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 explore the relationship between the occurrence and development of colorectal cancer and the risk of BRCA1 and BRCA2 gene mutations. Methods:Sixty-one patients with colorectal adenocarcinoma admitted to Beijing Friendship Hospital Affiliated to Capital Medical University from January 2022 to March 2022 were tested by second-generation sequencing. Information such as age of onset, gender, histological grade and TNM stage were collected. According to whether the BRCA1 and BRCA2 gene had systemic mutation, the patients were divided into BRCA1 and BRCA2 gene system mutation group and unmutated group. There were 8 cases in the BRCA1 and BRCA2 gene system mutant group and 53 cases in the non-mutant group. The main outcome measures were the relationship between pathogenic or likely pathogenic germline mutations in colorectal cancer and clinicopathological data of patients, including age of onset, gender, tumor location, TNM stage, histological differentiation, and family history. The secondary outcome was the relationship between BRCA1 and BRCA2 gene system mutations and clinicopathological data. Measurement data with normal distribution were expressed as mean±standard deviation ( ± s), and comparison between groups was analyzed using the t-test. Measurement data with non-normal distribution were represented as M ( Q1, Q3), and comparison between groups was analyzed using the Mann-Whitney U test. Measurement data were expressed as the number of cases or percentage (%), and Chi-square test was used for comparison between groups. Results:Among 61 colorectal adenocarcinoma patients, the frequency of pathogenic or potentially pathogenic germ line mutations in colorectal cancer was 13.1% (8/61), and the frequency of BRCA1 and BRCA2 mutations was 3.3% (2/61). The frequency of BRCA1 and BRCA2 mutations was 13.1% (8/61). Women with BRCA1 and BRCA2 mutations (75.0% vs 37.7%, χ2=3.947, P=0.047) and right colon cancer (75.0% vs 26.4%, χ2=7.889, P=0.019) were significantly higher than those without mutation. Conclusions:The frequency of BRCA1 and BRCA2 gene mutation is higher in colorectal cancer patients. BRCA1 and BRCA2 gene mutations are recommended for colorectal cancer patients with a family history of breast or ovarian cancer.

Objective:To investigate the predictive value of visceral adipose for early major complications after rectal cancer surgery by CT scan.Methods:A retrospective case-control study method was used to recruit a total of 135 patients with rectal cancer who underwent radical resection at Beijing Friendship Hospital, Capital Medical University from January 2017 to June 2018. There were 89 males and 46 females, aged from 30 to 88 years, with a median age of 63 years. The patients were divided into complication group ( n=16) and control group ( n=119) according to whether serious complications occurred within 30 days after operation. Measurement data with normal distribution were expressed as Mean±SD, and comparison between groups was analyzed by using independent sample t-test. Measurement data with skewed distribution were represented as M ( Q1, Q3) and analyzed by using the Mann-Whitney U test. Count data were expressed as constituent ratio, and analyzed using the chi-square test or Fisher exact test. Logistic regression model was used to analyze the factors affecting the occurrence of early severe complications after radical resection of rectal cancer. The area under the receiver operating characteristic (ROC) curve (AUC) was used to analyze the predictive ability of the model for early severe complications after radical resection of rectal cancer. Results:Univariate analysis showed that there were significant differences in intraoperative blood loss [100 (62, 187) mL vs 50 (40, 100) mL, Z=-2.038, P=0.042], operation time [(325 (212, 375) min vs 260 (180, 310) min, Z=-2.04, P=0.041)], preoperative blood glucose [4.67 (4.44, 5.09) mmol/L vs 5.20 (4.80, 5.72) mmol/L, Z=-3.33, P=0.001] and visceral fat area/subcutaneous fat area (V/S) (1.23±0.54 vs 0.96±0.40, t=-2.39, P=0.018) between the complication group and the control group. Multivariate Logistic regression model showed that V/S ratio ( OR=3.978, 95% CI: 1.160-13.636, P=0.028) and preoperative blood glucose level ( OR=0.168, 95% CI: 0.055-0.512, P=0.002) were independent risk factors for early major complications after radical resection of rectal cancer. Conclusions:Visceral fat and preoperative blood glucose level are independent risk factors for early major complications after radical resection of rectal cancer, V/S is expected to be a predictor of early major complications after radical resection of rectal cancer.

Hip arthroplasty is a common surgical method with good clinical effect. However, there are many influencing factors, among which the position of prosthesis is the key factor determining the prognosis. At present, 3D printing technology is widely used in hip replacement, which has an important effect in improving the position of hip replacement prosthesis. This paper reviews the application of 3D printing guide plate in hip arthroplasty.

Objective To analyze the hemodynamic parameters of Stanford type B aortic dissection based on computational fluid dynamics (CFD), so as to make a thorough evaluation of the disease.Methods Based on CTA images of a patient with complex Stanford type B aortic dissection, the three-dimensional model and hemodynamic numerical simulation were carried out to analyze the velocity distribution of flow field and intersecting fracture profile, as well as the wall shear stress. Results The maximum velocity of blood flow at the entry tear and re-entry tear could reach 1.2 m/s and 2 m/s, respectively, providing references for further evaluation on aortic rupture position and prediction of aortic rupture risk. An obvious low wall shear stress zone was formed on false lumen wall near the entry tear, which was consistent with the thrombus position in the patient. Conclusions CFD could effectively analyze the hemodynamic characteristics of complex aortic dissection, obtain the correlation between aortic dissection and wall shear stress at aorta arch and descending aorta, which contributed to guiding clinical assessment of aortic function for preventing the diseases.

Objective To investigate the effect of different adhesive materials on all-ceramic restoration. Methods The all-ceramic restoration system model of mandibular first molar was established by spiral computed tomography (CT) scanning and computer-aided design (CAD) modeling. Four types of resin adhesive materials (Duo Cement,Lute-It,Rely-X ARC,Variolink II) used in clinics were selected, and the stress distribution was calculated using the ABAQUS software. Results The stress at the bonding interface was the highest when low filler adhesive Lute-It was used. Based on the viscoelasticity analysis, resin adhesives with a larger storage modulus and loss modulus could yield lower stress extremes. Conclusions The study suggests that high-filler type resin adhesives with a large energy storage modulus and loss modulus should be used clinically.

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 nuclear factor-kappa B (NF-κB)signaling pathway in propofol-induced suppression of up-regulation of inducible nitric oxide synthase (iNOS) gene expression in LPSstimulated RAW264.7 cells.Methods RAW264.7 cells were purchased from cell bank of Chinese Academy of Sciences and cultured in DMEM culture medium containing 10％ fetal bovine serum.The cells were seeded in 6 cm diameter dishes (3 ml/dish) or in 6-well plates (2 ml/well) with a density of 5 × 105/ml and randomly divided into 3 groups ( n =18): normal control group (group C),group LPS (group L)and group LPS + propofol (group LP).The cells were incubated with LPS 1 μg/ml in groups L and LP.Propofol 50μmol/L was added to the culture medium at 2 h before LPS in group LP.Cells were harvested at 30 min after being stimulated with LPS.Phosphorylation of IκB kinase(p-IKK) and NF-κB activity were detected by Western blot.The expression of iNOS mRNA was determined after 6 h exposure of the cells to LPS.Results LPS significantly up-regulated the expression of p-IKK and iNOS mRNA and increased NF-κB activity in group L as compared with group C.Propofol pretreatment significantly attenuated the effects of LPS on p-IKK,iNOS mRNA expression and NF-κB activity.Conclusion NF-κB signaling pathway is involved in the propofol-induced suppression of up-regulation of iNOS mRNA expression in LPS-stimulated RAW264.7 cells.