[摘 要] 目的：探究环状核酸适配体-药物偶联物（ApDC）联合抗CD19嵌合抗原受体T/NK（CAR19-T/NK）细胞对Nalm6白血病细胞杀伤效果的增强作用。方法： 用数据库分析寻找白血病细胞的标志物蛋白酪氨酸激酶7（PTK7），设计合成靶向PTK7的核酸适配体sgc8，进一步合成两种ApDC：核酸适配体偶联吉西他滨（sgc8-GEM）和环状核酸适配体偶联吉西他滨（C-sgc8-GEM），琼脂糖凝胶电泳分析其稳定性。用CD19-CAR过表达慢病毒转染人外周血T/NK细胞构建CAR19-T和CAR19-NK细胞，流式细胞术检测sgc8与Nalm6细胞的结合力，CCK-8法和流式细胞术检测sgc8-GEM、C-sgc8-GEM，以及其分别与CAR19-T和CAR19-NK细胞联合应用对Nalm6细胞的杀伤能力。结果： PTK7 mRNA在白血病细胞中呈高表达（P < 0. 01）；C-sgc8-GEM比sgc8-GEM稳定性更高，与GEM比较，sgc8-GEM更能有效杀伤Nalm6细胞（P < 0.001）；C-sgc8-GEM或sgc8-GEM分别与CAR19-T/NK细胞联合应用比单独用C-sgc8-GEM、sgc8-GEM、CAR19-T/NK细胞对Nalm6细胞的毒性均更强（P < 0.001）。结论：成功建立环状ApDC与CAR19-T/NK细胞联合应用法，通过双靶点有效提高了对Nalm6细胞的毒性，为急性淋巴细胞白血病提供了新的治疗思路。

Chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) are both chronic progressive respiratory diseases that cannot be completely cured. COPD is characterized by irreversible airflow limitation, chronic airway inflammation, and gradual decline in lung function, whereas PH is characterized by pulmonary vasoconstriction, remodeling, and infiltration of inflammatory cells. These diseases have similar pathological features, such as vascular hyperplasia, arteriolar contraction, and inflammatory infiltration. Despite these well-documented observations, the exact mechanisms underlying the occurrence and development of COPD and PH remain unclear. Evidence that mitochondrial dynamics imbalance is one major factor in the development of COPD and PH. Mitochondrial dynamics is precisely regulated by mitochondrial fusion proteins and fission proteins. When mitochondrial dynamics equilibrium is disrupted, it causes mitochondrial and even cell morphological dysfunction. Mitochondrial dynamics participates in various pathological processes for heart and lung disease. Mitochondrial dynamics may be different in the early and late stages of COPD and PH. In the early stages of the disease, mitochondrial fusion increases, inhibiting fission, and thereby compensatorily increasing adenosine triphosphate (ATP) production. With the development of the disease, mitochondria decompensation causes excessive fission. Mitochondrial dynamics is involved in the development of COPD and PH in a spatiotemporal manner. Based on this understanding, treatment strategies for mitochondrial dynamics abnormalities may be different at different stages of COPD and PH disease. This article will provide new ideas for the potential treatment of related diseases.
Humans ; Mitochondrial Dynamics/physiology* ; Pulmonary Disease, Chronic Obstructive/metabolism* ; Hypertension, Pulmonary/metabolism* ; Mitochondria/metabolism* ; Animals

Objective: To investigate the impact of childhood traumatic experiences on individual risktaking decisions in early adulthood using functional nearinfrared spectroscopy (fNIRS), so as to provide the reference for clarifying the brain mechanisms underlying the impact of childhood trauma on individual risky decision. Methods: From December 2023 to March 2024, 28 children with childhood trauma experiences (trauma group) and 32 healthy college students (control group) were selected from Jining Medical University by a combination of stratified descent and convenient sampling methods. All subjects participated in the Iowa Game task fNIRS scanning. The brain activation, functional connectivity, graph theory properties (degree centrality, betweenness centrality, and local efficiency), and Receiver Operating Characteristic (ROC) analysis were performed by using preprocessing fNIRS data. Results: Compared with control group, trauma group showed significantly fewer choice times in the inferior deck (Z=-0.88), and showed significantly decreased activation levels in the right frontalpolar (Z=-2.59), as well as showed significant decreased functional connectivity between left dorsolateral prefrontal and in right dorsolateral prefrontal (Z=-3.78), and between left dorsolateral prefrontal cortex and the right frontal pole (Z=-3.68)(P<0.05). The central index of right inferior frontal gyrus in the trauma group was higher than that in the control group, while the central index of left and right dorsolateral frontal lobes was lower than that in the control group (Z=2.13, -2.53, -2.12, P<0.05). The centrality index of the right inferior frontal gyrus in the trauma group was higher than that in the control group (Z=2.47, P<0.05). The local efficiency indicators of the right inferior frontal gyrus, left and right frontal pole in the trauma group were higher than those in the control group (Z=2.51, 2.17, 2.53, P<0.05). The results of the ROC curve analysis showed that the local efficiency achieved the highest area under the curve (AUC=0.68). Conclusions Young adults with childhood trauma experience tend to choose lower loss, and the frontal pole shows a lack of activation in the whole process of risk decision performance. The abnormalities in the brain connectivity and network properties might be the neural basis of excessive defense mechanisms that childhood trauma leads to risky decisions.

Objective:To explore the risk factors for different severities of epiphyseal injury caused by distal tibial fractures in adolescents.Methods:A retrospective analysis was conducted on 195 children with distal tibial fractures accompanied by epiphyseal injuries who were admitted to the Honghui Hospital Affiliated to Xi'an Jiaotong University from January 2018 to December 2023. Among them, there were 132 males and 63 females; the age was 11.7±2.1 years (range, 5-15 years). Among them, 91 cases were on the left side and 104 cases were on the right side. Salter-Harris classification of epiphyseal injuries: there were 42 cases of type I, 90 cases of type II, 34 cases of type III, 26 cases of type IV, and 3 cases of type V. Causes of injury: 37 cases were sports injuries, 29 cases were traffic accident injuries, 120 cases were fall injuries, and 9 cases were fall from height injuries. Dias-Tachdjian classification of injury mechanisms: there were 65 cases of supination-adduction type, 59 cases of supination-plantar flexion type, 35 cases of supination-external rotation type, and 36 cases of pronation-abduction-external rotation type. Among them, 72 cases were complicated with fibular fractures, and 56 cases were accompanied by periosteum incarceration. The age, gender, side of injury, body mass index, cause of injury, presence or absence of fibular fracture, and injury mechanism of children with each type of Salter-Harris injury were compared. The indicators with statistically significant differences were included in the multiple logistic regression analysis to determine the independent risk factors for each type of Salter-Harris injury.Results:The ages of patients with type I-IV were 10.70±2.77, 12.18±1.70, 11.32±2.08, 12.35±1.19, and 11.67±2.08 years old respectively, and the difference was statistically significant ( F=4.794, P=0.001). The body mass indexes were 11.90±3.84, 21.30±4.48, 21.41±4.08, 22.42±3.74, and 24.32±4.82 kg/m 2 respectively, and the difference was statistically significant ( F=1.914, P=0.009). The numbers of cases of sports injuries/traffic accident injuries/fall injuries/fall-from-height injuries were 6/7/23/6, 17/12/59/2, 6/5/22/1, 7/4/15/0, and 1/1/1/0 respectively, and the difference was statistically significant ( P=0.032). The numbers of cases of supination-adduction/pronation-abduction-external rotation/supination-plantar flexion/supination-external rotation were 21/6/9/6, 21/16/37/16, 19/6/8/1, 4/7/4/11, and 0/1/1/1 respectively, and the difference was statistically significant ( P=0.001). The numbers of cases of periosteum incarceration (none/yes) were 32/10, 54/36, 27/7, 25/1, and 1/2 respectively, and the difference was statistically significant (χ 2=17.156, P=0.002). There was no statistically significant difference in gender, side of injury, and presence or absence of fibular fracture among patients with each type of epiphyseal injury ( P>0.05). Age, body mass index, cause of injury, injury mechanism, and periosteum incarceration were included in the multiple logistic regression analysis. The results showed that age [ OR=1.337, 95% CI (1.097, 1.628), P=0.004], the supination varus type of the injury mechanism [ OR=0.257, 95% CI (0.075, 1.013), P=0.015] in the Salter-Harris type II, and the supination plantar flexion type of the injury mechanism [ OR=0.154, 95% CI (0.027, 0.872), P=0.034] in the Salter-Harris type IV were independent risk factors for the severity of epiphyseal injury caused by distal tibial fractures in adolescents. Conclusion:The severity of distal tibial fractures accompanied by epiphyseal injuries in adolescents is related to multiple factors such as age, body mass index, cause of injury, injury mechanism, and periosteum incarceration. For every one-year increase in age, the risk of epiphyseal injury in children with Salter-Harris type II is 1.337 times higher than that in those with type I. The type I epiphyseal injury caused by supination varus injury is 3.891 times that of type II injury, and the type I epiphyseal injury caused by supination plantar flexion injury is 6.493 times that of type IV injury.

Objective:To explore the risk factors for different severities of epiphyseal injury caused by distal tibial fractures in adolescents.Methods:A retrospective analysis was conducted on 195 children with distal tibial fractures accompanied by epiphyseal injuries who were admitted to the Honghui Hospital Affiliated to Xi'an Jiaotong University from January 2018 to December 2023. Among them, there were 132 males and 63 females; the age was 11.7±2.1 years (range, 5-15 years). Among them, 91 cases were on the left side and 104 cases were on the right side. Salter-Harris classification of epiphyseal injuries: there were 42 cases of type I, 90 cases of type II, 34 cases of type III, 26 cases of type IV, and 3 cases of type V. Causes of injury: 37 cases were sports injuries, 29 cases were traffic accident injuries, 120 cases were fall injuries, and 9 cases were fall from height injuries. Dias-Tachdjian classification of injury mechanisms: there were 65 cases of supination-adduction type, 59 cases of supination-plantar flexion type, 35 cases of supination-external rotation type, and 36 cases of pronation-abduction-external rotation type. Among them, 72 cases were complicated with fibular fractures, and 56 cases were accompanied by periosteum incarceration. The age, gender, side of injury, body mass index, cause of injury, presence or absence of fibular fracture, and injury mechanism of children with each type of Salter-Harris injury were compared. The indicators with statistically significant differences were included in the multiple logistic regression analysis to determine the independent risk factors for each type of Salter-Harris injury.Results:The ages of patients with type I-IV were 10.70±2.77, 12.18±1.70, 11.32±2.08, 12.35±1.19, and 11.67±2.08 years old respectively, and the difference was statistically significant ( F=4.794, P=0.001). The body mass indexes were 11.90±3.84, 21.30±4.48, 21.41±4.08, 22.42±3.74, and 24.32±4.82 kg/m 2 respectively, and the difference was statistically significant ( F=1.914, P=0.009). The numbers of cases of sports injuries/traffic accident injuries/fall injuries/fall-from-height injuries were 6/7/23/6, 17/12/59/2, 6/5/22/1, 7/4/15/0, and 1/1/1/0 respectively, and the difference was statistically significant ( P=0.032). The numbers of cases of supination-adduction/pronation-abduction-external rotation/supination-plantar flexion/supination-external rotation were 21/6/9/6, 21/16/37/16, 19/6/8/1, 4/7/4/11, and 0/1/1/1 respectively, and the difference was statistically significant ( P=0.001). The numbers of cases of periosteum incarceration (none/yes) were 32/10, 54/36, 27/7, 25/1, and 1/2 respectively, and the difference was statistically significant (χ 2=17.156, P=0.002). There was no statistically significant difference in gender, side of injury, and presence or absence of fibular fracture among patients with each type of epiphyseal injury ( P>0.05). Age, body mass index, cause of injury, injury mechanism, and periosteum incarceration were included in the multiple logistic regression analysis. The results showed that age [ OR=1.337, 95% CI (1.097, 1.628), P=0.004], the supination varus type of the injury mechanism [ OR=0.257, 95% CI (0.075, 1.013), P=0.015] in the Salter-Harris type II, and the supination plantar flexion type of the injury mechanism [ OR=0.154, 95% CI (0.027, 0.872), P=0.034] in the Salter-Harris type IV were independent risk factors for the severity of epiphyseal injury caused by distal tibial fractures in adolescents. Conclusion:The severity of distal tibial fractures accompanied by epiphyseal injuries in adolescents is related to multiple factors such as age, body mass index, cause of injury, injury mechanism, and periosteum incarceration. For every one-year increase in age, the risk of epiphyseal injury in children with Salter-Harris type II is 1.337 times higher than that in those with type I. The type I epiphyseal injury caused by supination varus injury is 3.891 times that of type II injury, and the type I epiphyseal injury caused by supination plantar flexion injury is 6.493 times that of type IV injury.

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Male ; Humans ; Middle Aged ; Asparaginase/therapeutic use* ; Prognosis ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Etoposide ; Cyclophosphamide ; Methotrexate/therapeutic use* ; DNA/therapeutic use* ; Treatment Outcome

Aim To investigate the molecular mechanisms of alcohol extracts of Euphorbia fischeriana steud. against hepatocellular carcinoma (HCC) through a combination of network pharmacology analysis and experimental validation. Methods The active ingredients and targets of alcohol extracts of Euphorbia fischeriana steud. were determined through TCMSP, Swiss ADME, Swiss Target Prediction database and references. The databases DisGeNET and GeneCards were employed to screen potential HCC-related genes. Venny platform, STRING platform and Cytoscape software were applied to construct active ingredient-target-disease and protein-protein interaction (PPI) network maps. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the DAVID database. To assess the effects of Euphorbia fischeriana steud. alcohol extracts on BEL-7402 cells, the proliferation and apoptosis were detected by CCK-8, EdU and flow cytometry assays, and the related protein levels of JAK2/STAT3 pathway were analyzed by Western blot. Additionally, H22 hepatocellular carcinoma mouse model was used to evaluate the in vivo efficacy of Euphorbia fischeriana steud. alcohol extracts. Results A total of 916 HCC targeted genes, 30 active ingredients containing the related 567 potential targeted genes, and 115 intersection targets of disease and compounds were obtained. KEGG enrichment analysis identified JAK2/STAT3 signaling as a critical pathway. In vitro experiments showed the alcohol extracts of Euphorbia fischeriana steud. could inhibit proliferation, promote apoptosis and suppress JAK2/STAT3 signaling pathway in a dose-dependent manner in BEL-7402 cells. In addition, the alcohol extracts of Euphorbia fischeriana steud., either alone or in combination with sorafenib, dramatically blocked tumor growth in in vivo tests. Conclusions Euphorbia fischeriana steud. alcohol extracts have anti-cancer effects in HCC, and the molecular mechanisms may be connected to the regulation of JAK2/STAT3 signaling pathway.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Objective To perform prokaryotic expression and preliminary characterization of the recombinant poly-epitope vaccine EgG1Y162-2 (4) against cystic echinococcosis. Methods The recombinant poly-epitope vaccine EgG1Y162-2 (4) against Echinococcus granulosus based on the linker GSGGSG was subjected to structural three-dimensional (3D) modeling using immunoinformatics to analyze the structural changes and evaluate the antigenicity of the vaccine. The pET30a-EgG1Y162-2 (4) recombinant plasmid was generated using double digestion with EcoR I and Sal I, and then transformed into competent cells. Following protein induction with isopropyl-β-D-thiogalactoside (IPTG), the prokaryotic expression proteins were characterized using Western blotting, and the antigenicity of the recombinant protein was analyzed using sera from cystic echinococcosis patients and health volunteers. Results The four EgG1Y162-2 proteins coupled by the 3D structure of the recombinant vaccine EgG1Y162-2 (4) presented independent and effective expression and good antigenicity. The highest protein expression was detected in the supernatant following induction of the recombinant plasmid pET30a-EgG1Y162-2 (4) by 0.2 mmol/L IPTG at 37 °C for 4 h, and a pure protein component was seen following elution with 60 mmol/L imidazole. Western blotting analysis of the recombinant multiepitope protein HIS-EgG1Y162-2 (4) showed a band at approximately 39 kDa, and this band was recognized by sera from cystic echinococcosis patients. Conclusion A recombinant poly-epitope vaccine EgG1Y162-2 (4) against cystic echinococcosis has been successfully constructed, which provides a preliminary basis for researches on recombinant multi-epitope vaccine against cystic echinococcosis.

Objective: To study the effects of vibration on the expression of mitochondrial fusion and fission genes and ultrastructure of skeletal muscle in rabbits. Methods: Thirty-two 3.5-month-old New Zealand rabbits were randomly divided into low-intensity group, medium-intensity group, high-intensity group and control group, with 8 rabbits in each group. The rabbits in the experimental group were subjected to hind limb vibration load test for 45 days. The vibration intensity of the high intensity group was 12.26 m/s(2), the medium intensity group was 6.13 m/s(2), and the low intensity group was 3.02 m/s(2) according to the effective value of weighted acceleration[a(hw (4))] for 4 hours of equal energy frequency. The control group was exposed to noise only in the same experimental environment as the medium-intensity group. The noise levels of each group were measured during the vibration load experiment. After the test, the mRNA expression of mitochondrial fusion gene (Mfn1/Mfn2) and fission gene (Fis1, Drp1) by RT-PCR in the skeletal muscles were measured and the ultrastructure of the skeletal muscles were observed in high intensity group. Results: The mRNA expression of mitochondrial in the skeletal muscle tissues of control group, low intensity group, medium intensity group and high intensity group were Mfn1: 3.25±1.36, 3.85±1.90, 4.53±2.31 and 11.63±7.68; Mfn2: 0.68±0.25, 1.02±0.40, 0.94±0.33 and 1.40±0.45; Fis1: 1.05±0.62, 1.15±0.59, 1.53±1.06 and 2.46±1.51 and Drp1: 3.72±1.76, 2.91±1.63, 3.27±2.01 and 4.21±2.46, respectively. Compared with the control group, the expressions of Mfn1 mRNA, Mfn2 mRNA and Fis1 mRNA in the high-intensity group increased significantly (P<0.05) , and the expressions of Mfn2 mRNA in the medium-intensity group and the low-intensity group increased significantly (P<0.05) . Compared with the control group, the ultrastructure of skeletal muscle of high intensity group showed mitochondrial focal accumulation, cristae membrane damage, vacuole-like changes; Z-line irregularity of muscle fibers, and deficiency of sarcomere. Conclusion: Vibration must be lead to the abnormal mitochondrial morphology and structure and the disorder of energy metabolism due to the expression imbalance of mitochondrial fusion and fission genes in skeletal muscles of rabbits, which may be an important target of vibration-induced skeletal muscle injury.
Animals ; Hindlimb/metabolism* ; Mitochondria/metabolism* ; Mitochondrial Dynamics ; Mitochondrial Proteins/pharmacology* ; Muscle, Skeletal ; Rabbits ; Vibration/adverse effects*