Abstract:Targeted protein degradation (TPD) is emerging as a promising strategy for chemical knockdown and drug discovery. TPD strategies eliminate disease-associated proteins by hijacking the intracellular proteolysis machinery, including the ubiquitin-proteasome system or the lysosomal pathway. Compared to traditional small-molecular inhibitors, TPD strategies exhibited significant advantages in reducing toxic side effects and the risk of drug resistance, and expanding the target space to “undruggable” proteins. Inspired by our research findings in the field of TPD, this review aims to summarize recent advances of major TPD technologies, e.g., proteolysis targeting chimaera, molecular glue, lysosome-targeting chimaera, autophagosome-tethering compound, autophagy-targeting chimera, and discuss their potential applications and developing trend.

Abstract:Adolescent idiopathic scoliosis (AIS) is a spinal deformity involving 3 planes of the spine during adolescence. The pathogenesis of AIS is still unknown. Posterior spinal fusion (PSF) is the most widely used surgery in treating AIS. Its postoperative complications have gradually attracted attention. Deformity-related complications, such as adding-on phenomenon, proximal junctional kyphosis, distal junctional kyphosis, coronal imbalance and shoulder imbalance, are the most common ones. Understanding the definition, diagnostic criteria, incidence, natural history, risk factors, and preventive measures of these complications is essential to make surgical strategies for AIS. This article reviews the latest research on the deformity-related complications of PSF in patients with AIS.

Abstract:Objective To compare the distribution characteristics of the main thoracic curve Cobb angle in Lenke type 1 adolescent idiopathic scoliosis (AIS) patients, and differences in flexibility, correction rate, and correction index measured by different segmental suspension traction methods. Methods Totally 48 Lenke type 1 AIS patients, who underwent one-stage posterior 3-dimensional spinal deformity correction with bone graft fusion and internal fixation in The First Affiliated Hospital of Naval Medical University (Second Military Medical University) from Jan. 2015 to Dec. 2018, were enrolled. The main thoracic curve was divided into proximal (T₅-T₇ or T₆-T₈), middle (T₇-T₉ or T₈-T₁₀), and distal (T₉-T₁₁ or T₁₀-T₁₂) segments, and Cobb angles were measured for each segment. Flexibility, correction rate, and correction index (correction rate/preoperative flexibility) were calculated for different segments. Statistical analysis was performed using the analysis of variance of randomized block for comparison. Results The preoperative average age was (14.31±2.24) years, the total Cobb angle was (51.25±11.86)°, and the average Risser grade was 2.88±1.93. The average follow-up time was (38.75±8.82) months. The preoperative Cobb angle of the proximal segment was similar to that of the distal segment (［13.31±5.10］ ° vs ［13.94±5.67］ °, P＝0.757), and the Cobb angle of the middle segment (24.00±5.61)° was greater than that of the proximal and distal segments (both P＜0.001). The proportions of the proximal, middle and distal Cobb angle to the total Cobb angle were (25.72±7.97)%, (47.08±5.22)% and (27.20±8.00)%, respectively. Preoperative lateral flexion flexibility of the distal segment was significantly higher than that of the proximal and middle segments (［64.01±24.18］% vs ［35.00±18.02］%, ［41.49±17.65］%, both P＜0.001). The correction rates at 1 week postoperatively were as follows: proximal segment (74.61±15.80)%, middle segment (65.66±16.36)%, and distal segment (73.76±19.41)%, with no significant difference (P＝0.280). The correction indexes were as follows: proximal segment 2.41±1.20, middle segment 2.03±1.45, and distal segment 1.49±1.31, and the correction index of the proximal segment was significantly higher than that of the distal segment (P＝0.040). At the last follow-up, the correction rates were: proximal segment (71.10±14.07)%, middle segment (62.39±13.47)%, and distal segment (69.75±17.53)%, with no significant difference (P＝0.226). The correction indexes were as follows: proximal segment 2.24±1.10, middle segment 1.92±1.30, and distal segment 1.39±1.10, and the correction index of the proximal segment was significantly higher than that of the distal segment (P＝0.026). Conclusion In Lenke type 1 AIS patients, the proximal, middle, and distal segments account for 25.72%, 47.08%, and 27.20% of the main thoracic curve Cobb angle, respectively. The suspension traction method has the strongest ability to evaluate the flexibility of the distal segment, that is, the distal segment is most flexible under the suspension position, and the postoperative correction rate of each segment is similar.

Abstract:Objective To evaluate the correlation between proximal thoracic curve fusion and postoperative distal adding-on in Lenke type 2A adolescent idiopathic scoliosis (AIS) patients with low left shoulder. Methods The data of 104 patients with Lenke type 2A AIS with low left shoulder who underwent posterior thoracolumbar fusion in our hospital were retrospectively analyzed. All patients were followed up for at least 2 years, and the imaging parameters were measured by X-ray. The patients were divided into ≥T₃ group (upper instrumented vertebra ［UIV］ at T₃ or above T₃) and ＜T₃ group (UIV below T₃) according to the choice of UIV. The imaging parameters, the incidence of distal adding-on and the quality of life (scoliosis research society-22 questionnaire score) were compared between the 2 groups before and after operation and at the last follow-up. Results The average age of the 104 patients was (14.8±3.2) years old, and the average follow-up time was (33.0±9.6) months. There were 71 cases in ≥T₃ group and 33 cases in ＜T₃ group. The preoperative clinical and imaging parameters of the 2 groups were matched (P＞0.05). At the last follow-up, 27 (26.0%) patients had distal adding-on, and its incidence in ≥T₃ group was significantly higher than that in ＜T₃ group (31.0% ［22/71］ vs 15.2% ［5/33］, P＜0.001). Postoperative shoulder imbalance (PSI) occurred in 15 (14.4%) patients, including 4 (12.1%) patients in ＜T₃ group and 11 (15.5%) patientsin ≥T₃ group. There was no significant difference in quality of life scores between the 2 groups (P＞0.05). Multivariate logistic regression analysis showed that Risser grade and UIV selection were independent influencing factors for postoperative distal adding-on in Lenke type 2A AIS patients with low left shoulder (both P＜0.05). Conclusion For patients with Lenke type 2A AIS and lower left shoulder, the choice of UIV is related to the incidence of distal adding-on after operation. For such patients, the fusion of the proximal thoracic curve may increase the risk of distal adding-on.

Abstract:Objective To analyze the biomechanical basis of adding-on phenomenon using finite element method to simulate orthodontic surgery for adolescent idiopathic scoliosis (AIS) under different lowest instrumented vertebra (LIV) selections, so as to provide reference and theoretical support for the prevention of adding-on phenomenon after operation. Methods A Lenke type 1BN AIS patient (age 13 years old, body height 152 cm, body weight 51 kg) treated in Department of Spinal Surgery of The First Affiliated Hospital of Naval Medical University (Second Military Medical University) was enrolled. A 3-dimensional finite element model of the patient’s spine was constructed. Then, the AIS orthomorphia under different LIV options was simulated by computer to study the sub-curve compensation and maximum stress of the different unfused intervertebral discs. Results The maximum stress of the unfused intervertebral discs gradually increased from distal to proximal. When the LIV was located at L₁ (the lower end vertebra), the maximum stress of the L_1/2 disc was about 85% higher than that of the L_2/3 disc. When the LIV was located at L₂ and L₃, the maximum stress difference between unfused intervertebral discs was about 20%. Conclusion For Lenke type 1BN AIS patients, LIV below the lower end vertebra can reduce the risk of adding-on phenomenon.

Abstract:Objective To analyze risk factors for adolescent lumbar disc herniation (ALDH) and to develop a tool for quantitative assessment. Methods The clinical data and imaging data of 75 adolescent patients with ALDH (case group) and adolescent patients with low back pain but without ALDH (control group), who were treated in The First Affiliated Hospital of Naval Medical University (Second Military Medical University) from Aug. 2010 to Aug. 2021, were retrospectively analyzed. The patients were randomly divided into training set and validation set according to a ratio of 7∶3 in both groups. Age, gender, body mass index (BMI), occupation, waist trauma, smoking, lumbosacral transitional vertebra (LSTV), ratio of intercrestal line to L₅ transverse process (ICL/L₅TP), facet tropism (FT), thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), and pelvic incidence (PI) were compared between the case group and control group in the training set. Logistic regression model was used to analyze the independent influencing factors of ALDH risk, and a nomogram for quantitative assessment of ALDH risk was plotted by R 4.1.3 software. The training set and validation set data were used for internal validation and external validation of the nomogram model, respectively, and the value of the nomogram model was analyzed by receiver operating characteristic curve, C index, calibration curve, and decision curve. Results Gender, BMI, occupation, waist trauma, smoking, LSTV, ICL/L₅TP, FT, LL, and SS were significantly different between the case group and control group in the training set (all P＜0.05); multivariate logistic regression analysis showed that waist trauma, smoking, BMI, ICL/L₅TP, FT, and LL were independent influencing factors of ALDH risk (all P＜0.05); and a nomogram model was established based on these 6 factors. In the training and validation sets, the nomogram model had a high predictive value for ALDH risk (AUC values of 0.980 and 0.969, respectively) with high accuracy (C indexes of 0.71 and 0.76, respectively), calibration (P＝0.562 and 0.985, respectively), and clinical benefit. Conclusion Waist trauma, smoking, BMI, ICL/L₅TP, FT, and LL are strongly associated with the risk of ALDH, and the nomogram based on these 6 factors can be used to quantitatively assess prevalence risk of ALDH.

Abstract:Objective To develop a rapid fluorescence assay testing method for microRNA-721 (miRNA-721) detection using catalytic hairpin assembly for signal amplification without the need of enzymes. Methods A DNA hairpin probe H1 labeled with 5-carboxyfluorescein (FAM) was modified on the surface of gold nanoparticle (AuNP) to form probe AuNP-H1, and the fluorescence of H1 was quenched by AuNP. When the target miRNA was introduced, it caused the fluorescein modified in H1 on the AuNP to move away from the AuNP and emit fluorescence. This was followed by cyclic self-assembly between H1 and H2, and the target cycle was used to amplify the fluorescence signal. The fluorescence intensity of the system was measured at 480 nm excitation wavelength after co-reacting with the probe AuNP-H1, probe H2 and different concentrations of miRNA-721. Results When biomarker of acute myocarditis miRNA-721 was used as a model target, 20 μL of probe AuNP-H1 and 50 μL of 3 μmol/L probe H2 (annealing buffer of 20 mmol/L Tris-HCl, 100 mmol/L NaCl, 5 mmol/L MgCl₂, pH 7.4) were co-reacted with 50 μL of miRNA-721 at various concentrations ranging from 0.1 to 5 μmol/L at 30℃ for 20 min. The change in relative fluorescence intensity at 520 nm (∆_F＝F－F₀) had a good linear relationship with the concentration of miRNA-721 (C), and the fitted linear equation was ∆_F＝29 232×lgC－52 435 (R²＝0.991 0). The detection limit of this fluorescence method was 1.23 nmol/L. The recovery rate in normal human serum ranged from 92.71% to 104.02%. A comprehensive miRNA analysis could be completed in just 20 min. Conclusion The present method can be applied to detect miRNA-721 in biological samples, which providing a rapid diagnostic tool for acute myocarditis.

Abstract:Objective To explore the expression and function of circular RNA (circRNA) circNEIL3 in breast cancer (BC) and its influence on the expression levels of cell cycle-related proteins. Methods Clinical and pathological data from 50 patients with pathologically confirmed BC, along with samples of their BC tissues and para-cancer tissues were collected. circRNA sequencing was used to analyze the differentially expressed circRNAs in 3 pairs of BC tissues and para-cancer tissues. The characteristic of differentially expressed circRNA circNEIL3 was verified by ribonuclease (RNase) digestion and cytoplasmic/nuclear fractionation experiments. The expression of circNEIL3 in BC tissues and cells was detected by quantitative polymerase chain reaction. The relationship between circNEIL3 expression and the patients’ clinicopathological data was also analyzed. The effect of circNEIL3 on proliferation of BT-549 and MCF-7 cells was identified by cell counting kit 8 and colony-formation assays. The changes of cell apoptosis and cell cycle were detected by flow cytometry. The expression levels of cyclin D1 (CCND1), cyclin-dependent kinase (CDK) 4, cyclin E1 (CCNE1) and CDK2 were measured by Western blotting. Results circNEIL3 differentially expressed in BC tissues and adjacent tissues was not easily degraded by RNase R and mainly located in the cytoplasm of BC cells. Compared with normal breast tissues and cells, the expression levels of circNEIL3 in BC tissues and cells were significantly up-regulated (all P＜0.05). circNEIL3 was highly expressed in BC patients with tumor maximum diameter＞2 cm and at high TNM stage (stage Ⅲ) (both P＜0.05). Overexpression of circNEIL3 enhanced proliferation of BC cells and up-regulated the levels of CCND1, CDK4, CCNE1 and CDK2 (all P＜0.05). Knockdown of circNEIL3 induced cell apoptosis (P＜0.01), resulting in cell cycle arrest at G1 phase (P＜0.01). Conclusion High expression of circNEIL3 in BC tissues and cells can promote the proliferation of BC cells by up-regulating the expression levels of cycle-related proteins.

Abstract:Objective To evaluate the correlations between cardiomyocyte injury markers and cardiac function, infarct volume and reperfusion injury in patients with ST segment elevation myocardial infarction (STEMI). Methods A total of 53 patients with acute STEMI were enrolled from Zhongshan Hospital of Fudan University from Sep. 2022 to Dec. 2023. Cardiac magnetic resonance (CMR) was done 4 to 7 d after percutaneous coronary intervention (PCI). The patients were divided into intramyocardial hemorrhage (IMH) group (33 cases) and non-IMH group (19 cases). The differences and correlations of CMR parameters and cardiomyocyte injury markers were analyzed between the 2 groups at different time points. The diagnostic value of cardiomyocyte injury markers at different time points for IMH was evaluated by receiver operating characteristic curve. Results Compared with the non-IMH group, the left ventricular ejection fraction of the IMH group was significantly decreased (［47.25±8.50］% vs ［55.08±9.01］%, P＝0.003), and the infarct volume percentage was significantly higher (［36.82±13.33］% vs ［19.73±10.90］%, P＜0.001). There was a negative correlation between IMH volume percentage and left ventricular ejection fraction in the IMH patients (r_s＝－0.640, P＜0.001). Cardiac troponin T after PCI immediately had a good effect for diagnosing IMH (area under curve was 0.890, P＜0.001), and it was negatively correlated with left ventricular ejection fraction (r_s＝－0.453, P＜0.01) and positively correlated with infarct volume percentage and IMH volume percentage (r_s＝0.540, P＜0.01; r_s＝0.773, P＜0.01). Conclusion IMH can lead to more severe myocardial infarction and has short-term adverse effects on left ventricular systolic function. Cardiomyocyte injury markers may provide a convenient way to detect IMH in STEMI patients after PCI. Higher cardiomyocyte injury markers indicate worse cardiac function, larger infarct volume and more severe reperfusion injury.

Abstract:Objective To investigate the electroencephalogram (EEG) characteristics of anxiety disorder patients and high-risk populations, and to provide Objective support for the military psychological selection and the theory of multi-quality integration. Methods The EEG data from anxiety disorder patients (anxiety disorder group, n＝38), individuals at high risk for anxiety disorders (anxiety high-risk group, n＝39), and healthy volunteers (normal group, n＝38) were collected and analyzed by the eeglab software to investigate the multi-quality integration indicators (power spectral density ［PSD］, time-frequency amplitude, and functional connectivity). Whether PSD and weighted phase lag index (wPLI) could serve as neurophysiological indicators for assessing anxiety disorder-related brain abnormalities were examined. Binary classification among the 3 groups was performed by support vector machine and K-nearest neighbors (KNN) classifiers from the Python 2.0 Scikit-Learn package. Results There were significant differences in the PSD among the 3 groups in the δ, θ, and α low-frequency bands. The main effect of the δ band between groups was significant (F＝97.55, P＜0.001), with the PSD of the anxiety disorder group (6.16±0.61)＞the high-risk anxiety group (5.22±0.73)＞the normal group (3.36±0.06). The main effect of the θ band between groups was significant (F＝65.87, P＜0.001), with the PSD of the anxiety disorder group (2.25±0.07)＞the high-risk anxiety group (2.23±0.08)＞the normal group (1.34±0.39). The main effect of the α band between groups was significant (F＝178.73, P＜0.001), with the PSD of the anxiety disorder group (2.02±0.45)＞the high-risk anxiety group (1.94±0.57)＞the normal group (0.98±0.02). In the β1, β2, and γ high-frequency bands, there were fluctuating increases in PSD in the prefrontal (FP1, FP2) and temporal (T₃, T4) regions of the high-risk anxiety group. In the β1 band, the differences in wPLI between the anxiety disorder group and normal group were significant at the TP7-FC3 (t＝2.45, P＜0.05) and T₅-FC3 electrode pairs (t＝－3.01, P＜0.05). By integrating behavioral, frequency domain, time-frequency, and functional connectivity features into machine learning, the multi-quality integration indicators improved the accuracy of identifying high-risk anxiety individuals from normal individuals from 75.00% to 82.61%, compared to using behavioral indicators alone. Conclusion Combination of a multi-quality integration approach with machine learning can identify distinguishing features of individuals at risk for anxiety disorders, which holds potential implications for military psychological selection and clinical assessments.

Abstract:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairment of cognition, emotion, language, and memory. Existing treatments for AD are mainly pharmacological treatments, but they can only improve patients’ clinical symptoms and cannot effectively slow down the progression of the disease. Therefore, finding effective treatments for AD is urgent. Research has confirmed that gene mutation and family inheritance are closely related to the development and progression of AD, and gene therapy has made some progress in animal models of AD. Common drugs and some small molecule drugs are often unable to enter the brain through the blood-brain barrier, while nanocarriers can solve this problem through immune escape or other methods. In this paper, we review the gene therapy strategies related to AD and summarize the existing gene therapy and nanomedicine combination of AD therapeutic theories, so as to provide new ideas for the clinical treatment of AD.

Abstract:Hepatocellular carcinoma (HCC) is a common malignant tumor. Surgical treatment is the first choice, but it is only applicable to a few patients, and the recurrence rate is high. Therefore, it is crucial to develop effective postoperative adjuvant therapies to reduce the recurrence rate and improve patient survival. In recent years, local and systemic therapies (e.g., hepatic artery perfusion chemotherapy, radiotherapy, targeted therapy, and immunotherapy) have shown promising anti-tumor effects in the treatment of advanced HCC, which provides more strategies for postoperative adjuvant treatment of HCC. This article summarizes the current postoperative adjuvant therapies for HCC and the research status.

Abstract:Mesenchymal stem cell (MSC) treatment of osteoarthritis is currently a frontier and focus of research. Studies have demonstrated that macrophages play a significant role in the treatment of osteoarthritis with MSCs. The polarization of macrophages towards the selectively activated macrophage (M2 phenotype), promoted by MSCs, is a crucial mechanism for the treatment of osteoarthritis. This mechanism involves the regulation of certain proteins and miRNAs secreted by MSCs. In addition, MSC paracrine substances (such as exosomes) show similar efficacy and mechanism to MSCs in the treatment of osteoarthritis. This article provides a comprehensive overview of the role of macrophages in the development and progression of osteoarthritis, the impact of MSCs on macrophages, as well as the role and mechanism of macrophages in the treatment of osteoarthritis with MSCs, so as to lay a theoretical foundation for the clinical applications of MSCs in the treatment of osteoarthritis.

Abstract:Objective To explore the sleep status and its influencing factors of individuals working on islands, and to provide a scientific basis for targeted intervention. Methods A total of 897 individuals on islands were surveyed with general information questionnaire, Pittsburgh sleep quality index (PSQI), depression anxiety stress scale-21 (DASS-21), simplified coping style questionnaire (SCSQ), and Connor-Davidson resilience scale (CD-RISC). The correlations among PSQI, DASS-21, SCSQ and CD-RISC scores were tested by Pearson or Spearman correlation analyses. The PSQI score＞7 was considered as sleep disorder. The general data and DASS-21, SCSQ and CD-RISC scores were compared between sleep disorder group and non-sleep disorder group. The influencing factors of sleep quality were explored by multivariate logistic regression analysis. Results The PSQI score of the individuals was 8.0 (6.0, 10.0). There were 512 (57.08%) individuals in the sleep disorder group, and 385 (42.92%) in the non-sleep disorder group. There were significant differences in gender, age, marital status, whether experienced major upheavals during growth, and DASS-21, SCSQ and CD-RISC scores between the sleep disorder group and non-sleep disorder group (all P＜0.05). PSQI score was positively correlated with DASS-21 score and negative coping style score of SCSQ (both P＜0.01), while negatively correlated with positive coping style score of SCSQ and CD-RISC score (both P＜0.01). Multivariate logistic regression analysis showed that DASS-21 score (P＜0.001), SCSQ positive coping style score (P＝0.017) and negative coping style score (P＝0.005) were the independent influencing factors for sleep quality of the individuals working on islands. Conclusion Sleep quality of individuals working on islands is poor. Emotional state and coping style are the independent influencing factors of sleep quality.

Abstract:Objective To assess the levels of interleukin (IL)-6, IL-10, and C reactive protein (CRP) in plasma perioperatively in patients undergoing elective hepatectomy and liver radiofrequency ablation, and to explore the extent of perioperative inflammatory responses and their relationship with short-term prognosis. Methods Totally 37 patients with hepatic lesions were enrolled, including 19 patients undergoing elective hepatectomy and 18 undergoing liver radiofrequency ablation. The plasma levels of IL-6, IL-10 and CRP were detected by enzyme-linked immunosorbent assay preoperatively, immediately after surgery, and at various time points postoperatively. The dynamic changes before and after treatment were determined by non-parametric tests. The levels of perioperative inflammatory factors and prognostic indexes were compared between the 2 surgical methods. Results Significant dynamic changes were observed in the perioperative plasma levels of IL-6, IL-10, and CRP in patients undergoing hepatectomy, as well as in the levels of IL-6 and CRP in patients undergoing liver radiofrequency ablation (all P＜0.05). The levels of IL-6 at 24 and 48 h after hepatectomy, IL-10 immediately after surgery, and CRP at 24, 48, and 72 h postoperatively were significantly higher than those before surgery (all P＜0.05). After liver radiofrequency ablation, the level of IL-6 immediately after surgery was significantly higher than that before surgery (P＜0.05), while the levels of IL-10 or CRP before or after surgery were not significantly different (all P＞0.05). Compared with patients undergoing hepatectomy, the CRP level at 48 h after radiofrequency ablation was significantly lower, and the postoperative hospital stay was significantly shorter (both P＜0.05). Conclusion Postoperative systemic inflammatory response is relatively lower after liver radiofrequency ablation, which may accelerate rehabilitation.

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