Esophageal cancer （EC） is a highly prevalent malignant tumor in China. The phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， as one of the key oncogenic pathways， can promote the cell cycle progression， proliferation， migration， and invasion， induce chemoresistance， and inhibit apoptosis and autophagy of EC cells. Traditional Chinese medicine （TCM）， with the advantages of targeting multiple points with multiple components to delay cancer progression， can target the PI3K/Akt signaling pathway for EC treatment. This article preliminarily discusses the molecular mechanism and role of the PI3K/Akt signaling pathway in EC and elaborates on the specific targets and efficacy of TCM in treating EC through intervention in the PI3K/Akt signaling pathway in the past five years. TCM materials and extracts inhibiting the PI3K/Akt signaling pathway in EC include Borneolum， spore powder of Ganoderma lucidum without spore coat， extract of Celastrus orbiculatus， root extract of Taraxacum， and Bruceae Fructus oil emulsion. TCM active ingredients exerting the effect include flavonoids， terpenoids， saponins， phenols， polysaccharides， alkaloids， and other compounds. TCM compound prescriptions with such effect include Qige San， Huqi San， Xuanfu Daizhetang， Tongyoutang and its decomposed prescriptions， Liujunzi Tang， and Xishenzhi Formula. In addition， TCM injections such as Compound Kushen Injection and Kang'ai injection also inhibit the PI3K/Akt signaling pathway in EC. This paper summarizes the role of the PI3K/Akt signaling pathway in EC and the TCM interventions， aiming to provide reference for the research and clinical application of new drugs for EC.

Compared with total knee arthroplasty, unicondylar knee replacement has the advantage of preserving the knee tissue structure and motor function to the greatest extent. Pre-clinical in-vitro test is an important tool to evaluate the safety and effectiveness of unicondylar knee prostheses, and it is also a key focus of the product registration process. Through collection, comparison, and analysis of current regulations, technical standards, guidelines, and related research literature, this paper expounds on the relevant research methods for the pre-clinical in-vitrotesting of unicondylar knee prostheses. At the same time, in conjunction with current evaluation requirements and experience, the study discusses the focus of pre-clinical performance research for unicondylar knee prostheses during the registration process to clarify the performance evaluation requirements of this product category. This aims to provide a reference for the pre-clinical performance research of unicondylar knee prostheses and to standardize industry testing standards.
Knee Prosthesis ; Arthroplasty, Replacement, Knee ; Humans ; Prosthesis Design ; Materials Testing

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

G protein-coupled receptor kinase 2 (GRK2) participates in the phosphorylation and desensitization of G protein-coupled receptor (GPCR), impacting various biological processes such as inflammation and cell proliferation. Dysregulated expression and activity of GRK2 have been reported in multiple cells in rheumatoid arthritis (RA). However, whether and how GRK2 regulates synovial hyperplasia and fibroblast-like synoviocytes (FLSs) proliferation is poorly understood. In this study, we investigated the regulation of GRK2 and its biological function in RA. We found that GRK2 transmembrane activity was increased in FLSs of RA patients and collagen-induced arthritis (CIA) rats. Additionally, we noted a positive correlation between high GRK2 expression on the cell membrane and serological markers associated with RA and CIA. Immunoprecipitation-mass spectrometry and pull-down analyses revealed tumor necrosis factor receptor-associated factor 2 (TRAF2) as a novel substrate of GRK2. Furthermore, surface plasmon resonance (SPR) and molecular docking assays determined that the C-terminus of GRK2 binds to the C-terminus of TRAF2 at the Gln340 residue. GRK2 knockdown and the GRK2 inhibitor CP-25 attenuated synovial hyperplasia and FLS proliferation in CIA both in vitro and in vivo by decreasing GRK2 membrane expression and activity. Mechanistically, increased GRK2 transmembrane activity contributed to the recruitment of TRAF2 on the cell membrane, promoting GRK2-TRAF2 interactions that facilitate the recruitment of the E3 ubiquitin ligase TRIM47 to TRAF2. This enhanced TRAF2 Lys63 polyubiquitylation and induced nuclear factor (NF)-κB activation, leading to synovial hyperplasia and abnormal proliferation of FLSs. Our study provides a mechanistic and preclinical rationale for further evaluation of GRK2 as a therapeutic target for RA.

Objective:To evaluate the efficacy and adverse effects of 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phel-Tyr3-Thr8-octreotide (DOTA-TATE) in patients with advanced pheochromocytoma and paraganglioma (PPGL). Methods:Sixteen patients with metastatic PPGL, treated with 177Lu-DOTA-TATE in the Affiliated Hospital of Southwest Medical University between April 2020 and December 2023, were retrospectively included. Among these patients, nine were male and seven were female, with an a median age of 44.5(26.5, 51.0) years. Treatment response was assessed based on changes in blood catecholamine level and 68Ga-DOTA-TATE PET/CT imaging. Evaluation criteria included the response evaluation criteria in solid tumors (RECIST) 1.1 and the modified PET response criteria in solid tumors (PERCIST) 1.0. Treatment-related adverse events were graded according to the common terminology criteria for adverse events (CTCAE) 5.0. All patients received long-term follow-up after treatment, with endpoints including disease progression and death. Paired t-test was used to compare laboratory parameters before and after treatment. Results:The median number of treatment cycles of 177Lu-DOTA-TATE was 3(3, 4) per patient, with an average dose of (7.51±0.67) GBq per cycle. Grade 1 hematologic toxicity was observed in 4 patients (4/16), while grade 2 hematologic toxicity occurred in 2 patients (2/16), primarily manifesting as leukopenia and anemia. A slight decrease was noted post-treatment in PLT ( t=4.06, P=0.001) and Hb levels ( t=2.85, P=0.012), while WBC counts showed no statistically significant change ( t=1.57, P=0.137). No grade 3 or 4 hematologic, renal, or hepatic toxicities were observed. The glomerular filtration rate ( t=-0.29, P=0.778), creatinine ( t=0.04, P=0.697), alanine transaminase ( t=0.08, P=0.938), aspartate transaminase ( t=0.08, P=0.463), and total bilirubin ( t=-0.37, P=0.719) after treatment were not significantly different from those before treatment. According to RECIST 1.1, 13 patients achieved stable disease, 2 patients showed partial response and 1 had progression disease. Based on the modified PERCIST 1.0, stable disease was observed in 11 patients, partial response in 3 patients, and progression disease in 2 patients. Among 9 patients with catecholamine-secreting PPGL, 8 showed reduction in blood norepinephrine level. The median follow-up duration was 21.5(21.1, 42.6) months, with a median progression-free survival of 8.6(6.0, 14.6) months, and no mortality reported during the follow-up period. Conclusion:177Lu-DOTA-TATE appears to be a safe and promising therapeutic option for patients with advanced PPGL demonstrating elevated somatostatin receptor expression.

Purpose To investigate correlation of ADP ribosylation-like factor 6 interacting protein 4(ARL6IP4)expression with the pathological characteristics and clinical prognosis in primary colon cancer.Methods The ARL6IP4 mRNA expression in tumor and adjacent normal tissues of 133 colon cancer patients was analyzed by RT-qPCR,and its relationship with tumor location,pathological TNM stage,and 3-year survival prognosis was assessed.Additionally,ARL6IP4 protein expression was analyzed by immunohistochemistry in 30 cases,of which 16 cases were analyzed by immunofluorescence.Results The colon cancer presented significantly higher mRNA and protein levels of ARL6IP4 than adjacent normal tissues(t=4.221,P=5.200 × 10-5;t=7.421,P=3.537 × 10-8).The relative ex-pression level of ARL6IP4 mRNA in colon cancer was positively correlated with pathological TNM stage,N stage and M stage(P＜0.05),and negatively correlated with 3-year cumulative survival probability(P＜0.01).Additionally,sig-moid colon cancer presented significantly higher ARL6IP4 expression than other colon cancers,and at the cellular lev-el,ARL6IP4 was predominantly expressed in the cell nucleus.Conclusion The ARL6IP4 expression in colon cancer is higher than that in adjacent normal tissues,which is closely related to tumor metastasis and clinical prognosis.

Objective To evaluate the efficacy and safety of Qixian Tongluo Formula in the treatment of post-cerebral infarction paralysis with kidney deficiency and blood stasis syndrome,and to preliminarily explore the molecular mechanism of Qixian Tongluo Formula in improving impaired motor function from the perspective of cross-kingdom regulation of Chinese medicine microRNA(miRNA).Methods A pragmatic randomized controlled trial was conducted with 102 patients in the recovery period of post-cerebral infarction paralysis with kidney deficiency and blood stasis syndrome in our hospital.Patients were randomly divided into trial group and control group,with 51 cases in each group.The control group received standard Western medicine standard treatment,while the trial group received Qixian Tongluo Formula in addition to the standard treatment,with one dose per day,boiled in water,and taken warm after breakfast and dinner for a course of 2 months.The disability rate was used as the main efficacy indicator,and the incidence of adverse reactions was used as a safety indicator.miRNA from patient serum and Qixian Tongluo decoction were extracted respectively,and high-throughput sequencing was performed.The two sequences were compared to screen out the cross-kingdom gene transfer of Chinese medicine miRNA.Finally,its target genes of miRNA were predicted,and GO function and KEGG pathway enrichment analysis were carried out.Results A total of 67 patients completed the clinical trial,including 36 cases in the trial group and 31 cases in the control group;The disability rate in the trial group(13.9%)was lower than that in the control group(35.5%)(P<0.05);The incidence of adverse reactions was similar between the trial group(7.69%)and the control group(6.06%)(P>0.05);A total of 9530 Qixian Tongluo decoction miRNA sequences were screened,with 150 potentially involved in cross-kingdom gene transfer,including families such as miR-15 and miR-17;According to the target gene prediction of the top 10 miRNAs in cross-kingdom gene transfer of Chinese medicine,345 overlapping target genes were obtained;GO functional enrichment analysis revealed 16 biological processes,7 cellular components,and 2 molecular functions among the top 25 enriched functions,while KEGG pathway analysis mainly focused on the transforming growth factor-βsignaling pathway,neurotrophin signaling pathway,which are closely related to neural repair and functional recovery processes such as glial scar formation and synaptic plasticity after cerebral ischemia.Conclusion Qixian Tongluo Formula can significantly improve the functional independence level of patients with kidney deficiency and blood stasis syndrome in the recovery period of paralysis after cerebral infarction,offering a safe and effective treatment option for these patients;There were a large number of miRNAs in Qixian Tongluo decoction,some of which could cross-kingdom transferred into the human blood circulation,and promote the recovery of motor function in patients with cerebral infarction through multi-target,multi link and multi pathway gene network regulation.This study provides a new idea for subsequent clinical and basic research.

BACKGROUND:The lower-limb muscle strength shows a significant physiological decline with aging.There may be a certain correlation between sedentary behavior,fear of falling,age and lower-limb muscle strength,but the influence path and effect relationship among them are not yet clear.OBJECTIVE:To examine the relationship between sedentary behavior and lower-limb muscle strength,and to explore the influences of fear of falling and age in such an association among community-dwelling older adults.METHODS:This cross-sectional study recruited 331 community-dwelling older adults(aged≥60 years)in Shanghai.A questionnaire survey was conducted to collect basic information,demographic data,etc.The Short Form of the International Physical Activity Questionnaire was applied to measure sedentary time.Lower-limb muscle strength was assessed by the 30-second chair-stand test.Fear of falling was measured by the Chinese version of Fall Efficacy Scale-International.Descriptive statistics analysis,correlation analysis,regression-based path analysis and mediation analyses were performed on the data.RESULTS AND CONCLUSION:Valid data from 318 community-dwelling older adults[78.9%females,mean age(67.8±5.5)years old]were finally included in the analysis.There were 185 with sedentary time≥3 hours and 133 with sedentary time<3 hours.(1)There was a positive correlation between sedentary behavior and fear of falling(P<0.01),and there were negative correlations between lower-limb muscle strength and sedentary behavior(P<0.01)and between lower-limb muscle strength and fear of falling(P<0.001).(2)Sedentary behavior negatively predicted lower-limb muscle strength(β=-0.125,P<0.05),and positively predicted fear of falling(β=0.182,P<0.01).Fear of falling negatively predicted lower-limb muscle strength(β=-0.293,P<0.001).(3)Fear of falling mediated the relationship between sedentary behavior and lower-limb muscle strength(β=-0.053,95%confidence interval:-0.100 to-0.018).(4)Sedentary behavior had a statistically significant predictive effect on fear of falling(β=0.164,P<0.01),indicating that age moderates the effect of sedentary behavior on fear of falling.

In recent years,significant breakthroughs have been achieved in the immunotherapy for Alzheimer's disease.In line with global advancements,two anti-amyloid-β monoclonal antibodies have been approved and successfully launched in China for clinical use.Lecanemab and Donanemab were officially used in June 2024 and April 2025 in China,respectively.In order to standardize the rational and safe application of anti-amyloid-β monoclonal antibodies for Alzheimer's disease in China,this article integrates recom-mendations from the clinical trials and real-world experience from the author's team and domestic peers to further update the recom-mendations for the clinical use of anti-amyloid-β monoclonal antibody based on the 2024 version.It includes indications for therapy,pre-treatment evaluation and preparation,administration protocols and safety measures during treatment,and post-treatment monitor-ing strategies.