ursolic acid has osteogenic effect on human periodontal ligament stem cells. OBJECTIVE:To investigate the effect of ursolic acid on proliferation and osteogenic differentiation of human periodontal ligament stem cells. METHODS:The human periodontal ligament stem cells were isolated and cultured.Passage 3 cells were selected and treated with ordinary medium containing different concentrations(0,1,2,4,6,8 μmol/L)of ursolic acid.After intervention for 1,3,5,7 days,the cell proliferation was detected by CCK-8 assay and the appropriate intervention concentration was screened.Passage 3 human periodontal ligament stem cells were treated with osteogenic induction solution containing 0,1,2,4 μmol/L ursolic acid,respectively.After 7 days of intervention,the mRNA expressions of alkaline phosphatase,Runx2,and osteocalcin were detected by qRT-PCR.After 14 days of intervention,the formation of mineralized nodules was observed by alizarin red staining.Passage 3 human periodontal ligament stem cells were taken and the control group was added with osteogenic induction solution;the ursolic acid group and the antagonist group were added with osteogenic induction solution containing ursolic acid(2 μmol/L)and the bone morphogenetic protein signaling pathway antagonist Noggin,respectively.The ursolic acid+antagonist group was added with osteogenic induction solution containing ursolic acid(2 μmol/L)and Noggin,the inhibitor of bone morphogenetic protein signaling pathway,and cultured for 7 days.qRT-PCR and western blot assay were used to detect the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2. RESULTS AND CONCLUSION:(1)1,2,4 μmol/L ursolic acid could promote the proliferation of human periodontal ligament stem cells.6,8 μmol/L ursolic acid could inhibit the proliferation of human periodontal ligament stem cells,and 1,2,4 μmol/L ursolic acid was selected to intervene in subsequent experiments.(2)Compared with 0 μmol/L,1,2,4 μmol/L ursolic acid could promote the expression of alkaline phosphatase,Runx2,and osteocalcin mRNA and the formation of mineralized nodules(P<0.05),and the effect of 2 μmol/L ursolic acid was the most significant.(3)Compared with the control group,the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2 in the ursolic acid group were increased(P<0.05),while mRNA and protein expressions of the above indexes were decreased in the antagonist group(P<0.05).Compared with the ursolic acid group,mRNA and protein expressions of above indexes were decreased in ursolic acid+antagonist group(P<0.05).(4)The results indicate that ursolic acid promotes osteogenic differentiation of human periodontal ligament stem cells through bone morphogenetic protein signaling pathway.

Lacking therapeutic targets highlights the crucial roles of chemotherapy and radiotherapy in the clinical management of triple-negative breast cancer (TNBC). To relieve the side effects of the chemoradiotherapy combination regimen, we design and develop a self-assembled micelle nanosystem consisting of perfluorocarbon chain-modified cisplatin prodrug. By incorporating perfluorodecalin, this nanosystem can effectively carry ozone and promote irradiation-derived reactive oxygen species (ROS) production. By leveraging the perfluorocarbon sidechain, the nanosystem exhibits efficient internalization by TNBC cells and effectively escapes from lysosomal entrapment. Under X-ray irradiation, ozone-generated ROS disrupts the intracellular redox balance, thereby facilitating the release of cisplatin in a reduction-responsive manner mediated by reduced glutathione. Moreover, oxygen derived from ozone decomposition enhances the efficacy of radiotherapy by alleviating tumor hypoxia. Notably, the combination of irradiation with ozone-loaded cisplatin prodrug nano system synergistically prompts antitumor efficacy and reduces cellular/systemic toxicity in vitro and in vivo. Furthermore, the combo regimen remodels the tumor microenvironment into an immune-favored state by triggering immunogenic cell death and relieving hypoxia, which provides a promising foundation for a combination regimen of immunotherapy. In conclusion, our nanosystem presents a novel strategy for integrating chemotherapy and radiotherapy to optimize the efficacy and safety of TNBC clinical treatment.

Abstract Alzheimer′s disease(AD) is a common neurodegenerative disease. It has been found that AD is related to various pathogenic factors such as genetics, cardiovascular and cerebrovascular disease, and excessive phosphorylation of tau protein. However, no definitive conclusions on its pathogenesis have been reached. In this paper, the research progress on the pathogenesis of AD inC.elegansmodel and the therapeutic effects of traditional Chinese medicine extracts on AD are reviewed, providing a basis for further research on the alleviating effects of Chinese medicine extracts on AD.

[This corrects the article DOI: 10.1016/j.jpha.2023.08.006.].

Objective: To investigate the impact of milk and egg supplementation on body composition and bone mineral density of rural primary school students in Yunnan Province, so as to provide a reference for developing targeted nutritional intervention strategies. Methods: In December 2023, a cluster sampling method was adopted to select students from grades one to three in four primary schools each from Jinggu and Shidian countys of Yunnan Province, as the intervention group (662 students). Additionally, two boarding primary schools were selected from each county based on the principle of matching scale and student numbers as the control group (455 students). Starting from April 2023, the intervention group received 200 mL milk and 50 g eggs during the break on school days for 8 months, while the control group maintained their usual diet behavior. Body composition was measured by using bioelectrical impedance analysis, and distal radial bone mineral density was assessed via dual energy X-ray absorptiometry in April and December 2023. The intervention effects were analyzed by using a difference in-differences approach. Results: The final measurements of body fat percentage, skeletal muscle mass and fat free mass of the intervention group and the control group of primary school students were significantly higher than the baseline values, and the net effect of milk and egg intervention on these body composition indicators was not statistically significant ( P >0.05, both before and after adjustment). In contrast, bone mineral density increased significantly by 0.02 g/cm 2 in the intervention group. The net intervention effect on bone mineral density was statistically significant ( β=0.02, 95%CI =0.00-0.04), and remained significant after model adjustment ( β=0.02, 95%CI =0.00-0.04) (both P < 0.05). Subgroup analysis showed statistically significant effects of the intervention among girls ( β=0.02, 95%CI =0.00-0.04), day students ( β=0.04, 95%CI =0.01-0.07), and students with normal nutritional status ( β=0.02, 95%CI =0.00-0.04) (all P <0.05). No significant effect of milk and egg supplementation was observed on body composition indicators (all P <0.05). Conclusions Milk and egg supplementation can improve bone mineral density among rural primary school students in Yunnan Province. It is recommended that rural school aged children should increase intake of milk and eggs to support growth and development.

Objective:To summarize the clinical characteristics and key points of diagnosis and treatment in children with TCF3::HLF fusion gene-positive acute lymphoblastic leukemia (ALL).Methods:A case series study was conducted. Clinical data of 8 children diagnosed with TCF3::HLF positive ALL at the Hematology Center of Beijing Children′s Hospital, Capital Medical University and the Hematology Oncology Department of Henan Children′s Hospital between January 2019 and January 2024 were collected. Descriptive analysis was performed on their clinical features, laboratory findings, treatment regimens and prognosis.Results:The cohort included 8 children (3 males and 5 females) with the age of 5.5 (3.5, 7.0) years. Bone pain was the primary clinical manifestation in 4 cases, with multi-site skeletal involvement in 4 cases, hypercalcemia in 5 cases, and coagulation abnormalities in 6 cases. Immunophenotyping revealed common B-cell lineage with myeloid markers in 7 cases and common B-cell phenotype in 1 case. All 8 children were positive for the TCF3::HLF fusion gene. Regarding treatment, 1 case abandoned therapy after diagnosis, while the remaining 7 cases received chemotherapy following the Chinese Children′s Leukemia Group-ALL2018 high-risk protocol. Only 1 case achieved minimal residual disease (MRD) negativity by day 33 of induction therapy. Among the 3 cases with MRD negativity before consolidation therapy, 1 case achieved it via conventional chemotherapy, while 2 cases required additional agents (venetoclax or blinatumomab). One case failed to achieve MRD negativity after consolidation therapy and later discontinued treatment (survival periods: 7months).Of the 4 cases who achieved MRD negativity after consolidation, 2 cases received conventional chemotherapy and 2 cases achieved negativity following chimeric antigen receptor T-cell therapy (CART). All 4 cases underwent hematopoietic stem cell transplantation (HSCT). Two cases in the CART combined with HSCT group survived as of the last follow-up (survival periods: 22 and 13 months). In the conventional chemotherapy combined HSCT group, 1 case relapsed and died (survival: 38 months), and 1 case died from transplant complications (survival: 11 months). The other 2 cases achieved MRD negativity before consolidation therapy but did not receive regular subsequent chemotherapy. After MRD recurrence, they underwent CART therapy without HSCT and remained alive at the last follow-up (survival periods: 49 and 12 months).Conclusions:Children with TCF3::HLF positive ALL often present with bone destruction accompanied by hypercalcemia and coagulopathy at initial diagnosis. This subtype of ALL shows poor response to conventional chemotherapy regimens, characterized by low early remission rates and high relapse risk even after HSCT. Better therapeutic outcomes have been observed with small molecule targeted drugs, immunotherapy and CART therapy.

Ovarian cancer has the highest mortality rate in female malignant tumors of reproduc-tive system,with high recurrence rate and secondary resistance to platinum-containing chemotherapy.In recent years,adoptive cell immunotherapy(ACT),as an emerging immunotherapeutic strategy,shows great potential in the treatment of ovarian cancer.Although the immunosuppressive microenvironment and limited target selection are still the main challenges facing the current ACT treatment for ovarian cancer,it is still expected that the efficacy of ACT in ovarian cancer patients can be further improved by optimizing the cell production techniques and combining multiple thera-peutic approaches.This paper aims to provide a reference for the development of innovative thera-pies for ovarian cancer by reviewing the latest research progress on the mechanism and application of ACT therapy in ovarian cancer.

Objective To investigate the effects of preoperative multidimensional pre-rehabilitation based on the concept of accelerated rehabilitation surgery(ERAS)on postoperative gastrointestinal function and psychological status in patients who received gastrointestinal surgery.Methods A total of 110 patients who underwent gastrointestinal surgery in our hospital from January 2022 to January 2024 were enrolled in this study.Patients who underwent gastrointestinal surgery from January 2022 to June 2023(n=55)were assigned into control group and offered with routine intervention,while patients from July 2023 to January 2024(n=55)were assigned into trial group and offered with postoperative multidimensional rehabilitation interventions based on ERAS.The two groups were compared in terms of recovery of gastrointestinal function,psychological state,cognitive function and the incidence of postoperative complication.Results The trial group demonstrated earlier recovery of bowel sound,flatus passage,first defecation,off-bed ambulation and nasogastric extubation than that of the control group.The trial group had significantly higher difference values of total protein,prealbumin and albumin of blood test between day-3 after surgery and the day of admission(all P<0.001).The trial group exhibited significantly difference values of scores on the patient health questionnaire-9(PHQ-9)and higher scores on the mini-mental state examination(MMSE)between day-3 after surgery and the day of admission than those in the control group(all P<0.001).The trial group was significantly lower than that of the control group(P<0.001).Conclusion Multi-dimensional pre-rehabilitation based on the ERAS can promote a rapid recovery of gastrointestinal function,improve mental status and cognitive function,and reduce complications in the patients with gastrointestinal surgery.

Objective To construct mice hepatocellular carcinoma models with different tumor immune microenvironments(TIME)and explore the differences.Methods H22 and hepa1-6 were used to construct subcutaneous transplantation tumor model of C57 mice as homologous hepatocellular carcinoma cell lines(denoted as H22 group and hepal-6 group,each n=8),and the differences of TIME were evaluated.Immunohistochemistry was used to detect and quantify the infiltration of T cells,CD4+T cells,CD8+T cells,regulatory T cells and B cells in TIME.Flow cytometry was performed to detect the differences of composition of immune cell subpopulations in peripheral blood and tumor parenchyma.Gene expression profile characteristics of tumor tissue were analyzed based on high-throughput transcriptome sequencing technology,and enrichment analyses of immune-related signaling pathways were evaluated combined with gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG).Results H22 group showed cold and hepa1-6 group showed hot TIME characteristics.The number of T cells,CD4+T cells and CD8+T cells in tumor tissue of H22 group were all lower,while the proportion of T cells,CD4+T cells and CD8+T cells in peripheral blood were all higher than those of hepa1-6 group(all P＜0.05).Compared with H22 group,up-regulated genes of tumor tissue in hepa1-6 group expressed significantly enriched in tumor immune activation-related signaling pathways.Conclusion H22 and hepa1-6 hepatocellular carcinoma models showed distinct TIME characteristics of cold and hot tumors,respectively,and the amount of immune cells in tumor tissue of the former were significantly lower than those in the latter.