Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg ^-/- Rag2 ^-/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

OBJECTIVES: To investigate the mechanism by which chitosan (CS) hydrogel loaded with human umbilical cord mesenchymal stem cell (HUVECs)-derived exosomes (hUCMSC-exos) (Exos@CS-Gel) improves diabetic wound healing. METHODS: hUCMSC-exos were extracted and Exos@CS-Gel was prepared. The effect of Exos@CS-Gel on proliferation and migration of HUVECs were evaluated using scratch wound assay and CCK-8 assay. Diabetic rat models with full-thickness skin wounds established by streptozotocin induction were randomized divided into 4 groups for treatment with Exos@CS-Gel (100 µg hUCMSC-exos dissolved in 100 µL 24% CS hydrogel), hUCMSC-exos (100 µg hUCMSC-exos dissolved in 100 µL PBS), CS hydrogel (100 µL 24% CS hydrogel), or PBS (control group). Wound healing and the therapeutic mechanisms were assessed using immunohistochemistry, HE staining, immunofluorescence, and qRT-PCR. RESULTS: In cultured HUVECs, Exos@CS-Gel treatment significantly promoted cell proliferation and migration. In the rat models of chronic diabetic wounds, the wound healing rate in Exos@CS-Gel group reached 92.7% on day 14, significantly higher than those in hUCMSC-exos group (9.12%), CS hydrogel group (16.28%), and control group (25.98%). Microvessel density and the expression levels of vascular endothelial growth factor and transforming growth factor β-1 were significantly increased in the Exos@CS-Gel group. CONCLUSIONS Exos@CS-Gel promotes survival capacity of hUCMSC-exos in vitro and accelerates diabetic wound healing in rats by promoting angiogenesis and cell proliferation.
Animals ; Wound Healing ; Humans ; Chitosan ; Exosomes ; Mesenchymal Stem Cells/cytology* ; Diabetes Mellitus, Experimental ; Rats ; Umbilical Cord/cytology* ; Hydrogels ; Human Umbilical Vein Endothelial Cells ; Cell Proliferation ; Rats, Sprague-Dawley ; Male

Objective:This paper analyzed the current situation of clinical research continuing review in China, and puts forward countermeasures to strengthen continuing review in combination with the requirements of the Measures for the Ethical Review of Life Science and Medical Research Involving Humans, so as to provide a certain reference for standardizing the ethical continuing review of research institutions.Methods:Through literature research, this paper systematically sorted out the current situation of continuing review, and analyzed many problems and related reasons in the process of continuing review of clinical research in China based on the practical experience of ethical review.Results:The requirements for continuing review in the Measures for Ethical Review of Life Science and Medical Research Involving Humans included demphasizing the implementation of continuing review, the entrusted ethics committee should be responsible for continuing review, clarifying the responsibility for continuing review of cooperative research, clarifying the responsibility of participating research institutions for continuing review, and increasing the responsibility of the ethics committee to supervise the submission of continuing review. Countermeasures to strengthen continuing review included the health authorities urging research institutions to strengthen continuing review, research institutions to increase efforts to implement continuing review, establishing a standardized continuing review process, strengthening the ethics training of researchers and other relevant personnel, establishing a multi-channel communication and consultation method between the ethics committee and researchers, strengthening the review capacity of ethics committee members, allocating a corresponding number of ethics committee staff, and using information technology to improve quality and efficiency.Conclusions:Continuing review is indispensable in the whole process of research development, and all parties should take measures to ensure the quality and efficiency of continuing review, standardize continuing review, and promote the healthy development of life science and medical research.

Objective:To analyze the current situation of the archives management of ethics committees in China, combine the requirements of the Implementation Regulations of the Archives Law of the People′s Republic of China and the ethics review regulations, and propose countermeasures to strengthen the archives management of ethics committees, thereby further standardizing the archives management of ethics committees.Methods:Through the literature research method, this study systematically reviewed the current situation of the archives management of ethics committees and analyzed its problems and causes in China in combination with related practice experiences.Results:The requirements for ethics committee archives included supervision and management, the establishment of rules and regulations, personnel, site and environment, storage period, confidentiality, and information construction. Countermeasures to strengthen the archives management of ethics committees were suggested including strict daily supervision, strengthening management awareness, establishing and improving the scientific management system and standard operating procedures, setting up independent ethics committee offices and dedicated archives, strictly implementing the confidentiality system, strengthening information construction, and improving utilization rate.Conclusions:To better construct and manage ethics committee archives, a standardized archives management system should be established to effectively evaluate the quality of ethics review and ensure the proper functions of the ethics committee.

Objective:To investigate the interactive effect of mismatch repair (MMR) protein status and adverse clinicopathological features on prognosis of stage Ⅰ-Ⅲ colon cancer.Methods:The retrospective cohort study was conducted. The clinicopathological data of 1 650 patients with colon cancer of stage Ⅰ-Ⅲ who were admitted to 7 hospitals in China from January 2016 to December 2017 were collected. There were 963 males and 687 females, aged 62(53,71)years. Patients were classified as 230 cases of MMR deficiency (dMMR) and 1 420 cases of MMR proficiency (pMMR) based on their MMR protein status. Observation indicators: (1) comparison of clinicopathological characteristics between patients of different MMR protein status; (2) analysis of factors affecting the survival outcomes of patients of dMMR; (3) analysis of factors affecting the survival outcomes of patients of pMMR; (4) interaction analysis of MMR and adverse clinicopathological features on survival outcomes. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the Mann-Whitney U test. The random forest interpolation method was used for missing values in data interpolation. Univariate analysis was conducted using the COX proportional risk regression model, and multivariate analysis was conducted using the COX stepwise regression with forward method. The coefficient of multiplication interaction effect was obtained using the interaction term coefficient of COX proportional risk regression model. Evaluation of additive interaction effects was conducted using the relative excess risk due to interaction ( RERI). Results:(1) Comparison of clinicopathological characteristics between patients of different MMR protein status. There were significant differences in age, T staging, the number of lymph node harvest, the number of lymph node harvest <12, high grade tumor between patients of dMMR and pMMR ( P<0.05). (2) Analysis of factors affecting the survival outcomes of patients of dMMR. Results of multivariate analysis showed that T staging, N staging, the number of lymph node harvest <12 were independent factors affecting the disease-free survival (DFS) of colon cancer patients of dMMR ( hazard ratio=3.548, 2.589, 6.702, 95% confidence interval as 1.460-8.620, 1.064-6.301, 1.886-23.813, P<0.05). Age and N staging were independent factors affecting the overall survival (OS) of colon cancer patients of dMMR ( hazard ratio=1.073, 10.684, 95% confidence interval as 1.021-1.126, 2.311-49.404, P<0.05). (3) Analysis of factors affecting the survival outcomes of patients of pMMR. Results of multivariate analysis showed that age, T staging, N staging, vascular tumor thrombus were independent factors affecting the DFS of colon cancer patients of pMMR ( hazard ratio=1.018, 2.214, 2.598, 1.549, 95% confidence interval as 1.006-1.030, 1.618-3.030, 1.921-3.513, 1.118-2.147, P<0.05). Age, T staging, N staging, high grade tumor were independent factors affecting the OS of colon cancer patients of pMMR ( hazard ratio=1.036, 2.080, 2.591, 1.615, 95% confidence interval as 1.020-1.052, 1.407-3.075, 1.791-3.748, 1.114-2.341, P<0.05). (4) Interaction analysis of MMR and adverse clinicopathological features on survival outcomes. Results of interaction analysis showed that the multiplication interaction effect between the number of lymph node harvest <12 and MMR protein status was significant on DFS of colon cancer patients ( hazard ratio=3.923, 95% confidence interval as 1.057-14.555, P<0.05). The additive interaction effects between age and MMR protein status, between high grade tumor and MMR protein status were significant on OS of colon cancer patients ( RERI=-0.033, -1.304, 95% confidence interval as -0.049 to -0.018, -2.462 to -0.146). Conclusions:There is an interaction between the MMR protein status and the adverse clinicopathological features (the number of lymph node harvest <12, high grade tumor) on prognosis of colon cancer patients of stage Ⅰ-Ⅲ. In patients of dMMR, the number of lymph node harvest <12 has a stronger predictive effect on poor prognosis. In patients of pMMR, the high grade tumor has a stronger predictive effect on poor prognosis.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective:To investigate the efficacy and safety of protein A immunoadsorption (PAIA) combined with rituximab (RTX) in highly sensitized patients who underwent haplo-hematopoietic stem cell transplantation (haplo-HSCT) .Methods:The clinical data of 56 highly sensitized patients treated with PAIA and RTX before haplo-HSCT at the First Affiliated Hospital of Soochow University and Soochow Hopes Hematonosis Hospital between March 2021 and June 2023 were retrospectively analyzed. The number of human leukocyte antigen (HLA) antibody types and the mean fluorescence intensity (MFI), humoral immunity, adverse reactions during adsorption, and survival within 100 days before and after adsorption were measured.Results:After receiving the PAIA treatment, the median MFI of patients containing only HLA Ⅰ antibodies decreased from 7 859 (3 209-12 444) to 3 719 (0-8 275) ( P<0.001), and the median MFI of HLA Ⅰ+Ⅱ antibodies decreased from 5 476 (1 977-12 382) to 3 714 (0-11 074) ( P=0.035). The median MFI of patients with positive anti-donor-specific antibodies decreased from 8 779 (2 697-18 659) to 4 524 (0–15 989) ( P<0.001). The number of HLA-A, B, C, DR, and DQ antibodies in all patients decreased after the PAIA treatment, and the differences were statistically significant (A, B, C, DR: P<0.001, DQ: P<0.01). The humoral immune monitoring before and after the PAIA treatment showed a significant decrease in the number of IgG and complement C3 ( P<0.001 and P=0.002, respectively). Forty-four patients underwent HLA antibody monitoring after transplantation, and the overall MFI and number of antibody types decreased. However, five patients developed new antibodies with low MFI, and nine patients continued to have high MFI. The overall survival, disease-free survival, non-recurrent mortality, and cumulative recurrence rates at 100 days post-transplantation were 83.8%, 80.2%, 16.1%, and 4.5%, respectively. Conclusions:The combination of PAIA and RTX has a certain therapeutic effect and good safety in the desensitization treatment of highly sensitive patients before haplo-HSCT.

Objective:To explore the chain mediating effect of anxiety and flow experience on perceived stress and mobile phone addiction in nursing college students.Methods:In December 2021, a cross-sectional design survey was conducted on 4 179 freshmen and sophomores in a nursing college in Heilongjiang Province. The Chinese perceived stress scale, generalized anxiety disorder-7, flow state scale, and mobile phone addiction tendency scale were selected separately to assess perceived stress, anxiety symptoms, flow experience and mobile phone addiction. SPSS 26.0 software was used for descriptive analysis, independent sample t-test, Spearman correlation analysis, and AMOS 24.0 software was used for mediating effect test. Results:(1) Among the 3 050 nursing students, there were 714(23.41%) students who were addicted to mobile phones. (2) Spearman correlation analysis indicated that perceived stress(27.31±9.56) was positively correlated with anxiety(7.00(1.00, 10.00), r=0.441, P<0.05), flow experience((12.00±3.40), r=0.517, P<0.05), and mobile phone addiction((42.42±13.05), r=0.476, P<0.05).Anxiety was positively correlated with flow experience ( r=0.430, P<0.01) and mobile phone addiction ( r=0.538, P<0.01).Flow experience was positively correlated with mobile phone addiction ( r=0.490, P<0.01). (3) Anxiety and flow experience played seperate mediating and chain mediating roles between perceived stress and mobile phone addiction, accounting for 26.06%(0.165/0.633), 23.54%(0.149/0.633) and 3.48%(0.022/0.633) of the total effect. Conclusion:Perceived stress not only directly affects the mobile phone addiction of nursing students, but also indirectly affects mobile phone addiction through the independent and chain mediating effects of anxiety and flow experience.

Objective:To explore the impact of parenting style on social anxiety among college students, and examine the mediating effect of core self-evaluation.Methods:From November 2022 to January 2023, a total of 1 126 college students in Harbin were taken as research subjects.Interaction anxiousness scale(IAS), short-egna minnen betraffende upfostran-Chinese(s-EMBU-C) and core self-evaluations scale(CSES) were used for analysis. Data were analyzed using SPSS 26.0 software for correlation analysis and analysis of variance.AMOS 27.0 software was used for mediation effect test.Results:Social anxiety (42.31±8.23) was negatively correlated with positive parenting style (5.44±1.45) ( r=-0.072, P<0.05) and core self-evaluation (32.12±6.01) ( r=-0.350, P<0.01), while positively correlated with negative parenting style (7.40±1.74)( r=0.302, P<0.01). Core self-evaluation was positively correlated with positive parenting style ( r=0.362, P<0.01) and negatively correlated with negative parenting style ( r=-0.346, P<0.01).Parent parenting styles had a significant mean direct effect on social anxiety of college students ( βpositive=0.098, βnegtive=0.222).Mediation analyses indicated that core self-evaluation played a masking role between positive parenting styles and social anxiety, with an absolute value of 90.82% for the ratio of indirect(-0.089) to direct effects(0.098).Core self-evaluation had partial mediating effect on negative parenting styles, with direct effect and indirect effect accounting for 73.03% and 26.97% of the total effect, respectively. Conclusion:Parenting style can either directly affect college students' social anxiety or indirectly through the mediating effect of core self-evaluations, with core self-evaluations playing a masking role in the positive parenting styles pathway.

Objective To observe the value of arterial phase contrast-enhanced CT radiomics model for predicting progression-free survival(PFS)of patients with small cell lung cancer(SCLC).Methods A total of 210 patients with pathology confirmed SCLC were retrospectively enrolled and randomly divided into training set(n=147)and test set(n=63)at the ratio of 7∶3.Clinical independent influence factors of PFS rate were selected with Cox proportional hazards regression.The radiomics features of tumors were extracted from arterial phase contrast-enhanced CT,and those being most relevant to PFS rate selected in training set were used to construct the radiomics model.Then Radscores were calculated,and the risks of disease progression were stratified,and PFS rates of patients with different risks were compared.A clinical-radiomics model was constructed combining clinical independent influence factors and radiomics features.The differentiation,calibration,and net benefit of each model for predicting PFS rates of SCLC patients were evaluated and compared in test set.Results Extensive stage was an independent risk factor for shorter PFS of SCLC patients(HR=1.841,95％CI[1.288,2.633],P=0.001).Five radiomics features which relevant to PFS rate were selected based on training set.The patients were categorized as low-risk(Radscore＜0.235)or high-risk(Radscore 0.235)for disease progression,and those with high-risk had lower PFS rates than the low-risk ones(P＜0.001).In test set,the area under the curve(AUC)of receiver operating characteristic curves of the clinical model,radiomics model and clinical-radiomics model for predicting PFS rate within 6 months was 0.646,0.920 and 0.931,respectively,while within 12 months was 0.591,0.917 and 0.919,respectively.The concordance index(C-index)of the radiomics model was 0.878,of the clinical-radiomics model was 0.884,both higher than that of the clinical model(C-index=0.595).Compared with clinical model,the radiomics model had net reclassification index(NRI)of 75.82％(P＜0.001)and integrated discrimination index(IDI)of 59.76％(P＜0.001),clinical-radiomics model had NRI of 78.94％(P＜0.001)and IDI of 61.13％(P＜0.001),which were not statistically different between the latter two models(both P＞0.05).DCA showed that both radiomics model and clinical-radiomics model had higher net benefit than clinical model.Conclusion Arterial phase contrast-enhanced CT radiomics model was helpful to predicting PFS rate of patients with SCLC,providing incremental information for individualized treatment.