Objective To explore the effect and possible mechanism of aerobic exercise and empagliflozin(EMPA)on isoproterenol(ISO)-induced pathological cardiac remodeling.Methods Mice were divided randomly into control(Con),ISO,exercise(EX)+ISO,EMPA+ISO,and EX+EMPA+ISO groups.Mice in the EX groups were trained continuously for 6 weeks,mice in the EMPA groups were gavaged continuously for 4 weeks,and mice in the ISO groups were injected subcutaneously with ISO for 7 days before dissection.After euthanasia,the whole heart mass index,left heart mass index,heart mass to tibial length ratio,and left heart mass to tibial length ratio were calculated by weighing and measuring.Pathological changes,collagen fiber deposition,and myocardial cell cross-sectional area in the hearts were detected by hematoxylin and eosin,Sirius red,and wheat germ agglutinin staining.The expression levels of genes and proteins related to cardiac fibrosis and hypertrophy,macrophage infiltration,ferroptosis,and the phosphoinositide 3-kinase(PI3K)/AKT pathway were examined by quantitative reverse transcription-polymerase chain reaction,Western Blot,and immunofluorescence staining.Results(1)The whole heart mass index,left heart mass index,heart mass to tibial length ratio,and left heart mass to tibial length ratio showed downward trends in the EX+ISO group compared with the ISO group.The whole heart mass index and left heart mass index were significantly decreased in the EMPA+ISO group(P＜0.01,P＜0.05),and the heart mass to tibial length ratio and left heart mass to tibial length ratio were both down regulated.Mice in the EX+EMPA+ISO group had a significant decrease in whole heart mass index(P＜0.05),and the other three indicators were all down-regulated.(2)Myocardial cells were more orderly in the three intervention groups compared with the ISO group,with significant reductions in inflammatory cell infiltration(P＜0.01),the area of cardiac fibrosis,and the cross-sectional area of myocardial cells(P＜0.001).(3)The mRNA and protein expression levels of Col 1 and Anp were significantly reduced in the three intervention groups compared with the ISO group(P＜0.05,P＜0.01,P＜0.001).Col 3 mRNA expression significantly reduced in the EMPA+ISO and EX+EMPA+ISO groups(P＜0.05),and showed a downward trend in the EX+ISO group.(4)Macrophage infiltration and IL-6 mRNA levels were significantly reduced in the three intervention groups compared with the ISO group(P＜0.05,P＜0.01,P＜0.001).(5)Nrf2 and Gpx4 mRNA levels were upregulated in the three intervention groups compared with the ISO group,with a significant increase in GPX4 protein expression(P＜0.01,P＜0.001)and a significant decrease in HO-1 protein expression(P＜0.01,P＜0.001).(6)Pi3k mRNA levels were significantly increased in the EX+ISO group compared with the ISO group(P＜0.05),and Pi3k mRNA was upregulated in the EMPA+ISO and EX+EMPA+ISO groups.Akt mRNA levels showed an upward trend in the three intervention groups.PI3K and phospho-AKT protein levels were significantly increased in the EX+ISO group(P＜0.01,P＜0.05),and showed an increasing trend in the EMPA+ISO and EX+EMPA+ISO groups.Conclusions Moderate intensity aerobic exercise,the novel hypoglycemic drug EMPA,and their combination can alleviate ISO-induced pathological cardiac remodeling,possibly via a mechanism related to activation of the PI3K/AKT signaling pathway and inhibition of cardiac ferroptosis.

BACKGROUND:Tissue engineering is considered an ideal treatment for growth plate regeneration.However,most of the current research on regenerative tissue engineering is the traditional scaffold-based strategy.As the limitations of traditional scaffolds are gradually revealed,the research direction is gradually diversifying. OBJECTIVE:To summarize the application of scaffold-based and scaffold-free strategies in the treatment of growth plate cartilage regeneration and their respective advantages and disadvantages. METHODS:The relevant articles were searched from PubMed,Wiley,and Elsevier.The search terms were"growth plate injury,regeneration,tissue engineering,scaffold,scaffold-free,biomimetic,cartilage"in English.The time was limited from 1990 to 2023.Finally,104 articles were included for review. RESULTS AND CONCLUSION:The biomimetic strategy is to reduce the cell composition,biological signals and unique mechanical properties of each region to the greatest extent by simulating the unique organizational structure of the growth plate,so as to build a biomimetic microenvironment that can promote tissue regeneration.Therefore,the design of a biomimetic scaffold is to simulate the original growth plate as far as possible in terms of composition,structure and mechanical properties.Although some results have been achieved,there is still the problem of the unstable regeneration effect.The scaffold-free strategy believes that the limitations of scaffolds will have adverse effects on regenerative therapy.Therefore,the design of scaffold-free constructs relies as much as possible on the ability of cells to generate and maintain extracellular matrix without interfering with cell-cell signals or introducing exogenous substances.However,there are some problems,such as poor stability,low mechanical strength and greater difficulty in operation.Biomimetic strategy and scaffold-free strategy have different emphases,advantages and disadvantages,but they both have positive effects on growth plate cartilage regeneration.Therefore,subsequent studies,whether adopting a biomimetic strategy or a scaffold-free strategy,will focus on the continuous optimization of existing technologies in order to achieve effective growth plate cartilage regeneration therapy.

Objective:To study the distribution and antibiotics resistance of the main pathogens of neonatal purulent meningitis in different regions of China.Methods:A retrospective descriptive clinical epidemiological study was conducted in children with neonatal purulent meningitis which admitted to 18 tertiary hospitals in different regions of China between January 2015 to December 2019. The test results of blood and cerebrospinal fluid, and drug sensitivity test results of the main pathogens were collected. The distributions of pathogenic bacteria in children with neonatal purulent meningitis in preterm and term infants, early and late onset infants, in Zhejiang Province and other regions outside Zhejiang Province, and in Wenzhou region and other regions of Zhejiang Province were analyzed. The chi-square test was used for statistical analysis.Results:A total of 210 neonatal purulent meningitis cases were collected. The common pathogens were Escherichia coli ( E. coli)(41.4%(87/210)) and Streptococcus agalactiae ( S. agalactiae)(27.1%(57/210)). The proportion of Gram-negative bacteria in preterm infants (77.6%(45/58)) with neonatal purulent meningitis was higher than that in term infants (47.4%(72/152)), and the difference was statistically significant ( χ2=15.54, P=0.001). There were no significant differences in the constituent ratios of E. coli (36.5%(31/85) vs 44.8%(56/125)) and S. agalactiae (24.7%(21/85) vs 28.8%(36/125)) between early onset and late onset cases (both P>0.05). The most common pathogen was E. coli in different regions, with 46.7%(64/137) in Zhejiang Province and 31.5%(23/73) in other regions outside Zhejiang Province. In Zhejiang Province, S. agalactiae was detected in 49 out of 137 cases (35.8%), which was significantly higher than other regions outside Zhejiang Province (11.0%(8/73)). The proportions of Klebsiella pneumoniae, and coagulase-negative Staphylococcus in other regions outside Zhejiang Province (17.8%(13/73) and 16.4%(12/73)) were both higher than those in Zhejiang Province (2.9%(4/137) and 5.1%(7/137)). The differences were all statistically significant ( χ2=14.82, 12.26 and 7.43, respectively, all P<0.05). The proportion of Gram-positive bacteria in Wenzhou City (60.8%(31/51)) was higher than that in other regions in Zhejiang Province (38.4%(33/86)), and the difference was statistically significant ( χ2=6.46, P=0.011). E. coli was sensitive to meropenem (0/45), and 74.4%(32/43) of them were resistant to ampicillin. E. coli had different degrees of resistance to other common cephalosporins, among which, cefotaxime had the highest resistance rate of 41.8%(23/55), followed by ceftriaxone (32.4%(23/71)). S. agalactiae was sensitive to penicillin, vancomycin and linezolid. Conclusions:The composition ratios of pathogenic bacteria of neonatal purulent meningitis are different in different regions of China. The most common pathogen is E. coli, which is sensitive to meropenem, while it has different degrees of resistance to other common cephalosporins, especially to cefotaxime.

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.

BACKGROUND: The effect of intra-operative chemotherapy (IOC) on the long-term survival of patients with colorectal cancer (CRC) remains unclear. In this study, we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection. METHODS: 1820 patients were recruited, and 1263 received IOC and 557 did not. Clinical and demographic data were collected, including overall survival (OS), clinicopathological features, and treatment strategies. Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models. A regression model was developed to analyze the independent effects of IOC. RESULTS: Proportional hazard regression analysis showed that IOC (hazard ratio [HR]=0.53, 95% confidence intervals [CI] [0.43, 0.65], P  < 0.001) was a protective factor for the survival of patients. The mean overall survival time in IOC group was 82.50 (95% CI [80.52, 84.49]) months, and 71.21 (95% CI [67.92, 74.50]) months in non-IOC group. The OS in IOC-treated patients were significantly higher than non-IOC-treated patients ( P  < 0.001, log-rank test). Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model (HR=0.53, 95% CI [0.43, 0.65], P  < 0.001), model 2 (adjusted for age and gender, HR=0.52, 95% CI [0.43, 0.64], P  < 0.001), and model 3 (adjusted for all factors, 95% CI 0.71 [0.55, 0.90], P  = 0.006). The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II (HR = 0.46, 95% CI [0.31, 0.67]) or III disease (HR=0.59, 95% CI [0.45, 0.76]), regardless of pre-operative radiotherapy (HR=0.55, 95% CI [0.45, 0.68]) or pre-operative chemotherapy (HR=0.54, 95% CI [0.44, 0.66]). CONCLUSIONS: IOC is an independent factor that influences the survival of CRC patients. It improved the OS of patients with stages II and III CRC after radical surgery. TRIAL REGISTRATION chictr.org.cn, ChiCTR 2100043775.
Humans ; Fluorouracil/therapeutic use* ; Leucovorin/therapeutic use* ; Colorectal Neoplasms/pathology* ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Proportional Hazards Models ; Prognosis

Objective:To summarize and evaluate the target and dose design of 125I seed brachytherapy treatment plan of pediatric borderline tumor in head neck region. Methods:Eleven patients underwent definitive 125I brachytherapy or combined with surgery in Peking University Hospital of Stomatology from January 2010 to December 2018 were retrospective analyzed. The target region was set by extending the tumor gross region by 0.5 to 1.0 cm. The prescription dose and activity ranged from 80 to 120 Gy and 18.5 MBq, respectively. The treatments were performed according to the plan under general anesthesia. Response and toxic reaction were recorded during follow-up. The preoperative and postoperative dosimetric results were compared; and the local control rate, objective response rate, complete response rate and acute toxic reaction rate were calculated. Results:There was no statistically significant difference between preoperative and postoperative dosimetric results ( P>0.05). The follow-up time ranged from 33 to 131 months, with a median of 48 months. The local control rate, objective response rate, complete response rate and acute toxic reaction rate were 100%, 100%, 71.4% and 81.8%, respectively. Conclusions:Under well-designed target and dose, 125I brachytherapy for treatment of pediatric borderline tumor in head neck region would bring ideal therapeutic and toxic outcomes, and could be regarded as a feasible therapy.

Epiphyseal plate injury in children is very common, which can be caused by fracture, infection, malignant tumors, iatrogenic injury or other causes.Growth arrest and angulation or rotation deformity after epiphyseal plate injury would seriously affect the physical and mental health of children.At present, the success rate of bone bridge resection combined with corresponding material filling is super low.The construction of bioactive epiphyseal cartilage using cartilage tissue engineering technology has become a new research direction for the treatment of epiphyseal plate injury in children.Therefore, this review focuses on the current research on the regeneration of epiphyseal cartilage from the perspective of 3 elements of tissue engineering: seed cells, growth factors, and tissue engineering scaffolds.

Objective: To investigate the feasibility and dosimetric characteristics of using dual-arc volumetric modulated arc therapy and multiple partial-arc VMAT for T3 lung cancer. Methods: From June 2016 to May 2018, thirteen lung cancer patients with large planning target volume were replanned with dual full arcs VMAT(F-VMAT) and six partial-arc s VMAT(P-VMAT)on RayStation v4.5 RayArc function.PTV volume median was 550.9cm³(ranged 402.2-834.8cm³) and to a prescribed dose of 60 Gy in 30 fractions.Equivalent target coverage was required for all plans, and clinical goals were evaluated using various dose-volume metrics.These included PTV dose conformity, mean lung/heart dose, lung V₅, V₁₀, V₂₀, V₃₀, heart V₃₀ and V₄₀, and Dmax of spinal canal.The total monitor units (MUs) were also examined. Results: All VMAT plans satisfied the treatment criteria.F-VMAT achieved better homogeneity index(HI) and MUs than P-VMRT(t=-3.904, P=0.002), and the conformal number(CN) of tumor volumes was likely clinically indistinguishable.However, F-VMAT significantly reduced lung V₅, V₁₀ and mean lung dose[V5: (51.31±5.36)% vs.(43.44±5.28)%, t=6.908, P=0.00; V10: (38.34±3.26)% vs.(34.05±3.74)%, t=4.632, P=0.001; Dmean: (1 449±117.19)cGy vs.(1 375.38±148.98)cGy, t=4.93, P=0.00], and heart dosimetric parameters were also observed in favor of P-VMRT[V₃₀: (20.6±10.4)% vs.(16.4±8.9)%, t=3.822, P=0.02; V₄₀: (14.6±7.5)% vs.(11.88±7.1)%, t=3.096, P=0.009; Dmean: (1 442.9±651.2)cGy vs.(1 263.5±605.6)cGy, t=3.986, P=0.02], and there were no statistically significant differences in lung V₂₀, V₃₀ and spinal cord Dmax between the two groups(all P>0.05). Conclusion VMAT is an effective treatment for stage T3 lung cancer patients.The primary advantage of P-VMAT was the reduction in low dose area and decreased risk of symptomatic radioactive lung injury.It may be a priority for pulmonary malignancy patients with the large planning target volume.

Objective To investigate the effects of mesenchymal stem cells(MSCs)on the pathological structure and cytokine expression of lung tissue in septic model of diabetic rats. Methods Diabetic rats were ran-domly divided into control,sham-operation,sepsis and MSC-treated groups. The diabetic model was induced by high-sucrose and high-fat diet combined with streptozotocin and cecal ligation and puncture. The pathological changes of lung tissue were observed at 6,12,18 and 24 hours after operation respectively,and the expression of SP-D,TNF-α,IFN-γ and IL-10 in lungs were measured.Results The levels of SP-D,TNF-α and IFN-γ in lung tissue increased gradually with the elongation of time after CLP. The expression of IL-10 in lung tissue increased and then decreased. The trend of MSC intervention increased the content of SP-D,TNF-α and IL-10 in the lung tissue of non-diabetic septic rat model and reduced the content of IFN-γ.MSC intervention reduced the SP-D and TNF-α content.The intervention of MSC had no effect on the content of IFN-γ in the lung tissue of diabetic septic rats.However,it increased and then decreased the content of IL-10.Conclusions The model of sepsis in diabetic rats can be established by feeding combined high-sugar and high-fat diet and streptozotocin combined with cecal ligation and puncture. Mesenchymal stem cells affect sepsis inflammation and organ damage. But its specific role depends on the immune status and the timing of mesenchymal stem cell selection.