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.

The impact of maintenance therapy on progression?free survival and overall survival as well as quality of life of Chi?nese patients with metastatic colorectal cancer has long been under discussion. Recently, some phase III clinical trials have revealed that maintenance therapy can signiifcantly prolong the progression?free survival while maintain an acceptable safety proifle. Based on this evidence and common treatment practice in China, we now generated one Expert Consensus on Maintenance Treatment for Metastatic Colorectal Cancer in China to further specify the neces?sity of maintenance therapy, suitable candidates for such treatment, and appropriate regimens.

Objective To predict the risk of 28-day mortality in septic patients in intensive care unit (ICU) with the combination of Weighted index of comorbidities (WIC) and sepsis-related organ failure assessment (SOFA) score.Methods The clinical data of adult severe sepsis/septic shock patients in Department of Emergency Medicine of Changzheng Hospital and Department of Critical Care Medicine of Jinan Military General Hospital from October 2011 to February 2013 were analyzed retrospectively.The etiological factor,past history,having severe sepsis or not were recorded.Age score,WIC score,acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score and SOFA score were calculated at or 24 hours after admission.The logistic regression was used and the receiver operating characteristic curve (ROC curve) was drawn to calculate the patients' outcome.Results In 310 enrolled patients,223 (71.9％) patients survived and 87 (28.1％) died.Univariate analysis showed that the P values of the age score,WIC score,APACHE Ⅱ score and SOFA score,chronic cardiac insufficiency,type 2 diabetes,cerebrovascular disease,tumor,multiple injury,pulmonary infection and having severe sepsis or not were all less than 0.2.The above 11 variables were put into the multivariate logistic regression equation 1,of which predicted probability was reserved.It revealed that 5 variables were independently associated with 28-day prognosis,of which influence power in descending order were SOFA score [odds ratio (OR) =1.308,95％ confidence interval (95％ CI):1.158-1.478,P=0.000],having severe sepsis or not (OR =0.206,95％ CI:0.100-0.424,P=0.000),APACHE Ⅱ score (OR =1.090,95％CI:1.021-1.164,P=0.010),WICscore (OR=1.441,95％CI:1.067-1.947,P=0.017),agescore (OR=1.228,95％CI:1.027-1.468,P=0).024),the Walswere 18.554,18.369,6.725,5.662,5.067,respectively.The 3 variables,age score,WIC score and SOFA score,were brought into the multivariate logistic regression equation 2,of which predicted probability was reserved too.It revealed that age score (OR=1.330,95％CI:1.145-1.546,P=0.000),WIC score (OR =1.496,95％ CI:1.145-1.546,P=0.000) and SOFA score (OR =1.429,95％ CI:1.303-1.567,P=0.000),were independently associated with the septic patients' 28-day prognosis.There was no significant difference in the area under receiver operating characteristic curve (AUC) between the SOFA score and APACHE Ⅱ score (0.784 vs.0.780,Z=0.014,P=0.989).However,compared with APACHE Ⅱ score,the AUC of equation 1 (0.888) and 2 (0.851) were much more (Z=4.333,P=0.000; Z=2.669,P=0.008).Conclusion The sensitivity of 28-day prognosis by WIC score was improved greatly with the combination of SOFA score and age score.