Atherosclerosis, a chronic inflammatory disease, is markedly influenced by both immune and inflammatory reactions throughout its progression. Dendritic cells, as pivotal antigen-presenting entities, play a crucial role in the initiation of immune responses and the preservation of immunological homeostasis. Accumulating data indicates that dendritic cells are present in healthy arteries and accumulate significantly in atherosclerotic plaques. Novel immunotherapeutic approaches and vaccination protocols have yielded substantial clinical advancements in managing chronic inflammatory diseases, with dendritic cell-centric modalities emerging for atherosclerotic management. In this review, we delineate the essential functions and underlying mechanisms of dendritic cells and their subsets in the modulation of atherosclerotic inflammation and immune responses. We underscore the immense promise of dendritic cell-based immunotherapeutic strategies, including vaccines and innovative combinations with nanotechnological drug delivery platforms for atherosclerosis treatment. We also discuss the challenges associated with dendritic cell immunotherapy and provide perspectives on the future direction of this field.

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Objective To investigate the association between the variability of remnant cholesterol inflammatory index(RCII),a novel composite biomarker,and the risk of stroke,in order to provide a theoretical basis for stroke prevention.Methods A prospective cohort study was conducted on 38 659 Kailuan individuals who took annual physical examinations in 2006,2008,and 2010.These subjects were grouped based on the quartiles of RCII variability,which was represented by standard deviation(SD)and average real variability(ARV),and were followed up every 2 years,with the occurrence of stroke(including ischemic and hemorrhagic strokes),death,or the end of follow-up on December 31,2022 as the endpoints.Kaplan-Meier method was used to calculate the cumulative incidence rate of endpoint events across different groups,and log-rank test was used to compare the difference of cumulative incidence of endpoint events in each group.Multivariate Cox proportional hazards regression model was adopted to analyze the association between RCII variability and risk of stroke.Results Among the 38 659 participants,a total of 2 539 strokes occurred during a mean follow-up period of 11.22±2.26 years.After adjusting confounding factors,when the participants were grouped by the quartiles of RCII-SD,the hazard ratio(HR)for stroke was 1.034(95%CI:0.917～1.167,P=0.584),1.146(95%CI:1.018～1.290,P=0.025),and 1.209(95%CI:1.066～1.370,P=0.003),respectively in the Q2,Q3,and Q4 groups,when compared with the Q1 group(Ptrend<0.05).When they were grouped by the quartiles of RCII-ARV,the HR for stroke was 1.008(95%CI:0.894～1.136,P=0.901),1.109(95%CI:0.986～1.248,P=0.085),and 1.152(95%CI:1.018～1.303,P=0.025),respectively,in the Q2,Q3,and Q4 groups,when compared with the Q1 group.Furthermore,both sensitivity and stratified analyses yielded similar results.Conclusion RCII variability is significantly associated with stroke,and the risk of stroke is gradually increasing with increment of the variability.Countermeasures Relevant authorities can focus on reducing RCII variability as a central objective by establishing regular monitoring mechanism,strengthening lifestyle interventions,and standardizing dietary,exercise,and weight management in order to suppress the index fluctuations.The principle of stable lipid-lowering in medication and optimization of therapeutic regimens with stable efficacy should be emphasized to prevent the risk of additional vascular damage.

OBJECTIVE To compare the ability of ultra-high-resolution CT(U-HRCT)and multi-slice spiral CT(MSCT)to display key vocal transmission structures in the middle ear.METHODS Subjects with normal middle ear structures who underwent 0.1 mm layer thickness U-HRCT and 0.625 mm layer thickness MSCT scans at the same time in Beijing Friendship Hospital affiliated to Capital Medical University from December 2019 to August 2024 were retrospectively enrolled.Two experienced head and neck radiologists reconstruct standard transsectional,coronal images based on the thinnest layer thickness.According to the 5-point method,16 key sound transmission structures of the middle ear,including malleus,incus and stapes,as well as joints,ligaments and tendons,were evaluated for image quality scoring.The standard deviation(SD)value,signal noise ratio(SNR),and contrast noise ratio(CNR)of bone in the malleus region and intratympanic gas were measured and calculated on the two examination images.RESULTS Thirty patients(47 sides)with normal middle ear structure were included,including 18 males and 12 females.The two physicians compared the results of U-HRCT in showing malleus head,malleus neck,malleus handle,incus body,long process,and short process,5 points accounted for 100%,and the 5-point scores of incudomalleolar joint space,incudostapedial joint space,stapes footplate and annular ligament were 100%,98.29%,75.83%and 77.83%,respectively,which were significantly higher than those of MSCT(P<0.001).In addition,U-HRCT showed higher scores for lenticular process,stapes head,anterior arch of stapes,posterior arch of stapes,annular ligament,stapes muscle,and tendo musculi tensoris tympani than MSCT(P<0.001),and the lenticular process showed a 100%display rate.There was no significant difference in the SNR between the two groups(P>0.05),but the SD value of the malleus in U-HRCT was 161.6±36.4,which was significantly lower than that in MSCT(297.8±128.1),and the difference was statistically significant(P<0.001).CONCLUSION U-HRCT can clearly visualize the key sound transmission structures of the middle ear,and its visualization ability is significantly better than that of MSCT.

This study aimed to identify mutations in the human insulin receptor gene (INSR) and investigate their role in the pathogenesis of severe insulin resistance syndrome. Sanger sequencing of the INSR gene was performed on a patient clinically suspected of having type A insulin resistance syndrome admitted to the Department of Endocrinology, the First Medical Center of Chinese PLA General Hospital. Upon identifying mutations, relevant exons were sequenced in her first-degree relatives. Additionally, control groups consisting of individuals with type 2 diabetes and those with normal glucose tolerance were screened for the mutation detected in the patient. Functional predictions of the INSR protein were made using MutationTaster, SIFT, and PolyPhen2 software. A previously unreported heterozygous missense mutation, c.3652G/A (Asp1218Asn), in exon 20 was identified in both the proband and her father. This mutation was not present in any of the control individuals. Multiple prediction tools indicate that this mutation likely disrupts gene/protein structure or function. The c.3652G/A (Asp1218Asn) heterozygous mutation in INSR is a novel variant that plays a significant role in the pathogenesis of severe insulin resistance in this Chinese family.

Objective:To investigate multi-system involvement in Kennedy′s disease and its association with disease progression.Methods:We retrospectively reviewed the clinical, laboratory, and electrophysiological data from 48 genetically confirmed patients with Kennedy′s disease at the Department of Neurology, First Medical Center of the Chinese PLA General Hospital, between February 2016 and February 2024. The disease progression rate was calculated based on the functional scores at baseline and follow-up. Correlation analyses and multiple linear regression models were employed to assess the relationships among clinical variables and to identify potential predictors of disease progression.Results:The age of muscle weakness onset ranged from 16 to 66 years (mean 42±11 years), with a diagnostic delay of 5.0 (3.0, 9.8) years. Lower limb weakness was the most common initial symptom in 72.9% (35/48) of patients, and 37.5% (18/48) exhibited non-motor manifestations prior to the onset of weakness. Core motor manifestations included bulbar weakness (89.6%, 43/48) and symmetric proximal limb weakness (83.3%, 40/48), frequently accompanied by gynecomastia (74.2%, 23/31) and sexual dysfunction (64.6%, 31/48). The median CAG repeat length was 43 (42, 46), which showed a significant negative correlation with the age at onset ( r=-0.406, P=0.004). Patients with CAG repeats > 43 had a higher prevalence of sexual dysfunction. Elevated serum muscle enzymes were observed in 97.9% (47/48), and abnormal sex hormone levels were detected in 81.2% (39/48). Sensory neuropathy was present in 68.1% (32/47), with CAG repeat length inversely correlating with compound muscle action potential (CMAP) amplitudes in the median ( β=-0.29; t=-2.27, P=0.029) and ulnar ( β=-0.22; t=-2.23, P=0.031) nerves. Low-frequency repetitive nerve stimulation (RNS) revealed a decrement in 43.3% (13/30) of patients, most commonly affecting the axillary and spinal accessory nerves. The disease progression rate was 1.3±0.3 (range: 0.5-2.0). Furthermore, serum creatine kinase-MB (CK-MB) levels were negatively correlated with disease progression rate ( r=-0.303, P=0.036). Conclusions:Kennedy′s disease presents with diverse initial manifestations and frequent multi-system involvement. Non-motor manifestations may precede muscle weakness, serving as valuable clues for early diagnosis. Widespread sex hormone abnormalities (particularly testosterone/luteinizing hormone dysregulation) support the role of androgen insensitivity in disease pathogenesis. Sensory neuropathies are frequent and not length-dependent. The presence of decremental responses on low-frequency RNS suggests neuromuscular junction dysfunction, which may underlie motor impairment in patients with Kennedy′s disease. Finally, serum CK-MB may serve as a potential biomarker for disease progression.

OBJECTIVE: To summarize the research progress on knee laxity of biomechanics and prevention and treatment after posterior cruciate ligament (PCL) reconstruction. METHODS: The domestic and international literature on the prevention and treatment of knee laxity after PCL reconstruction in recent years was extensively reviewed and analyzed. RESULTS: Different degrees of knee laxity often occur after PCL reconstruction, which can lead to poor prognosis in patients. The causes are associated with a variety of factors, including abnormal graft remodeling (such as differences in healing time and biomechanics among different types of grafts), tunnel position deviation (such as graft wear caused by the "killer turn" effect), and mechanical factors in postoperative rehabilitation (such as improper early weight-bearing and range of motion). These factors may promote graft elongation, increase early posterior tibial translation, and thereby induce knee laxity. CONCLUSION While PCL reconstruction improves knee stability, it is crucial to focus on and prevent postoperative knee laxity. However, current surgical methods are limited by factors such as graft characteristics, surgical technique flaws, and rehabilitation protocols, and thus can not fully correct the issue of abnormal postoperative laxity. Surgical techniques and treatment strategies still need further improvement and optimization to enhance patients' postoperative outcomes and quality of life.
Humans ; Joint Instability/surgery* ; Posterior Cruciate Ligament Reconstruction/adverse effects* ; Posterior Cruciate Ligament/surgery* ; Knee Joint/physiopathology* ; Biomechanical Phenomena ; Range of Motion, Articular ; Postoperative Complications/prevention & control* ; Knee Injuries/surgery*

OBJECTIVE: To summarize research progress on enhanced recovery after posterior cruciate ligament (PCL) reconstruction, clarify the core contradictions, effective intervention methods, and evaluation shortcomings in current clinical practice, and provide theoretical support for optimizing clinical rehabilitation strategies. METHODS: Relevant domestic and international literature in recent years was systematically searched. The key technologies and challenges for enhanced recovery after PCL reconstruction were analyzed from three aspects: the core issues of enhanced recovery after PCL reconstruction, treatment strategies, and the post-reconstruction effectiveness evaluation system. RESULTS: Enhanced recovery after PCL reconstruction mainly faces two core problems. First, there is a balance dilemma between graft tendon protection and knee joint function recovery: the tensile capacity of the graft tendon is weak in the early postoperative period, so excessive weight-bearing easily leads to relaxation, while overly conservative immobilization causes muscle atrophy and joint adhesion. Second, the return-to-sport rate is significantly affected by injury type and treatment method: patients with combined multiple ligament or meniscus injuries have a much lower return-to-sport rate than those with isolated PCL injury, and the risk of return-to-sport failure is higher. Current research mainly promotes rehabilitation from two aspects: physical therapy and surgical technology. Physical therapy runs through the perioperative period: preoperatively, muscle strength training, swelling control, and maintenance of joint range of motion are used to optimize surgical conditions; postoperatively, phased intervention is implemented. Surgical technology focuses on minimally invasive and anatomical approaches: arthroscopic surgery reduces injury, double-bundle reconstruction and internal tension-relief technology improve stability, and modified tunnel positioning and special surgical methods avoid the risk of "Killer Turn". Postoperative functional evaluation adopts multi-dimensional indicators: subjective evaluation relies on scales such as Lysholm and International Knee Documentation Committee (IKDC); objective evaluation assesses stability through Telos stress test and posterior drawer test; imaging evaluation takes MRI as the core; psychological evaluation is assisted by the Tampa scale of kinesiophobia-11 (TSK-11). However, there are obvious shortcomings, such as the lack of PCL-specific evaluation tools. CONCLUSION Enhanced recovery after PCL reconstruction requires the integration of precise surgery, individualized rehabilitation, and comprehensive subjective and objective evaluation. In the future, biomaterials and digital technologies should be integrated to optimize the full-cycle management of PCL reconstruction, thereby improving functional recovery and the effect of return to sports.
Humans ; Posterior Cruciate Ligament Reconstruction/rehabilitation* ; Posterior Cruciate Ligament/injuries* ; Recovery of Function ; Knee Joint/physiopathology* ; Knee Injuries/rehabilitation* ; Return to Sport ; Enhanced Recovery After Surgery ; Tendons/transplantation* ; Arthroscopy

Objective To investigate the effect of bone metastasis on the efficacy of immune check-point inhibitors(ICI)in treatment of advanced non-small cell lung cancer(NSCLC).Methods A retro-spective analysis was conducted in 248 patients with advanced NSCLC who received ICI therapy.The patients were divided into bone metastasis group(110 cases)and non-bone metastasis group(138 ca-ses)based on the presence of bone metastasis.Clinical characteristics,objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),and overall survival(OS)were compared between the two groups.The correlations of factors such as bone metastasis with the survival prognosis of NSCLC patients were analyzed using the Cox proportional hazards regression mod-el.A total of 60 treatment-naive NSCLC patients with bone metastasis were selected from research ob-jects,with 30 patients receiving ICI combined with conventional chemotherapy(combination group)and 30 patients receiving conventional chemotherapy alone(chemotherapy group).The therapeutic effects and incidence of treatment emergent adverse events(TEAE)were compared between the two groups.Results There were no statistically significant differences in ORR and DCR between the bone metastasis and non-bone metastasis groups(P＞0.05).The PFS of the bone metastasis group(5.53 months)was shorter than that of the non-bone metastasis group(7.72 months)(x2=3.674,P=0.045).However,there was no statistically significant difference in OS between the bone me-tastasis group and the non-bone metastasis group(16.98 versus 17.56 months,x2=1.333,P=0.248).Multivariate Cox regression analysis showed that bone metastasis was an independent prog-nostic factor for PFS in NSCLC patients(HR=1.52,95％CI,1.10 to 1.98,P=0.003),but not a prognostic factor for OS(P＞0.05).The ORR and DCR in the combination group were 43.33％and 93.33％,respectively,which were higher than 26.67％and 76.67％in the chemotherapy group(P＜0.05).The PFS in the combination group was longer than that in the chemotherapy group(x2=4.023,P=0.036).However,there was no statistically significant difference in OS be-tween the two groups(x2=1.235,P=0.267).There were no statistically significant differences in the overall incidence of TEAEs or the incidence of≥grade 3 TEAE between the two groups(P＞0.05).Conclusion Although the occurrence of bone metastasis has an adverse effect on the effica-cy of ICI therapy in advanced NSCLC,patients with bone metastasis can still achieve better thera-peutic effects through ICI combined with chemotherapy compared with chemotherapy alone.