Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL_(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL_(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.

Objective To analyze the clinical significance of subjective visual vertical (SVV) tests at different head deflection angles in assessing utricle function in patients with benign paroxysmal positional vertigo (BPPV). Methods A total of 61 BPPV patients who were treated at the Hearing Impairment and Vertigo Diagnosis and Treatment Center of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from August 2022 to May 2023 were retrospectively included, and 29 healthy adults were selected as controls. SVV tests were performed on all research subjects at different head deflection angles: upright head (0°), left head 45° (L45°), right head 45° (R45°). The test results between the two groups were compared. Results SVV absolute value at R45° in BPPV group was lower than that in the control group (P＝0.003); there was no significant difference in SVV values at 0° and L45° between the two groups. There was no statistical difference in SVV values at different head deflection angles between the control group and the left BPPV group. SVV absolute value at R45° in right BPPV group was lower than that in the control group (P＜0.001); there was no statistical difference in SVV values at 0° and L45° between the two groups. Conclusions SVV test can provide subjective information about the utricle, and SVV tests at different head deflection angles can fine-tune evaluate the function of the utricle in BPPV patients.

Objective:To unveil the dynamic molecular characteristics of colorectal cancer (CRC) progression, identify key molecules and signaling pathways driving disease development, and provide a theoretical basis for precision diagnosis and treatment.Methods:Differentially expressed genes (DEGs) were identified using DESeq2 based on the TCGA-CRC dataset (556 colorectal cancer samples) and three independent validation cohorts from the GEO database (GSE39582, GSE68468, GSE41258). Mfuzz time-series analysiswas applied to identify gene clusters with continuously upregulated expression during tumor progression. Functional enrichment analysis was performed using clusterProfiler, and protein-protein interaction (PPI) networks were constructed via the STRING online platform to pinpoint hub genes. Single-cell sequencing data (GSE132465/GSE144735) were integrated to resolve the cellular origins and intercellular communication of key genes. The prognostic value of genes was assessed using a univariate Cox proportional hazards model (likelihood ratio test), and single-cell sequencing data were analyzed using the Seurat pipeline with Wilcoxon rank-sum test to identify DEGs.Results:Time-series analysis identified Gene Cluster 4 (containing 186 genes) with a sustained upregulation trend across CRC stages from Ⅰ to Ⅳ. Functional enrichment revealed these genes were significantly involved in extracellular matrix (ECM) remodeling and pathways such as PI3K-Akt and MAPK signaling. PPI network analysis screened 10 hub genes ( COL10A1, THBS2, SPP1, etc.), whose high expression correlated significantly with poor patient prognosis. Single-cell sequencing demonstrated that these hub genes were predominantly expressed in fibroblast subpopulations, while SPP1 was enriched in macrophages. Cell-cell communication analysis confirmed that THBS2-CD47 and SPP1-CD44 were the primary pathways mediating fibroblast-immune/endothelial cell interactions. Conclusion:ECM-related genes are closely associated with the progression of CRC, in which the key molecules THBS2 and SPP1 may drive stromal-immune cell communication in the tumor microenvironment by mediating the THBS2-CD47 and SPP1-CD44 interaction pathways, thereby promoting the progression of CRC.

Objective:To investigate the impact of spousal support on the prognosis of colorectal cancer patients.Methods:Based on the US SEER database, a total of 110 652 patients with primary colorectal cancer were collected from 2010 to 2017, including 59 247 males and 51 405 females, aged 67 (54, 73) years, and the age range was 18 to 85 years. According to partner support status, they were married ( n=64 638), unmarried ( n=20 445), divorced or separated ( n=13 027), and widowed ( n=12 542). The primary outcome was cancer-specific survival (CSS). Non-normally distributed continuous variables were reported as M( Q1, Q3) and compared using the Kruskal-Wallis test. Categorical variables were described as cases and percentage (%) and analyzed via chi-square test. Kaplan-Meier survival curves and COX proportional hazards models were applied to systematically evaluate associations between gender, age, race, partner support status, and CSS. Results:Married patients exhibited the highest 5-year CSS (Stage I: 95.9%; Stage IV: 16.5%), while widowed patients had the poorest outcomes (Stage I: 91.4%; Stage IV: 12.9%; all P<0.001). After adjusting for confounders, lack of partner support (single/divorced/separated/widowed) remained an independent risk factor for CSS ( P<0.001). Subgroup analysis revealed no survival difference between widowed and single/divorced patients after age matching ( P>0.05). Among stage Ⅰ-Ⅱ widowed patients, males showed significantly worse prognosis than females ( P<0.05). Conclusions:Spousal support constitutes a critical social determinant of colorectal cancer prognosis. Integrating social support assessment into oncology care pathways and implementing targeted interventions for partnership-deprived populations are imperative to mitigate survival inequities.

Objective To retrospectively analyze the diagnostic value of thrombin-antithrombin complex(TAT),thrombomodulin(TM),and tissue plasminogen activator-inhibitor complex(t-PAIC)in severe cases of corona virus disease 2019(COVID-19).Methods A cohort of 79 patients clinically diagnosed with COVID-19 was retrospectively assembled and categorized into two groups based on disease severity:non-severe(n=51)and severe(n=28).In this study the differences of coagulation function and inflamma-tory marker levels between the two groups were compared.The correlations of TAT,TM and t-PAIC with other biomarkers were investi-gated.The diagnostic values of all the markers for severe COVID-19 were assessed.Results The patients of severe COVID-19 exhibi-ted significantly higher levels of TAT,TM,and t-PAIC compared to those of non-severe group(P＜0.001).The levels of TAT,TM and t-PAIC showed notable positive correlation with other biomarkers.TAT demonstrated the strongest positive correlation with the level of D-dimer(r=0.786,P＜0.001).Binary logistic regression analysis identified TAT(OR=1.346,P＜0.05)and t-PAIC(OR=1.128,P＜0.05)were independent risk factors in term of severe COVID-19.The combined ROC curve for TAT,TM and t-PAIC revealed high diagnostic efficacy in severe cases with the area under the curve(AUCROC)were 0.918,and the sensitivity and specificity were of 75％and 94.1％,respectively.Conclusion The results of combined measurement of TAT,TM and t-PAIC effectively demonstrates its diagnostic value in identifying severity and stratification of COVID-19 cases and may have important clinical significance for assessment of the severity and prediction of the prognosis.

Objective:To explore the risk factors associated with liver metastasis in T 1 stage colorectal neoplasms patients and establish a prognostic model. Methods:Clinicopathological data of T 1 stage colorectal neoplasms patients from the Surveillance, Epidemiology, and End Results (SEER) database between January 1, 2004, and December 31, 2019 were included. The differences in clinicopathological characteristics between patients with and without liver metastasis were compared using Chi-square test, Wilcoxon rank-sum test, and multivariate Logistic regression analysis. Survival curves were plotted using Kaplan-Meier method, and the Log-Rank test was used to compare survival differences between the two groups. Univariate and multivariate analysis of prognostic factors were performed using the proportional Cox regression hazards regression model. Patients were randomly divided into training set and validation set at a ratio of 6∶4 using simple random sampling method. A nomogram model was established based on independent prognostic factors based on the results of the multivariate Cox regression analysis. The predictive ability of the model was evaluated using time-dependent receiver operating characteristic (ROC) curves and calibration curves. Results:A total of 28 258 T 1 stage colorectal neoplasms patients were included in the study. The multivariate Logistic regression analysis for liver metastasis occurrence indicated that the neuroendocrine neoplasms, elevated carcinoembryonic antigen (CEA) levels, larger neoplasms size, positive lymph node metastasis, and presence of cancer nodules were statistically significant differences ( P<0.05). For T 1 stage colorectal neoplasms patients with liver metastasis, the results of the multivariate Cox regression analysis showed that age, primary site, ethnicity, chemotherapy, and surgical treatment were independent prognostic factors ( P<0.05). The nomogram constructed based on these five prognostic factors had time-dependent ROC areas under the curve of 0.758, 0.797 and 0.729 for 1-year, 3-year, and 5-year survival rates, respectively, 0.749, 0.857, 0.871 in the validation set. The calibration curves of the nomogram in the training and validation sets were close to the 45-degree diagonal line. Conclusions:Neuroendocrine neoplasms, elevated CEA levels, larger neoplasms size, positive lymph node metastasis, and presence of cancer nodules are independent risk factors for liver metastasis in T 1 stage colorectal neoplasms. Age, primary site, ethnicity, chemotherapy, and surgical treatment are independent prognostic factors. The nomogram constructed based on these clinical characteristics has good discrimination and calibration abilities.

Objective:To explore the practical application and clinical significance of modified grading system for Gastrointestinal Symptom Rating Scale (GSRS) scores in evaluating long-term postoperative gastrointestinal dysfunction (PGID) in patients after colon cancer surgery.Methods:A retrospective analysis was conducted on the case data of 122 patients who underwent right hemicolectomy for colorectal cancer at Beijing Friendship Hospital, Capital Medical University from September 2021 to September 2022. Among these patients, 69 were males (56.6%), and 53 were females (43.4%). The median age was 66.5 years, and the body mass index was (24.4±3.3) kg/m 2. The main observe indiator was GSRS scores of patients. The measurement data of normal distribution were represented as mean±standard deviation( ± s), and intergroup comparisons were conducted using ANOVA. The measurement data of non-normal distribution were expressed as the median (interquartile distance) [ M( Q1, Q3)], the Kruskal-Wallis H test was employed. Unordered count data comparisons were performed using the χ2 test, while comparisons for ordered count data between groups were conducted using the Kruskal-Wallis H test. GSRS scores were represented using density plots, and the scores were categorized into five symptom groups, presented using radar charts to illustrate the distribution of each symptom group. Results:Among the 122 patients, the most common long-term PGID syndromes was dyspepsia, followed by abdominal pain, diarrhea, and constipation. GSRS score data in the study population exhibited a nearly trimodal trend. Based on the overall data trend, the GSRS scale was refined, with cut-off values of 20 and 30, categorizing patients with right-sided colon cancer into low-risk, moderate-risk, and high-risk groups for quantifying the severity of long-term PGID. In terms of gender distribution, the differences among the three groups was statistically significant ( P=0.031), suggesting that males may be more susceptible to long-term PGID. However, there were no significant differences among the three groups concerning age, tumor location, surgical approach, anastomotic technique, lymph node dissection, pathological staging, adjuvant chemotherapy, and other factors. Conclusions:The modified grading system for GSRS scores aligns with the distribution characteristics of postoperative gastrointestinal function in colorectal cancer patients. It can quantify the risk of long-term PGID, allowing for a graded management approach to improve the postoperative quality of life for patients.

Objective:To subdivide clinical classification of refractory atlantoaxial dislocation, and evaluate the reliability of new subdivide clinical classification of refractory atlantoaxial dislocation.Methods:From January 2010 to December 2018, 48 patients with refractory atlantoaxial dislocation were treated, including 19 males and 29 females, aged 16 to 65 years, with an average of 39.2±13.3 years. According to the changes of relative anatomical position of C 1 and C 2 under general anesthesia with heavy traction of 1/6 body weight, subdivide clinical classification of refractory atlantoaxial dislocation were proposed, and refractory atlantoaxial dislocation was divided into traction loosening type (atlantoaxial angle≥5°) and traction stabilization type (atlantoaxial angle<5°). The traction loosening type was directly reduced by posterior atlantoaxial screw-rod fixation and fusion without anterior or posterior soft tissue release. For traction stabilization type, transoral soft tissue release was performed first, and then transoral anterior reduction plate fixation and fusion or posterior atlantoaxial screw-rod fixation and fusion were performed. Atlantodental interval (ADI) and atlantoaxial angle (AAA) were measured and collected before and after surgery to evaluate atlantoaxial reduction. The space available for the spinal cord (SAC) were measured to evaluate spinal cord compression. Visual analogue score (VAS) was used to evaluate the neck pain levels, and Japanese Orthopaedic Association (JOA) scores was used to evaluate the neurological function. American Spinal Cord Injury Association impairment scale (AIS) was used to evaluate the degree of spinal cord injury. One week, 3, 6, 12 months postoperatively and the annual review of the X-ray and CT scan were checked, in order to evaluate the reduction, internal fixation and bone graft fusion. Results:Among all 48 cases, 22 cases were traction loosening type, of which posterior atlantoaxial screw-rod fixation and fusion were performed in 16 cases and occipitocervical fixation and fusion in 6 cases. 26 cases were traction stabilization type, and they all underwent anterior transoral release, and then, anterior TARP fixation and fusion were performed in 24 cases and posterior screw-rod fixation and fusion in the other 2 cases. X-ray, CT and MRI images and of all patients 1 week after surgery showed good atlantoaxial reduction and decompression of spinal cord. In each of the two types, there was one case lost to follow-up. For 46 cases in follow-up, the follow-up time ranged from 6 to 72 months, with an average of 38.0±17.2 months. Among 46 cases, 21 cases of traction loosening type showed that, ADI reduced from preoperative 9.9±2.2 mm to 2.3±0.9 mm at 3 months after surgery and 2.3±1.0 mm at the last follow-up, AAA increased from preoperative 57.9°±12.3° to 91.0°±2.2° at 3 months after surgery and 90.9°±2.2° at the last follow-up, SAC increased from preoperative 9.8±1.3 mm to 15.1±0.7 mm at 3 months after surgery and 14.9±0.7 mm at the last follow-up, VAS score reduced from preoperative 1.5±2.1 to 0.7±1.0 at 3 months after surgery and 0.3±0.6 at the last follow-up, and JOA score increased from preoperative 10.2±1.7 to 13.3±1.3 at 3 months after surgery and 14.9±1.5 at the last follow-up. Twenty-five cases of traction stabilization type presented that, ADI reduced from preoperative 9.7±2.0 mm to 2.1±1.4 mm at 3 months after surgery and 2.1±1.3 mm at the last follow-up, AAA increased from preoperative 55.8°±9.2° to 90.9°±1.4° at 3 months after surgery and 90.9°±1.3° at the last follow-up, SAC increased from preoperative 10.5±1.0 mm to 15.4±0.5 mm at 3 months after surgery and 14.8±2.8 mm at the last follow-up, VAS score reduced from preoperative 1.7±2.1 to 0.7±0.9 at 3 months after surgery and 0.3±0.5 at the last follow-up, and JOA score increased from preoperative 10.1±1.3 to 12.9±1.5 at 3 months after surgery and 14.4±1.3 at the last follow-up. In the traction loosening type, all the 10 grade D patients were improved to grade E at the last follow-up. In the 2 grade C patients of traction stabilization type before surgery, 1 patient was improved to grade E, 1 patient was improved to grade D, and all 11 patients with grade D were improved to grade E at the last follow-up. Bony fusion was obtained in all patients from 3 to 6 months, with an average of 4.4±1.5 months. During follow-up period, no looseness of internal fixation or redislocation happened.Conclusion:Refractory atlantoaxial dislocation can be divided into traction loosening type and traction stabilization type. For traction loosening type, satisfactory reduction can be achieved by using posterior atlantoaxial screw-rod system without soft tissue release. For traction stabilization type, anterior release is preferable, and then anterior TARP or posterior screw-rod can be used to achieve satisfactory reduction.

Objective:To explore the preventive value of "integrated prevention strategy" for nipple and areola ischemia after single-port endoscopic subcutaneous mastectomy.Methods:The clinical data of 72 patients with breast cancer who received single-port endoscopic subcutaneous mastectomy in Beijing Friendship Hospital, Capital Medical University from July 2019 to July 2021 were retrospectively analyzed, they were all female. The follow-up period was up to July 2022. According to the perioperative treatment methods, the patients were divided into observation group ( n=40) and control group ( n=32). The patients in the observation group who adopted the "integrated prevention strategy" scheme, and patients in the control group who adopted the conventional treatment scheme. The incidence of postoperative nipple and areola ischemic was compared between the two groups, and the postoperative cosmetic effect, quality of life and satisfaction of patients were evaluated. Measurement data were expressed as mean ± standard deviation ( ± s), and t-test was used for comparison between groups; the Chi-square test was used to compare the data groups. Results:The postoperative drainage volume in the observation group was significantly lower than that in the control group [(632.40±226.37) mL vs (774.91±239.85) mL], and the difference was statistically significant ( P=0.013). Two weeks after operation, there was 1 case of nipple and areola ischemia in the observation group, and 7 cases in the control group, the difference was statistically significant between the two groups ( P=0.019). Twelve months after operation, the score of breast satisfaction (83.93±11.64 vs 67.28±11.52), chest satisfaction (89.63±8.06 vs 83.03±9.49) and psychosocial well-being (89.43±12.42 vs 78.88±10.40) in the observation group were better than those in the control group, the differences were statistically significant ( P<0.05). Conclusion:"Integrated prevention strategy" can effectively prevent the occurrence of nipple and areola ischemic after single-port endoscopic subcutaneous mastectomy and improve patient satisfaction, which has certain promotion value.