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 analyze the effects of massage therapy on the inflammatory state and lung function of pediatric refractory Mycoplasma pneumonia (RMPP). Methods A total of 320 children with RMPP treated in Hebei Seventh People′s Hospital from September 2022 to August 2023 were selected in the study. According to different treatment methods, they were divided into two groups, with 160 cases in each group. The western medicine group was given conventional anti-inflammatory and other symptomatic treatment, while the massage group was given dialectical massage treatment based on the western medicine group. The clinical efficacy, duration of disappearance of clinical symptoms, pulmonary function indexes, serum inflammatory factors, immune function indexes and total incidence of adverse reactions were compared between the two groups. Results The total effective rate of massage group was higher than that of control group (P < 0.05). The disappearance time of fever, cough, sputum and lung moist rales in observation group was shorter than that in control group (P < 0.05). After treatment, the peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF) and forced vital capacity (FVC) in the massage group were higher than those in the control group (P < 0.05). The levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the massage group were lower than those in the control group after treatment (P < 0.05). After treatment, CD3⁺, CD4⁺, CD4⁺/CD8⁺ in the massage group were higher than those in the control group (P < 0.05), and CD8⁺ was lower than that in the control group (P < 0.05). There was nosignificant difference in the total incidence of adverse reactions between the massage group and the western medicine group (P>0.05). Conclusion Massage based on syndrome differentiation combined with western medicine can effectively relieve fever, cough and other symptoms of RMPP children, reduce inflammatory response, improve lung function and immune function, and has less adverse reactions.

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate,

Objective To explore the value of DNA repair genes (DRGs) in predicting the effect of immunotherapy on lung adenocarcinoma based on second-generation sequencing technology. Methods The data of lung adenocarcinoma were obtained from the Cancer Genome Atlas, including the testing cohort and the validation cohort. In the testing set, according to the cut-off value of tumor mutational burden (TMB) score 15, the patients with lung adenocarcinoma were divided into two groups: the low TMB score group and the high TMB score group. And we analyzed the relation between TMB and the overall survival of lung adenocarcinoma patients. KRAS and TP53 co-mutation was used as the standard control, the differences in the mutation count and TMB score between only DRGs mutation group and KRAS or TP53 co-mutation groups were analyzed. In the validation cohort, the differences between DRGs and KRAS or TP53 co-mutation groups in TMB, tumor neoantigen burden and PFS were analyzed. Results The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with only TP53 or DRGs mutation (P < 0.05). The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with KRAS/TP53 co-mutation (P=0.037, P=0.044). In validation cohort analysis, the TP53/DRGs co-mutation patients also showed higher tumor neoantigens, higher TMB and longer progression-free survival than those patients with only TP53 or DRGs or KRAS/TP53 co-mutation groups. Conclusion TP53/DRGs co-mutation may be served as a pair of potential biomarkers for predicting the efficacy of immunotherapy on lung adenocarcinoma.

Objective:To analyze the cost difference between bilateral surgery and unilateral surgery in the same diagnosis-related group(DRG), and to explore the necessity of coefficient adjustment in DRG payment for bilateral surgery.Methods:The medical record frontpage information of all discharged patients who were divided into FJ25(complicated operation of venous system, without complications and accompanying diseases)by DRG in a tertiary hospital from 2017 to 2019 was selected, and the cost difference between unilateral operation and bilateral operation was compared.Results:A total of 359 patients were included, including 230 patients(64.07%) in unilateral operation group and 129 patients(35.93%) in bilateral operation group. There was no significant difference in gender, age and length of hospital stay between unilateral operation group and bilateral operation group( P>0.05). The hospitalization expenses of the bilateral operation group were higher than those of the unilateral operation group( P<0.05), and the differences mainly came from the expenses of consumables, operation, anesthesia and drugs. There was no significant difference in the expenses of diagnosis and treatment, and the cost of inspection between the two groups( P>0.05). The individual burden of patients with medical insurance in bilateral operation group was higher than that in unilateral operation group. Conclusions:In the same DRG group, the adjustment coefficient can be used to adjust the medical insurance payment for bilateral surgery, so as to avoid the occurrence of clinical decomposition hospitalization behavior.

Objective:To investigate the dosimetry advantage of 3D-printed minimally invasive guided template used in local advanced cervical cancer intracavitary combined with interstitial radiotherapy.Methods:A total of 68 cases with locally advanced cervical cancer who were admitted to Hebei Cangzhou Hospital of intergrated traditional Chinese medicine and western medicine from May 2016 to August 2019 were selected. All the patients had eccentric tumor or large tumor (tumor diameter >5 cm) after radiotherapy. Intensity modulated radiotherapy was used for external radiotherapy, and intracavitary combined with interstitial radiotherapy was used for brachytherapy. The prescription dose of high-risk clinical target volume (HR-CTV) is 6 Gy/fraction, once a week, five fractions in total. Sixty-eight patients were randomly divided into two groups, 35 cases in the template group who received minimally invasive 3D printing guided template assisted intrauterine tube implantation and insertion needle implantation, and 33 patients in the free implantation group who received free hand intrauterine tube implantation and insertion needle implantation. The position and depth of the insertion needle were adjusted by CT-guidance, and the final CT image was transmitted to the Oncentra Brachy treatment planning system, then the target volume and organs at risk were delineated for planning and treatment.Results:A total of 340 brchytherapy plans were made, including 175 in the template group and 165 in the free implantation group. The D90 values of the HR-CTV and intermediate-risk clinical target volume (IR-CTV) in the template group were increased ( t=3.63, 2.45, P<0.05), and D2 cm3 values (dose of 2 cm 3 of organ at risk) of bladder, rectum and sigmoid colon were significantly decreased ( t=-2.81, -2.54, -2.33, P<0.05). At the same time, the average CT scanning times of each treatment in the template group was (1.78±0.53) times, the average duration of each treatment was (11.35±3.98) min, and the average number of needles used in each implant treatment was (5.21±1.37). The result of free implantation group was higher than that of the template group. The differences were statistically significant ( t=-2.26, -4.53, -3.21, P<0.05). Conclusions:For localized advanced cervical cancer patients with eccentric or large tumors, the 3D printed minimally invasive guided template for intracavitary and interstitial implantation has obvious dosimetry advantages, and the operation is simpler and the duration is shorter.

Objective To explore chromobox protein homolog 2 (CBX2) expressions in relation to clinical features of patients and elucidate its role in the progression of hepatocellular carcinoma.Methods Using the Cancer Genome Atlas (TCGA) database,R language was used to analyze the distribution of differentially expressed mRNA in hepatocellular carcinoma.The different expression of CBX2 in HCC and adjacent tissues and its relationship with survival and clinical characteristics of patients were further analyzed.The expression of CBX2 in liver tissues,liver cancer tissue,and L02,HepG2 and SMMC-7721 cell lines was detected by real time-PCR and western blot.The expression of CBX2 was interfered by siRNA in hepatoma cell line.MTT,colony formation,transwell assays,and flow cytometry were used to identify the proliferation,apoptosis,invasion and clone-formation ability of HepG2 and SMMC-7721 cells after CBX2 down-regulation.According to the different data,t-test,ANOVA,chi-square test,and COX regression model were used for statistical analysis.Survival curve was plotted through Kaplan-Meier method.Results TCGA public database analysis showed that the expression of CBX2 mRNA in hepatocellular carcinoma tissues (7.296 ± 1.6115) was significantly higher than normal liver tissues (4.706 ± 0.940) (P =0.000).In addition,the overall survival time of patients with low CBX2 mRNA expression was significantly longer than that of patients with high CBX2 mRNA expression [(5.971 ± 0.411) years vs.(4.650 ± 0.503) years,P =0.001].The expression level of CBX2 mRNA was correlated with the pathological TNM stage (P =0.025) and differentiation degree (P ＜ 0.001) of liver cancer.COX regression analysis showed that CBX2 mRNA expression was an independent predictor of patient survival (P =0.013).siRNA was transfected and compared with the blank control group.The transgenic ability of HepG2 and SMMC-77221 cells decreased significantly at 72h (P ＜ 0.05) and 96h (P ＜ 0.05),and the apoptosis rate (11.430％ ± 0.215％) was higher than blank control group (6.6 00％ ± 0.170％) (P =0.003).The number of invasive cells ((both P ＜ 0.05) and relative colony forming cells ((both P ＜ 0.001) were significantly decreased.In 20 cases of tissue samples,the expression of CBX2 protein (relative expression level 3.020 ±0.269) in liver cancer was higher than that in adjacent tissues (relative expression level 0.886±0.065) (P ＜ 0.001).The overall survival time of patients with low CBX2 expression in liver cancer was longer than that of patients with high expression [(3.670 + 0.576) years vs.(0.834 + 0.153) years,P =0.004].Conclusion An evident high expression of CBX2 is an independent poor prognostic factor in hepatoma.Down-regulation of CBX2 expression can inhibit the progression of liver cancer.Therefore,CBX2 may be a prognostic biomarker and a new target for HCC treatment.

Objective To investigate the relationship between the methylation status of mucoprotein 3A (MUC3A)gene and the prognosis of children with neuroblastoma(NB).Methods A pathological section of 92 cases of NB from January 2013 to December 2015 in Department of Pathology,Children and Women′s Healthcare Hospital of Laiwu City,were co-llected.There were 43 males and 49 females;and their ages ranged from 3 months to 13 years old, in which 31 cases were less than 1 year old,and 61 cases were over 1 year old.Methylation specific polymerase chain reaction was used to detect the methylation status of MUC3A gene in 92 cases of NB,and the relationship between the methylation status of MUC3A gene and the clinicopathological features of NB were analyzed.According to the methyla-tion status of MUC3A gene,the 3-year survival rate and survival time of the MUC3A gene methylation positive group and the negative group were compared.Results For those over 1 year old,the pathological types were differentiated +undifferentiated and in clinical stage of stage Ⅲ+Ⅳ,their MYCN gene amplification,MUC3A gene methylation inci-dence(86.89%,91.80%,90.32%,81.82%)were significantly higher than those less than 1 year old,whose patho-logical types were well differentiated and in clinical stage of Ⅰ + Ⅱ,MYCN gene was not amplified(38. 71%, 29.03%,30. 00%,42.31%),and the differences were statistically significant(χ2= 23.007,39. 059,35. 480, 14.043,all P<0.001).The 3 year survival rate of MUC3A gene methylation positive children(26.15%)was signifi-cantly lower than that of MUC3A gene methylation negative children(66.67%),and the difference was statistically sig-nificant(χ2=13.283,P<0.001).The median survival time of MUC3A gene methylation positive children in 3-year old children was 19 months,significantly shorter than that of MUC3A gene methylation negative children(32 months), and the difference was statistically significant(log-rank:χ2=5.910,P=0.015).Conclusion The positive methyla-tion of MUC3A gene suggests that children with NB have poor prognosis.

Objective To establish the allele-specific real-time polymerase chain reaction (ASPCR) for detection of neonatal hyperbilirubinemia related gene SLCO1B1 A388G polymorphism and apply this assay to identify the clinical samples.Methods According to SLCO1B1 A388G polymorphism loci,specific primers were designed and the assay was established.Wide type plasmid and mutant plasmid were constructed.Fifty clinical samples were selected,including 30 samples of neonatal hyperbilirubinemia that had been diagnosed with SLCO1B1 A388G mutant and 20 samples of healthy newborns without SLCO1B1 A388G mutant were selected as the controls.Wide type plasmid,mutant plasmid and clinical samples were tested by specific and non-specific primers.A388G polymorphism was determined by difference in Ct (cycle threshold) between specific and non-specific primers.Then,the accuracy,sensitivity and specificity of assay were evaluated.Results The difference in Ct (cycle threshold) between specific and non-specific primers that amplified equivalent wide type template was 13.97 ±0.75.The assay could correctly distinguish the wide type and mutant plasmid.Probit regression analysis showed the sensitivity of the assay could reach to 5.28 copies/μL.For clinical samples,the Ct values of the samples with A388G mutation was less than 37.75 and showed positive results,while the samples without A388G mutation did not show any amplification nor Ct values were larger than 37.75,which showed negative results.Conclusions ASPCR is a fast,simple and effective method for SLCO1B1 A388G polymorphism detection of the clinical simples.It can be used for large sample screening for neonatal hyperbilirubinemia gene loci.