Intervertebral disc degeneration (IDD) is largely attributed to impaired endogenous repair. Nucleus pulposus-derived stem cells (NPSCs) senescence leads to endogenous repair failure. Small extracellular vesicles/exosomes derived from mesenchymal stem cells (mExo) have shown great therapeutic potential in IDD, while whether mExo could alleviate NPSCs senescence and its mechanisms remained unknown. We established a compression-induced NPSCs senescence model and rat IDD models to evaluate the therapeutic efficiency of mExo and investigate the mechanisms. We found that mExo significantly alleviated NPSCs senescence and promoted disc regeneration while knocking down thioredoxin (TXN) impaired the protective effects of mExo. TXN was bound to various endosomal sorting complex required for transport (ESCRT) proteins. Autocrine motility factor receptor (AMFR) mediated TXN K63 ubiquitination to promote the binding of TXN on ESCRT proteins and sorting of TXN into mExo. Knocking down exosomal TXN inhibited the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2) and activator protein 1 (AP-1). NRF2 and AP-1 inhibition reduced endogenous TXN production that was promoted by exosomal TXN. Inhibition of NRF2 in vivo diminished the anti-senescence and regenerative effects of mExo. Conclusively, AMFR-mediated TXN ubiquitination promoted the sorting of TXN into mExo, allowing exosomal TXN to promote endogenous TXN production in NPSCs via TXN/NRF2/AP-1 feed-forward circuit to alleviate NPSCs senescence and disc degeneration.

Ischemic stroke （IS） is a cerebrovascular disease caused by thrombosis or embolism that interrupts cerebral blood flow， resulting in brain tissue damage. Mitochondria serve as the primary site for energy metabolism and are also involved in key biological processes， including calcium signal regulation， reactive oxygen species generation， and apoptosis initiation. Therefore， the structural and functional integrity of mitochondrial is crucial for neuronal survival， and the mitochondrial quality control （MQC） system is fundamental for maintaining mitochondrial homeostasis. The MQC system maintains mitochondrial network homeostasis by synergistically regulating key processes such as biogenesis， dynamics balance （fusion and fission）， autophagy， oxidative stress clearance， and calcium homeostasis. However， following IS， neurons undergo pathological changes-including inflammatory responses， oxidative stress， and excitatory amino acid toxicity- due to ischemia and hypoxia. These factors collectively disrupt mitochondrial membrane potential and inhibit electron transport chain function， leading to MQC dysfunction. Recent studies have confirmed that acupuncture can restore MQC homeostasis after IS through multiple targets and pathways， specifically including promoting mitochondrial biogenesis， balancing mitochondrial fission and fusion， regulating mitochondrial autophagy， reducing oxidative stress damage， and inhibiting calcium overload. This article systematically reviews the relationship between MQC and IS， with a focus on elucidating the mechanistic basis of acupuncture-mediated IS treatment via regulating key MQC components. These findings provide a theoretical basis for the efficacy of acupuncture in IS management and offer novel perspectives for developing future stroke therapeutic strategies targeting MQC pathways.

Objective:To explore the mediating role of aging attitude and anxiety in the relationship between self-worth and depression among the elderly.Methods:From July to August 2022, a total of 536 elderly people in Shijiazhuang University for the Elderly were surveyed by the elderly self-worth scale, generalized anxiety disorder-7(GAD-7), attitudes to aging questionnaire(AAQ) and patient health questionnaire(PHQ-9). SPSS 26.0 software was used for descriptive statistics and correlation analysis.AMOS 24.0 was used to construct an intermediation model, and Bootstrap method was used for mediating effect testing.Results:(1)The score of self-worth was 101.00 (92.00, 112.00), the score of aging attitude was 92.00 (83.00, 101.75), the score of anxiety was 2.00(0, 6.00), and the score of depression was 2.00 (0, 5.00). (2)Self-worth was positively correlated with aging attitude ( r=0.67, P<0.01), while negatively correlated with anxiety ( r=-0.45, P<0.01) and depression ( r=-0.48, P<0.01). The aging attitude was negatively correlated with anxiety ( r=-0.41, P<0.01) and depression ( r=-0.41, P<0.01). Anxiety was positively correlated with depression ( r=0.71, P<0.01). (3)The indirect effect of aging attitude between self-worth and depression in the elderly was -0.016, accounting for 19.75% (-0.016/-0.081)of the total indirect effect.The indirect effect of anxiety between self-worth and depression in the elderly was -0.045, accounting for 55.56%(-0.045/-0.081) of the total indirect effect.The chain mediating effect of aging attitude and anxiety between self-worth and depression in the elderly was -0.020, accounting for 24.69%(-0.020/-0.081) of the total indirect effect. Conclusion:Aging attitude and anxiety play a chain mediating role between self-worth and depression in the elderly.

【Objective】 To confirm the role of Wnt signaling pathway in the occurrence and development of gastric cancer （GC）， establish a prognostic model composed of Wnt pathway related genes， and then evaluate the predictive value of the model. 【Methods】 We downloaded the gene expression data and survival data of GC in TCGA database， and used GSEA enrichment analysis to verify the enrichment of Wnt pathway in GC and para-cancer samples. In this study， univariable COX regression analysis and survival curve analysis were used to select the prognosis-related genes of GC. Then the multivariate COX proportional hazard regression model was used to obtain the prognostic model of Wnt signaling pathway related genes. Then， receiver operating characteristic （ROC） curve and forest plot were used to verify the clinical predictive value of the model. The model was then validated in GEO external database. Finally， by utilizing quantitative real-time PCR （qPCR）， we detected the expressions of Wnt signaling pathway related genes in 8 pairs of clinical GC and para-cancer samples. 【Results】 We downloaded 32 samples of normal para-cancer samples and 375 cancer samples and their corresponding clinical data. GSEA enrichment showed that compared with normal samples， Wnt pathway was significantly enriched in GC samples （P<0.05）. The results of univariate COX analysis showed that 13 Wnt pathway genes were closely related to the prognosis of GC patients. Multivariate COX determined that the model was multiplied and accumulated by ETV2， SERPINE1， CPZ， VPS35 and IGFBP1 and their corresponding coefficient β. The survival curve and ROC curve showed that the model could accurately predict the prognosis of GC patients， and the 1-year， 3-year， and 5-year areas under the curve （AUC） were 68.0%， 69.4% and 78.5%， respectively. Clinical univariate and multivariate COX analyses showed that the model could become an independent prognostic factor other than TNM system of GC. The external data set （GSE84437） validation results of GC showed that the model could better predict the prognosis of GC patients. qPCR results indicated that ETV2， SERPINE1， CPZ， VPS35 and IGFBP1 expressions were upregulated in GC samples compared with para-cancer samples. 【Conclusion】 This study further confirmed that Wnt pathway plays an important role in the progress of GC from the perspective of bioinformatics， and we have established a prognosis-related risk model， providing a new perspective for clinical genetic testing， targeted therapy and individualized therapy.

Objective To investigate the preventive and inhibitory effects of tumor cell lysate(TCL) combined with IL-2 on melanoma and the potential immune mechanism. Methods The B16F10 melanoma TCL cell were prepared using an ultrasonic disruptor. Twenty-four C57BL/6 mice were randomly divided into four groups which were immunized with PBS, IL-2, TCL and TCL+IL-2 for three weeks, and contra lateral tumors were implanted in the fourth week. We observed onset time of tumor and tumor size, collected peripheral blood continuously and monitored the expression of CD4⁺T and CD8⁺T cell subsets dynamically by flow cytometry. Spleen and tumor tissues of mice were also tested for CD4⁺T and CD8⁺T cell subsets by flow cytometry and immunohistochemistry, respectively. Results The preventive immunization of the TCL+IL-2 group significantly delayed the onset time of tumor (P=0.034); moreover, the tumor volume (P=0.023) and tumor weight (P=0.0015) were also significantly smaller than those in the control group. The expression of CD8⁺T cell subsets in the TCL+IL-2 group and the TCL-only group were significantly higher than that in the control group (P=0.0016, P=0.012). However, the CD4⁺T cell subsets of the TCL+IL-2 group decreased after tumor implantation, compared with the control group (P=0.0089). The expression of CD4⁺T and CD8⁺T cell subsets in spleen and tumor tissues were as same as those in peripheral blood. Conclusion The tumor vaccine of TCL combined with IL-2 could prevent the occurrence of melanoma in mouse and effectively inhibit tumor growth by activating CD8⁺T cells.

Objective:To differentiate the methamphetamine users according to the developmental stages of addictive behavior, and explore the characteristics of different stages in order to provid a theoretical reference for our clinical intervention.Methods:Take the male methamphetamine users in compulsory detoxification institute whom were admitted from September 2018 to December 2019 as research objects.All the objects were asked to complete clinical diagnosis, interview and questionnaire evaluation in one week.According to the developmental stages of addictive behavior, the subjects were divided into occasional use group ( n=51), regular use group ( n=95) and compulsive use group ( n=157).All subjects were evaluated using visual analogue scale(VAS), Barrett impulsiveness scale(BIS)and CogState scale.SPSS 20.0 software was used for statistical analysis, AVOVA or Kruskal-Wallis H test was used for group comparison.Multiple Logistic regression analysis was used to explore the factors associated with the development of addictive behavior. Results:(1)The compulsive use group had higher cumulative duration(24(8, 48), 12(4, 24), 22(10, 36)), average dose(6.6±3.8, 2.8±1.4, 4.5±3.4) and craving score(1(0, 5), 0(0, 1), 1(0, 3)) than the other two groups(all P<0.05).And individuals in compulsive use group had more previous heroin use experience(20.4%, 9.8%, 14.8%, P<0.05).The regular use group had more withdrawal times than the other two groups(1(1, 3), 1(0, 1), 1(1, 2), P<0.05).The total scores of Barrett impulsiveness scale(42.8±13.3, 34.5±13.6, 36.1±14.9) and the scores in all dimensions in the compulsive use group were significantly higher than those in the other two groups(motor impulsiveness: 37.5±15.8, 27.8±13.4, 29.2±17.8; attentional impulsiveness: 43.2±18.0, 39.4±17.0, 37.2±18.1; non-planning impulsiveness: 47.2±19.8, 38.8±18.7, 40.7±20.8; P<0.05) .In the compulsive use users, the ISL(16.50±4.87, 19.30±4.78, 18.33±4.91) and SEC(0.76±0.21, 0.89±0.22, 0.81±0.21) scores about cognitive assessment were significantly lower than other two groups(both P<0.05).(2)The results of multiple Logistic regression analysis showed that cumulative duration ( β=0.022, OR=1.022, 95% CI: 1.003-1.042), dosage( β=0.625, OR=1.869, 95% CI: 1.196-2.921), craving ( β=0.194, OR=1.214, 95% CI: 1.002-1.215), the total scores of Barrett impulse scale( β=0.036, OR=1.037, 95% CI: 1.013-1.061), scores of non-planning impulsiveness( β=0.040, OR=1.041, 95% CI: 1.004-1.038), scores of motor impulsiveness( β=0.033, OR=1.214, 95% CI: 1.001-1.068) were associated with the periodic grouping of addictions. Conclusions:Addictive behavior is a progressive process and methamphetamine users at different stages have different characteristics in substance use, impulsiveness and cognitive function.The development of addictive behavior is associated with the time, dosage and craving of substance use, as well as the personality impulsivity of users.And the compulsive users suffered more cognitive impairment than the other two groups. The methamphetamine users should be identified dynamically and targeted therapeutic intervention measures should be carried out to block the addictive process to achieve the goal of harm reduction.

Objective:To assess the therapeutic efficacy and safety of the gemcitabine combined with nedaplatin (GN) chemotherapy for metastatic human epidermal growth factor receptor-2 (HER-2) negative breast cancer patients.Methods:Forty-five patients with HER-2 negative recurrent metastatic breast cancer who had received prior adjuvant or neoadjuvant therapy with anthracycline and/or taxanes were enrolled. All the patients received GN regime from January 2014 to February 2019. The therapeutic efficacy was evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1. The adverse response was evaluated and monitored according to common terminology criteria for adverse events (CTCAE). The progression-free survival (PFS) and overall survival (OS) and prognostic factors were also analyzed.Results:All of the 45 patients received 4 course GN, 1 of them achieved complete response, 21 achieved partial response. The objective response rate was 48.9 (95% CI: 33.7%-64.1%). Grade 3-4 hematological toxicities include leukopenia occurred in 10 (22.2%) of patients, neutropenia in 13 (28.9%) patients, and thrombocytopenia in 8 (17.6%) patients. The grade 3-4 hematological toxicities mainly manifested as nausea and vomiting, and the incidence was 4.4% (2/45). Among the 45 patients, 34 died, the median PFS was 5.1 (95% CI: 3.9-6.1) months and the median OS was 17.6 (95% CI: 13.1-20.9) months. Conclusion:The combination of gemcitabine and nedaplatin is an effective and tolerable treatment for metastatic breast cancer patients previously treated with anthracyclines and/or taxanes.

Objective:To assess the therapeutic efficacy and safety of the gemcitabine combined with nedaplatin (GN) chemotherapy for metastatic human epidermal growth factor receptor-2 (HER-2) negative breast cancer patients.Methods:Forty-five patients with HER-2 negative recurrent metastatic breast cancer who had received prior adjuvant or neoadjuvant therapy with anthracycline and/or taxanes were enrolled. All the patients received GN regime from January 2014 to February 2019. The therapeutic efficacy was evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1. The adverse response was evaluated and monitored according to common terminology criteria for adverse events (CTCAE). The progression-free survival (PFS) and overall survival (OS) and prognostic factors were also analyzed.Results:All of the 45 patients received 4 course GN, 1 of them achieved complete response, 21 achieved partial response. The objective response rate was 48.9 (95% CI: 33.7%-64.1%). Grade 3-4 hematological toxicities include leukopenia occurred in 10 (22.2%) of patients, neutropenia in 13 (28.9%) patients, and thrombocytopenia in 8 (17.6%) patients. The grade 3-4 hematological toxicities mainly manifested as nausea and vomiting, and the incidence was 4.4% (2/45). Among the 45 patients, 34 died, the median PFS was 5.1 (95% CI: 3.9-6.1) months and the median OS was 17.6 (95% CI: 13.1-20.9) months. Conclusion:The combination of gemcitabine and nedaplatin is an effective and tolerable treatment for metastatic breast cancer patients previously treated with anthracyclines and/or taxanes.

Space reduction after the premature loss of the second primary molars is one of the important factors affecting the occurrence of malocclusion, often increasing the demand for orthodontic treatment. It has great significance to select and apply appropriate appliances to maintainthe space soon after the premature loss of the second primary molars. The space should be maintained until the adjacent teeth and the successors erupt successfully. This review summarizes the selection and clinical application of the space maintainer for the premature loss of the second primary molars in different periods, to improve dentists′ awareness of the importance of space maintainers and to provide advises for clinical choices.

The widespread application of next generation sequencing (NGS) in clinical settings has enabled testing, diagnosis, treatment and prevention of genetic diseases. However, many issues have arisen in the meanwhile. One of the most pressing issues is the lack of standards for reporting genetic test results across different service providers. The First Forum on Standards and Specifications for Clinical Genetic Testing was held to address the issue in Shenzhen, China, on October 28, 2017. Participants, including geneticists, clinicians, and representatives of genetic testing service providers, discussed problems of clinical genetic testing services across in China and shared opinions on principles, challenges, and standards for reporting clinical genetic test results. Here we summarize expert opinions presented at the seminar and report the consensus, which will serve as a basis for the development of standards and guidelines for reporting of clinical genetic testing results, in order to promote the standardization and regulation of genetic testing services in China.