BACKGROUND:Currently,treatment method for knee osteoarthritis includes oral medicine,joint cavity drug injection,and physiotherapy,but the curative effect is limited.Existing studies have confirmed that silicon-based bioceramics can promote cartilage and subchondral bone repair and vascular regeneration.OBJECTIVE:To explore the effect of different concentrations of silicon-based bioceramics injected into the knee joint cavity in the treatment of knee osteoarthritis in rats.METHODS:Silicon-based bioceramics-calcium silicate was prepared.Twenty-five SD rats were randomly divided into five groups,with five rats in each group.The healthy group did not receive any intervention,and the modeling group,low-dose calcium silicate group,high-dose calcium silicate group,and saline group used anterior cruciate ligament transection to establish bilateral knee osteoarthritis models.Four weeks after modeling,0.05 mL of 50 and 100 mg/mL calcium silicate solution were injected into the knee joint cavity in the low-dose calcium silicate group and high-dose calcium silicate group,respectively,and 0.05 mL of saline was injected into the knee joint cavity in the saline group,once a week for 4 consecutive weeks.In the fifth week of administration,bilateral knee joint Micro-CT detection,knee joint cartilage hematoxylin-eosin staining,and modified Mankin score were performed.RESULTS AND CONCLUSION:(1)Micro-CT quantitative analysis showed that compared with the healthy group,the volume fraction and number of trabeculae of the medial tibial plateau in the modeling group decreased(P＜0.05),and the separation of trabeculae increased(P＜0.05).Compared with the modeling group,the volume fraction and number of trabeculae of the medial tibial plateau in the low-dose calcium silicate group and the saline group increased(P＜0.05),and the separation of trabeculae decreased(P＜0.05).(2)Hematoxylin-eosin staining showed that the cartilage surface of the healthy group and the low-dose calcium silicate group was relatively smooth and flat,the chondrocytes were evenly distributed,without clustered chondrocytes,the tide line was complete,and the staining was uniform;the cartilage surface of the high-dose calcium silicate group was slightly uneven,the middle and deep cells were disordered,with a small number of clustered chondrocytes,the tide line was discontinuous,and the staining was uneven;the cartilage surface of the saline group and the modeling group was obviously rough,the cells were disordered,with a large number of clustered chondrocytes,the tide line disappeared,and the staining was uneven.The modified Mankin score of the healthy group was lower than that of the high-dose calcium silicate group,the saline group,and the modeling group(P＜0.05).The modified Mankin score of the high-dose calcium silicate group and the low-dose calcium silicate group was lower than that of the saline group and the modeling group(P＜0.05).(3)The results show that calcium silicate knee joint injection has a certain effect in the treatment of knee osteoarthritis.Compared with 100 mg/mL calcium silicate solution,50 mg/mL calcium silicate solution can promote the recovery of subchondral bone and cartilage.

BACKGROUND:Currently,treatment method for knee osteoarthritis includes oral medicine,joint cavity drug injection,and physiotherapy,but the curative effect is limited.Existing studies have confirmed that silicon-based bioceramics can promote cartilage and subchondral bone repair and vascular regeneration.OBJECTIVE:To explore the effect of different concentrations of silicon-based bioceramics injected into the knee joint cavity in the treatment of knee osteoarthritis in rats.METHODS:Silicon-based bioceramics-calcium silicate was prepared.Twenty-five SD rats were randomly divided into five groups,with five rats in each group.The healthy group did not receive any intervention,and the modeling group,low-dose calcium silicate group,high-dose calcium silicate group,and saline group used anterior cruciate ligament transection to establish bilateral knee osteoarthritis models.Four weeks after modeling,0.05 mL of 50 and 100 mg/mL calcium silicate solution were injected into the knee joint cavity in the low-dose calcium silicate group and high-dose calcium silicate group,respectively,and 0.05 mL of saline was injected into the knee joint cavity in the saline group,once a week for 4 consecutive weeks.In the fifth week of administration,bilateral knee joint Micro-CT detection,knee joint cartilage hematoxylin-eosin staining,and modified Mankin score were performed.RESULTS AND CONCLUSION:(1)Micro-CT quantitative analysis showed that compared with the healthy group,the volume fraction and number of trabeculae of the medial tibial plateau in the modeling group decreased(P＜0.05),and the separation of trabeculae increased(P＜0.05).Compared with the modeling group,the volume fraction and number of trabeculae of the medial tibial plateau in the low-dose calcium silicate group and the saline group increased(P＜0.05),and the separation of trabeculae decreased(P＜0.05).(2)Hematoxylin-eosin staining showed that the cartilage surface of the healthy group and the low-dose calcium silicate group was relatively smooth and flat,the chondrocytes were evenly distributed,without clustered chondrocytes,the tide line was complete,and the staining was uniform;the cartilage surface of the high-dose calcium silicate group was slightly uneven,the middle and deep cells were disordered,with a small number of clustered chondrocytes,the tide line was discontinuous,and the staining was uneven;the cartilage surface of the saline group and the modeling group was obviously rough,the cells were disordered,with a large number of clustered chondrocytes,the tide line disappeared,and the staining was uneven.The modified Mankin score of the healthy group was lower than that of the high-dose calcium silicate group,the saline group,and the modeling group(P＜0.05).The modified Mankin score of the high-dose calcium silicate group and the low-dose calcium silicate group was lower than that of the saline group and the modeling group(P＜0.05).(3)The results show that calcium silicate knee joint injection has a certain effect in the treatment of knee osteoarthritis.Compared with 100 mg/mL calcium silicate solution,50 mg/mL calcium silicate solution can promote the recovery of subchondral bone and cartilage.

OBJECTIVE To provide evidence for further improving the rules governing the renewal round of national centralized drug procurement with volume-based purchasing （VBP） program for insulin.METHODS Based on publicly available policy documents， selection outcomes， and interview data， policy text analysis， descriptive statistical analysis， the Wilcoxon signed-rank test， and thematic analysis were used to compare the procurement rules and selection outcomes between the initial and renewal rounds of the national VBP programs for insulin， and to examine the mechanisms linking rule adjustments to changes in selection outcomes.RESULTS Compared with the initial round， the renewal round retained the six procurement groups and 11 bidding units， reduced the maximum valid bid price by 40%， and introduced competitive bidding selection， revival selection， and a price line for Category A products. A total of 42 products were selected in the initial round and 49 in the renewal round， including 37 that remained selected， 5 that exited， and 12 that were newly selected in the renewal round. Within the same procurement groups， the price range decreased significantly in the renewal round compared with the initial round （ P ＝0.031）， whereas the difference in average price between the two was not statistically significant （ P ＝0.063）. Domestic manufacturers were more likely to enter the A1 category， whereas multinational manufacturers were more likely to remain in categories B/C. Mechanism analysis suggested that the price line shaped the boundary of selected prices， while the classification and volume-allocation rules linked manufacturers’ bidding decisions to expected procurement volumes， potentially altering bidding incentives and corresponding to changes in the distribution of selection outcomes.CONCLUSIONS The renewal round of the insulin VBP program established an interrelated mechanism involving price boundaries， volume-based incentives， and supply constraints through the use of price lines， product classification， and contracted volume allocation. These rule adjustments corresponded to changes in the structure of selected products， price distributions， and manufacturer classifications. Future policy refinement should strengthen the coordination among reasonable price ranges， volume-based incentives， and supply performance.

To summarise the clinical experience of Professor TONG Xiaolin in treating prediabetes combined with overweight or obesity using the method of relieving depression and reducing turbidity. It is believed that prediabetes belongs to the category of "spleen-heat syndrome" in traditional Chinese medicine， and its core pathogenesis is center fullness with internal heat， while obesity is the initiating factor for exacerbating center fullness and internal heat， therefore， it is of great significance to reduce the risk of diabetes by interrupting the transformation between overweight， obesity and glucose metabolism abnormality. It is proposed that the main pathogenesis of prediabetes combined with overweight or obesity is qi depression and turbidity obstruction in middle jiao， with qi depression as the root and turbidity obstruction as the cause， forming a treatment idea with the method of relieving depression and reducing turbidity as the core. In clinic， Dahuang Huanglian Xiexin Decoction （大黄黄连泻心汤） is used as the basic prescription， with a primary focus on directing the turbid downward， supplemented by regulating qi， which embodies the concept of "promoting movement through descent， then figuring out the root of spleen-heat syndrome. Furthermore， the treatment is flexibly modified based on the patient's deficiency-excess syndrome to ensure individualized therapy.

Objective:To elucidate the molecular mechanisms through which high-dose dexamethasone exerts long-term effects on bone marrow mesenchymal stem cells (BMSCs), specifically its role in suppressing osteogenic differentiation, accelerating cellular senescence, triggering the senescence-associated secretory phenotype (SASP), and inducing apoptosis.Methods:Primary rat BMSCs were isolated and treated with high-dose dexamethasone (1×10 -4 mol/L) to establish the experimental group, while untreated cells served as the control. The gene and protein expression levels of osteogenic markers, bone alkaline phosphatase (bALP) and Runt-related transcription factor 2 (Runx2), were analyzed in both groups. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-gal) staining. The expression of senescence-related markers (P16 and P21), components of the senescence-associated secretory phenotype (SASP), including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ, as well as apoptosis-related proteins (Bcl-2, Bax, and Cleaved-Caspase-3), and key factors of the Nrf2/HO-1 signaling pathway were assessed at both transcriptional and protein levels using qRT-PCR, immunofluorescence, and Western-blot analyses. These comprehensive evaluations aimed to determine the senescent state, apoptotic features, and alterations in osteogenic differentiation of BMSCs. Results:Following treatment with dexamethasone and subsequent withdrawal, both qRT-PCR and Western blot analyses indicated a significant reduction in the expression of the osteogenic markers bALP and Runx2 at both mRNA and protein levels. The proportion of SA-β-gal positive cells was markedly higher in the dexamethasone group (74.33%±6.89%) than in the control group (20.30%±1.57%, t=17.300, P<0.001). qRT-PCR analysis revealed upregulated mRNA expression of the senescence-related genes P16 and P21 after dexamethasone treatment, which was further supported at the protein level by immunofluorescence showing increased P21 expression. Western-blot results confirmed that protein expression levels of P16 and P21 were significantly elevated in the dexamethasone group (7.025±0.255 and 6.362±0.456, respectively) compared with the control group (1.016±0.115 and 0.816±0.172; both P<0.05). Furthermore, gene expression levels of the senescence-associated secretory phenotype (SASP) factors TNF-α and IL-1β were significantly increased (TNF-α: 3.539±0.599 vs. 0.742±0.095; IL-1β: 4.469±0.331 vs. 0.799±0.175; both P<0.05), and their protein expression was consistently upregulated as validated by Western-blot. Additionally, protein expression levels of TNF-α, IL-1β, and IFN-γ were significantly higher in the dexamethasone-treated group (3.476±0.932 vs. 0.945±0.095; 4.111±0.220 vs. 0.762±0.105; 2.155±0.240 vs. 0.656±0.104; all P<0.05).Western-blot analysis also demonstrated that protein expression of Nrf2 and HO-1 was significantly suppressed in the dexamethasone group (0.21±0.07 and 0.19±0.06, respectively) compared with the control group (1.13±0.15 and 0.92±0.21; P<0.05). Moreover, Western-blot analysis revealed that the expression levels of the pro-apoptotic proteins Bax and Cleaved-Caspase-3 were significantly up, regulated in the dexamethasone, treated BMSCs (Bax: 3.673±0.397 vs. 0.453±0.111; Cleaved-Caspase-3: 3.863±0.399 vs. 0.465±0.057), while the expression of the anti-apoptotic protein Bcl-2 was markedly down, regulated (0.959±0.073 vs. 2.126±0.195), with all differences being statistically significant ( P<0.05). Conclusions:High-dose dexamethasone treatment of BMSCs, followed by withdrawal of dexamethasone, induces cellular senescence and enhances the expression of the senescence-associated secretory phenotype (SASP) through suppression of the Nrf2/HO-1 signaling pathway. Concurrently, it promotes apoptosis by activating the mitochondrial apoptotic pathway, collectively leading to impaired osteogenic differentiation of BMSCs.

Objective:To explore the efficacy and feasibility of hypomethylating agent (HMA) as preventive therapy in children with high-risk acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:A retrospective cohort study. Data from 173 children who underwent allo-HSCT for high-risk AML at Children′s Hospital of Soochow University between August 2019 and April 2023 were analyzed. Participants were categorized into a trial group receiving HMA and a control group. Further classification was based on HMA courses:≥4 and <4 courses. The efficacy and safety of HMA preventive treatment after allo-HSCT were evaluated. Survival analysis was performed using the Kaplan-Meier method with Log-Rank testing, the Fine-Gray model was used to assess cumulative relapse rates and Cox regression was used to identify prognostic factors. Adverse events during HMA were descriptively analyzed.Results:Among 173 patients, there were 100 males (57.8%) and 73 females (42.2%), with the age of 81 (34,127) months. The starting time of HMA was 123 (91, 191) d post-transplant, continuing 4.0 (3.0, 6.5) courses and the follow-up period was 24 (13, 32) months. The trial group (53 cases) showed better 2-year overall survival (OS) rate ((88.6±5.6)% vs. (76.6±4.3)%, χ 2=5.00, P=0.025) and relapse-free survival (RFS) rate ((89.2±4.7)% vs. (56.2±4.8)%, χ 2=15.75, P<0.001) than control group (120 cases). The 2-year OS rates and RFS rates were similar between ≥4 courses group (31 cases) and <4 courses group (22 cases)(both P>0.05). The cumulative relapse rate in the trial group was significantly lower ((10.8±0.2)% vs. (35.2±0.2)%, χ 2=10.84, P=0.001) than control group. Among children with molecular relapse, 8 cases (8/30, 26.7%) in the control group had hematological relapse compared to 1 case (1/2) in the trial group ( χ 2=0.81, P=0.369). The differences in incidence of acute and chronic graft-versus-host disease (GVHD) were not statistically significant (all P>0.05). Cox regression analysis revealed that minimal residual disease (MRD) positivity detected by flow cytometry before allo-HSCT and chronic GVHD were independent risk factors for OS (both P<0.05).The HMA preventive treatment was an independent protective factor for RFS, while age ≥10 years and MRD positivity detected by PCR before allo-HSCT were independent risk factors for RFS (all P<0.05). In trial group, 38 cases experienced grade 3 to 4 adverse events (71.7%). Conclusion:HMA is safe as preventive treatment in post-transplant children with high-risk AML, which can reduce the relapse risk and doesn't increase the risk of GVHD.

Mental disorders frequently co-occur with other physical illnesses,becoming one of the leading causes of disability worldwide.Early diagnosis and intervention are crucial for the effective management of these disorders.Currently,biomarker studies on mental disorders predominantly concentrate on genes,blood indicators,and imaging features of the brain.There is a growing interest in objective phenotypic markers as a research focus.It is established that the retina is part of the central nervous system(CNS),which extends from the mesencephalon and develops concurrently with the brain during the embryonic period.Given the overlapping pathophysiological mechanisms between neurodegenerative diseases and mental disorders,studying the structural and functional changes in the inner layers of the retina has emerged as a new direction in mental health research.The advent of optical coherence tomography(OCT)has enabled microscopic imaging of retinal structures.OCT is capable of objectively quantifying the retinal sub-layers and offers the advantages of being non-invasive,non-contact,and high-resolution.The use of OCT to explore structural changes in the retina among individuals with schizophrenia,bipolar disorder,major depression and other psychiatric disorders has been well documented;however,there is a paucity of reviews on this topic.This review summarizes current research on retinal structural alterations in patients with mental disorders,and the results demonstrate reduced thickness in certain sub-layers of the retina structure in patients with several mental disorders,which supports that the retina structure has the potential to be a biomarker for mental disorders and offers a novel avenue for research in the diagnosis and treatment.

Objective:To investigate the value of MULTI-parametric MR imaging with flexible design (MTP) combined with microview diffusion weighted imaging (DWI) in predicting pituitary tumor invasion of cavernous sinus.Methods:This was a cross-sectional study. The clinicopathological and imaging data of 59 patients with suspected pituitary tumor who were admitted to the First Affiliated Hospital of Dalian Medical University from December 2021 to August 2024 were prospectively analyzed. According to Knosp classification, patients with pituitary tumor were divided into non-invasive group (28 cases) and invasive group (31 cases). All patients underwent MTP and microview DWI sequence scanning, and the corresponding parameter values [T 1, R 2*, T 2* and apparent diffusion coefficient (ADC)] were measured on the MTP quantitative map and ADC map at the maximum diameter level of the pituitary tumor. Independent sample t test and Mann-Whitney U test were used to compare the clinical data, quantitative parameter values and proliferation index (Ki-67) between the non-invasive group and the invasive group. Quantitative parameter values with statistically significant differences were jointly included in logistic regression to construct the model. Receiver characteristic curve and area under the curve (AUC) were used to analyze single variables and logistic model in predicting the value invasion of pituitary tumor cavernous sinus invasion. Spearman correlation was used to analyze the correlation between the quantitative values and Ki-67 level. Results:There was no significant difference in age and gender between the non-invasive group and the invasive group ( P>0.05). T 1 and T 2* values in invasion group were higher than those in non-invasion group ( Z=4.42, P<0.001; Z=3.43, P<0.001), R 2* values and ADC values in the invasion group were lower than those in the non-invasion group, and the difference was statistically significant (t=4.07, P<0.001; Z=-3.07, P=0.002). The AUC values of T 1, R 2*, T 2*, ADC, logistic model 1(T 1+R 2*+ADC) and logistic model 2(T 1+T 2*+ADC) for predicting pituitary tumor cavernous sinus invasion were 0.835, 0.767, 0.760, 0.733, 0.926 and 0.925, respectively. Correlation analysis showed that the value of pituitary tumor T 1 was positively correlated with Ki-67 ( r=0.431, P=0.002). Conclusion:Quantitative parameters of MTP sequence and microview DWI sequence can quantitatively evaluate pituitary tumor invasion of cavernous sinus, and the combination of the two sequences can significantly improve the prediction efficiency.

BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

OBJECTIVE: To investigate the effects of 4-methylcatechol (4MC) on the migration and inflammatory response in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), as well as its underlying mechanisms of action. METHODS: RA-FLS was isolated from synovial tissue donated by RA patients, and the optimal concentration of 4MC was determined by cell counting kit 8 method for subsequent experiments, and the effect of 4MC on the migratory ability of RA-FLS was evaluated via a cell scratch assay. An inflammation model of RA-FLS was induced by tumor necrosis factor α (TNF-α). Real-time fluorescence quantitative PCR and ELISA were employed to detect the gene and protein expression levels of interleukin-1β (IL-1β) and IL-6 in RA-FLS and their culture supernatants, respectively, thereby investigating the anti-inflammatory effects of 4MC. Western blot was used to examine the expressions of nuclear factor κB (NF-κB) signaling pathway-related proteins, including inhibitor of NF-κB-α (IKBα), phosphorylated (P)-IκBα, NF-κB-inducing kinase α (IKKα), P-IKKαβ, P-p65, and p65. Cellular immunofluorescence was utilized to detect the expression and localization of p65 in RA-FLS, exploring whether 4MC exerts its anti-inflammatory effects by regulating the NF-κB signaling pathway. Finally, a collagen-induced arthritis (CIA) mouse model was established. The anti-RA effect of 4MC in vivo was evaluated by gross observation and histological examination. RESULTS: 4MC inhibited RA-FLS migration in a concentration-dependent manner. In the TNF-α-induced RA-FLS inflammation model, 4MC significantly decreased the gene and protein expression levels of IL-1β and IL-6. Furthermore, 4MC markedly reduced the ratios of P-IΚBα/IΚBα, P-IKKαβ/IKKα, and P-p65/p65, thereby blocking the transcriptional activity of p65 by inhibiting its nuclear translocation. This mechanism effectively suppressed the activation of the TNF-α-mediated NF-κB signaling pathway. Animal studies demonstrated that 4MC [10 mg/(kg·day)] significantly lowered serum levels of IL-1β, IL-6, and TNF-α, and alleviated arthritis severity and bone destruction in CIA mice. CONCLUSION 4MC not only inhibits the migration of RA-FLS but also mitigates their inflammatory response by suppressing the NF-κB signaling pathway, thereby effectively exerting its anti-RA effects.
Synoviocytes/metabolism* ; Arthritis, Rheumatoid/metabolism* ; Animals ; Cell Movement/drug effects* ; Humans ; Catechols/therapeutic use* ; Fibroblasts/drug effects* ; Mice ; Tumor Necrosis Factor-alpha/pharmacology* ; Interleukin-1beta/metabolism* ; Interleukin-6/metabolism* ; Signal Transduction/drug effects* ; NF-kappa B/metabolism* ; Transcription Factor RelA/metabolism* ; Synovial Membrane/cytology* ; Cells, Cultured ; Male ; Arthritis, Experimental ; Anti-Inflammatory Agents/pharmacology* ; NF-KappaB Inhibitor alpha ; Inflammation