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.

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 evaluate the short-term efficacy of single-session microwave ablation for benign thyroid nodule.METHODS Patients with benign thyroid nodules treated by microwave ablation between June 2019 and December 2022 at the Department of Otolaryngology Head and Neck Surgery,the First Affiliated Hospital of Xi'an Jiaotong University,were included for analysis.Thyroid function was tested 1 month after treatment,and ultrasound and thyroid function were performed 3 months,6 months and 1 year after treatment.Volume reduction rates(VRR)of nodules were calculated.Data of the last follow-up within 1 year were included for analysis.Variables including gender,age,whether Hashimoto's thyroiditis was present,longitudinal diameter of nodules,solid volume of nodules were included for univariate and multivariate analysis.RESULTS A total of 151 patients with 163 nodules were included.The perioperative complication rate was 1.99%(3/151).The VRR at half year after treatment was(79.58±17.70)%,and the success rate at half year after treatment was 93.43%(128/137).The VRR of at 1year after treatment was(81.24±24.29)%.The 1-year treatment success rate was 92.77%(77/83).Univariate and multivariate analysis showed that nodular solid volume and age were independent factors affecting VRR after ablation.Regression coefficient of age and solid volume was 0.34(P<0.05)and-0.47(P<0.05),respectively.For every 1 cm3 increase in solid volume,1-year VRR(%)decreased by 0.47.Regression equation:1-year VRR=68.92+0.34×age-0.47×solid volume.Serum FT4 gradually decreased and the thyroid stimulating hormone(TSH)gradually increased within 6 months after ablation,and the differences were statistically significant(P<0.05).After 6 months,serum FT4 gradually recovered to the normal level and TSH gradually recovered.However,TSH still did not reach the preoperative level one year after ablation.FT3 decreased gradually after treatment,but there was no significant difference between the values at each time point(P=0.40).After the ablation of thyroid nodule,the mean value of thyroid function index fluctuated,but all of them were within the normal reference range.CONCLUSION Microwave ablation is a safe and effective treatment method for benign thyroid nodules,with an overall success rate of over 90%.Solid nodule volume and age are independent factors affecting the microwave ablation effect of benign thyroid nodules.

Objective:To evaluate the effect of dexmedetomidine-based anesthesia on cerebral oxygen saturation in the patients undergoing total laparoscopic hysterectomy.Methods:Fifty American Society of Anesthesiologists Physical Status classificationⅠorⅡpatients, aged 20-64 yr, undergoing elective total laparoscopic hysterectomy, were divided into 2 groups ( n=25 each) using a random number table method: conventional group (C group) and dexmedetomidine group (D group). Bilateral regoinal oxygen saturation (rSO 2) was monitored using a cerebral oxygen saturation monitor. In D group, dexmedetomidine was intravenously infused as a bolus of 0.5 μg/kg before anesthesia induction, and 10 min later dexmedetomidine was then given by an infusion of 0.5 μg·kg -1·h -1 until 30 min before the end of operation. The equal volume of normal saline was given instead in C group. The remaining anesthesia regimen was the same in two groups. The maximum (LrSO 2max, RrSO 2max) and minimum (LrSO 2min, RrSO 2min) of bilateral rSO 2 were recorded from entry to 2 min after induction (D 1), from >2 min after induction to completion of tracheal intubation (D 2), from completion of tracheal intubation to the end of skin incision (D 3), from skin incision to completion of pneumoperitoneum (D 4), from pneumoperitoneum to completion of Trendelenburg position (D 5), within 20 min of Trendelenburg position (D 6), >20-40 min of Trendelenburg position (D 7), >40-60 min of Trendelenburg position (D 8), and from >60 min of Trendelenburg position to 10 min after return to supine position (D 9). The occurrence of 60% baseline value 0.05). Compared with C group, the LrSO 2min, LrSO 2max, RrSO 2min, and RrSO 2max were significantly increased in D 4-D 8 periods in D group ( P<0.05). No bilateral rSO 2 <75% baseline value was found in group D. Conclusions:Dexmetomidine-based anesthesia can elevate intraoperative rSO 2 in the patients undergoing total laparoscopic hysterectomy.

Objective:To evaluate the role of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway in 17β estradiol-induced reduction of long-term cognitive impairment induced by multiple propofol anesthesia in developing rats.Methods:Eighty 7-day-old clean-grade healthy newborn Sprague-Dawley rats of both sexes, weighing 11-17 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (group C), propofol group (group P), 17β estradiol plus propofol group (EP group) and 17β estradiol plus propofol plus BDNF/TrkB signaling pathway blocker K252a group (K group). Propofol 80 mg/kg was intraperitoneally injected every day for 5 days in P, EP and K groups.The equal volume of fat emulsion was given instead in group C. In EP and K groups, 17β estradiol 600 μg/kg was subcutaneously injected at 30 min before propofol injection.BDNF/TrkB signaling pathway blocker K252a 100 μg/kg was intraperitoneally injected in group K. Morris water maze test was performed on days 30-34 after birth to assess the cognitive function.The rats were sacrificed after the end of Morris water maze test, and the hippocampal tissues were removed for determination of the apoptosis rate of hippocampal neurons (by flow cytometry), expression of BDNF, p-Trkb and cleaved caspase-3 (by Western blot and immunofluorescence), and expression of Bcl-2 and Bax mRNA (by real-time polymerase chain reaction) and for microscopic examination of the pathological changes in hippocampal CA1 region (with a light microscope). Bax mRNA/Bcl-2 mRNA ratio was calculated. Results:Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of BDNF and p-TrkB was down-regulated, the expression of cleaved caspase-3 was up-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were increased ( P<0.05), and the pathological changes in hippocampal CA1 region were accentuated in group P. Compared with group P, the escape latency was significantly shortened, the number of crossing the original platform was increased, the expression of BDNF and p-TrkB was up-regulated, the expression of cleaved caspase-3 was down-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were decreased( P<0.05), and the pathological changes in hippocampal CA1 region were attenuated in group EP.Compared with group EP, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of BDNF and p-TrkB was down-regulated, the expression of cleaved caspase-3 was up-regulated, the apoptosis rate of hippocampal neurons and Bax mRNA/Bcl-2 mRNA ratio were increased( P<0.05), and the pathological changes in hippocampal CA1 region were accentuated in group K. Conclusions:BDNF/TrkB signaling pathway is involved in 17β estradiol-induced reduction of long-term cognitive impairment induced by multiple propofol anesthesia in developing rats.

Objective:To explore the application effect of Jiankuai psychosomatic active therapy in the elderly perioperative patients.Methods:From March 2018 to December 2019, 387 elderly patients in the urology department of the First People′s Hospital of Lianyungang City, Jiangsu Province were selected. According to the patients in two medical groups in the same ward, 193 patients in one medical group were divided into the experimental group and 194 patients in two medical groups as the control group. The experimental group was intervened by routine perioperative nursing combined with simple and fast psychosomatic active therapy, while the control group was only intervened by routine perioperative nursing. Self rating Anxiety Scale (SAS), Rosenberg Self-confidence Scale and General Self-efficacy Scale (GSEs) were used as the evaluation indexes before and after the implementation of the two groups.Results:The SAS score of the experimental group was 31.13 ± 3.64 and that of the control group was 48.45 ± 7.72 on the 7th day after operation. The difference between the two groups was statistically significant ( t value was 16.36, P < 0.05). The effective rate of self-confidence was 98.4% (190/193) and 94.8% (183/193) in the experimental group and 86.6% (168/194) and 85.1% (165/194) in the control group on the first day and the seventh day after operation, respectively. The difference between the two groups was statistically significant ( Z values were - 3.27 and 14.66, all P < 0.05). The GSEs score of the patients in the experimental group was 26.79 ± 2.17 and that of the control group was 16.86 ± 1.90. The difference between the two groups was statistically significant ( t value was 10.19, P < 0.05). Conclusions:The application of Jiankuai psychosomatic active therapy can effectively reduce the tension and anxiety of the elderly patients during the perioperative period, increase their self-confidence and self-efficacy, effectively improve the communication efficiency between doctors and patients, and promote rehabilitation.

Objective: To explore the method of the blood return of continuous blood purification therapy for patients with heart failure. Methods: A total of 69 patients with heart failure treated by continuous blood purification therapy in our ICU from January 2017 to January 2018 were randomly divided into experimental group (blood return with blood bag,35 patients) and the control group (blood return with machine,34 patients). The vital signs, clinical manifestations and hemodynamic indicators of each patient were collected during the blood return of the first CBP therapy, and the data were analyzed between the two groups. Results: After blood return of the first CBP therapy, the exacerbation of New York Heart Association (NYHA) heart function grade, SpO₂, CVP, HR of patients in the control group were 33.27% (11/31), 0.91 ± 0.06, (12.44 ± 1.43) cmH₂O (1cmH₂O=0.098 kPa), (118.17 ± 3.27) times per minute and those in the experimental group were 6.25% (2/32), 0.96±0.04, (8.98±1.36) cmH₂O, (90.45 ± 3.35)times per minute, respectively. The difference was statistically significant between the two groups (χ²=3.786, t=2.861, -7.565, 3.792, P< 0.05). Subgroup analysis showed that for patients within 24 hours of CBP treatment, the exacerbation of NYHA heart function grade, SpO₂, CVP, HR of the control group and the experimental group were respectively 76.92% (10/13), 0.86±0.01, (12.92±1.12) cmH₂O, (111.38±2.96) times per minute and 8.33% (1/12), 0.94±0.01, (8.11±0.74) cmH₂O, (90.34±1.32) times per minute, the difference was statistically significant (χ² =9.345, t=-14.101, 2.894, 7.648, P < 0.05). For patients treated with CBP therapy over 24 hours, the difference of the exacerbation of NYHA heart function grade, SpO₂, CVP, HR of the control group and the experimental group was not statistically significant (P>0.05). Conclusions In patients with heart failure treated with CBP, especially in those treated with CBP therapy within 24 hours, blood return with blood bag may avoid the recurrence of heart failure.

One major strategy to generate genetically modified mouse models is gene targeting in mouse embryonic stem (ES) cells, which is used to produce gene-targeted mice for wide applications in biomedicine. However, a major bottleneck in this approach is that the robustness of germline transmission of gene-targeted ES cells can be significantly reduced by their genetic and epigenetic instability after long-term culturing, which impairs the efficiency and robustness of mouse model generation. Recently, we have established a new type of pluripotent cells termed extended pluripotent stem (EPS) cells, which have superior developmental potency and robust germline competence compared to conventional mouse ES cells. In this study, we demonstrate that mouse EPS cells well maintain developmental potency and genetic stability after long-term passage. Based on gene targeting in mouse EPS cells, we established a new approach to directly and rapidly generate gene-targeted mouse models through tetraploid complementation, which could be accomplished in approximately 2 months. Importantly, using this approach, we successfully constructed mouse models in which the human interleukin 3 (IL3) or interleukin 6 (IL6) gene was knocked into its corresponding locus in the mouse genome. Our study demonstrates the feasibility of using mouse EPS cells to rapidly generate mouse models by gene targeting, which have great application potential in biomedical research.

Objective: To investigate the spectrum of gene mutations in adult patients with B-acute lymphoblastic leukemia (B-ALL), and to analyze the influences of different gene mutations on prognosis. Methods: DNA samples from 113 adult B-ALL patients who administered from June 2009 to September 2015 were collected. Target-specific next generation sequencing (NGS) approach was used to analyze the mutations of 112 genes (focused on the specific mutational hotspots) and all putative mutations were compared against multiple databases to calculate the frequency spectrum. The impact of gene mutation on the patients’ overall survival (OS) and recurrence free survival (RFS) was analyzed by the putative mutations through Kaplan-Meier, and Cox regression methods. Results: Of the 113 patients, 103 (92.0%) harbored at least one mutation and 29 (25.6%) harbored more than 3 genes mutation. The five most frequently mutated genes in B-ALL are SF1, FAT1, MPL, PTPN11 and NRAS. Gene mutations are different between Ph⁺ B-ALL and Ph^- B-ALL patients. Ph^- B-ALL patients with JAK-STAT signal pathway related gene mutation, such as JAK1/JAK2 mutation showed a poor prognosis compared to the patients without mutation (OS: P=0.011, 0.001; RFS: P=0.014,<0.001). Patients with PTPN11 mutation showed better survival than those without mutation, but the difference was not statistically significant (P value > 0.05). Besides, in Ph⁺ B-ALL patients whose epigenetic modifications related signaling pathway genes were affected, they had a worse prognosis (OS: P=0.038; RFS: P=0.047). Conclusion Gene mutations are common in adult ALL patients, a variety of signaling pathways are involved. The frequency and spectrum are varied in different types of B-ALL. JAK family gene mutation usually indicates poor prognosis. The co-occurrence of somatic mutations in adult B-ALL patients indicate the genetic complex and instability of adult B-ALL patients.

Objective To investigate the role of metastatic lymph node ratio (MLR) in the evaluation of prognosis of patients with gastric cancer (GC) at different lymph node numbers examined.Methods Clinical data were reviewed retrospectively in a total 535 patients who underwent surgery for GC.Spearman correlation analysis between MLR or number of metastatic lymph nodes (N) and examined lymph node numbers,Kaplan-Meier method was used for comparison survival rates of N stage and MLR stage.A receiver operating characteristic (ROC) curve was used to evaluate the role of N stage and MLR stage in the prognosis of GC patients.Results Metastatic lymph node ratio and number of metastatic lymph nodes correlated with the examined lymph node numbers (r =0.146,r =0.378,P ＜ 0.01,P ＜ 0.001).The 5 year survival rate of MLR0,MLR1,MLR2 and MLR3 patients were 57.5％,69.9％,40.0％ and 21.7％ respectively when examined lymph node numbers ＜ 6 (P ＜ 0.01).The 5-YSR of MLR0,MLR1,MLR2 and MLR3 patients were 86.8％,59.2％,35.8％ and 39.2％ respectively when between 6-10 (P ＜0.001) and the 5-YSR of MLR0,MLR1,MLR2 and MLR3 patients were 88.7％,62.5％,0 and 17.7％ respectively when they ＞ 10(P ＜0.001).AUC of MLR staging was 0.68 ±0.05 when the numbers ＜ 6 (P ＜ 0.001).AUC of MLR staging was 0.72 ± 0.04 at numbers 6-10 (P ＜ 0.001).AUC of MLR staging was 0.79 ± 0.03 when numbers ＞ 10 (P ＜ 0.001).Conclusions MLR was less influenced by lymph node number examined than N.MLR stage has potential superiority to that the N stage in assessing prognosis of GC patients,especially for patients with more than 6 lymph nodes examined.