Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and te...Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.展开更多
A layer of porous film containing Ca and P was prepared by the micro-arc oxidation method on the surface of a novel near β biomedical Ti-3Zr-2Sn-3Mo-25Nb alloy, and then NH2- active group was introduced to the films ...A layer of porous film containing Ca and P was prepared by the micro-arc oxidation method on the surface of a novel near β biomedical Ti-3Zr-2Sn-3Mo-25Nb alloy, and then NH2- active group was introduced to the films by activation treatment. The phase composition, surface micro-topography and elemental characteristics of the micro-arc oxidation films were investigated with XRD, SEM, EDS and XPS, and the osteoinduction of the micro-arc oxidation films was tested using the simulated body fluid immersion, the in-vitro osteoblast cultivation test and animal experiment. The results show that the oxide layer is a kind of porous ceramic intermixture and contains Ca and P. The films in the simulated body fluid can induce apatite formation, resulting in excellent bioactivity. The cell test discovers that osteoblasts can grow well on the surface of micro-arc oxidation films. And the Ti-3Zr-2Sn-3Mo-25Nb biomedical alloy coated with active porous calcium-phosphate films shows better osteoinduction in vivo.展开更多
Accurate characterization of the interactions between biomolecules not only provides fundamental insights into cellular processes but also paves the way for drug discovery and development. With recent increases in thr...Accurate characterization of the interactions between biomolecules not only provides fundamental insights into cellular processes but also paves the way for drug discovery and development. With recent increases in throughput and sensitivity, biophysical technologies have become prominent tools for studying biomolecular interactions. Biophysical techniques that can reduce costs, shorten detection time, simplify the complexity of the system under analysis, and simultaneously provide high-quality data content are particularly favored. Here, we summarize the qualitative and quantitative analysis of biomolecular interactions using Micro Scale Thermophoresis(MST), as well as extend the application of MST functions to explore thermodynamics, enzyme kinetics and protein folding-unfolding processes. MST has emerged as a simple and powerful biophysical approach for identifying and quantifying binding events based on the movement of molecules along microscopic temperature gradients. The advantages of MST over other competitive biophysical techniques include freedom from immobilization, rapid analysis times, lower sample consumption, and the ability to analyze binding affinities in cell lysates. This article discusses the instrumental setups, principles, experimental workflows, and examples of MST application in practice.展开更多
To the Editor:Umbilical cord blood transplant(UCBT)serves as an alternative option for treating patients with B cell acute lymphoblastic leukemia(ALL),in the absence of a compatible donor.However,disease recurrence pr...To the Editor:Umbilical cord blood transplant(UCBT)serves as an alternative option for treating patients with B cell acute lymphoblastic leukemia(ALL),in the absence of a compatible donor.However,disease recurrence presents a difficult challenge.Chimeric antigen receptor(CAR)-T cell therapy is a promising approach for treating patients with relapsed/refractory ALL.Among the intensive investigations of infusion of CAR-T cells after transplant,few focus on patients who were administered CAR-T therapy after they relapsed subsequently to UCBT.Here,we report the response rate,toxicity,and survival of CD19 CAR-T cells administered to 10 children and young adults with relapsed acute B lymphoblastic leukemia(B-ALL)after UCBT.Between April 2018 and September 2019,11 patients with relapsed B-ALL after UCBT were enrolled,including three females and eight males,the median age was 10 years(range 7-22 years)and median weight was 35.0 kg(range 21.0-72.0 kg).Patient 10 was excluded because of unsuccessful cell culture.展开更多
Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve depolarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this s...Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve depolarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this study,several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening,among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed,synthesized and compound 42(IC;=0.79μmol/L)was finally obtained.Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca;concentration.Subsequently,the analgesic effect was investigated by intragastric administration in pain models.Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury.Through homology modeling and molecular dynamics,the binding site was predicted to be located near the calcium-binding region betweenα6 andα8.Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.展开更多
Abstract Comparison is made between the MINQUE and simple estimate of the error variance in the normal linear model under the mean square errors criterion, where the model matrix need not have full rank and the disper...Abstract Comparison is made between the MINQUE and simple estimate of the error variance in the normal linear model under the mean square errors criterion, where the model matrix need not have full rank and the dispersion matrix can be singular. Our results show that any one of both estimates cannot be always superior to the other. Some sufficient criteria for any one of them to be better than the other are established. Some interesting relations between these two estimates are also given.展开更多
目的探讨亚肺叶切除和肺叶切除在原发浸润性肺腺癌中的预后效果。方法通过HIS系统(Hospital Information System)选择肿瘤大小在0~2cm的原发浸润性肺腺癌患者作为研究对象。通过倾向性匹配分析来消除潜在的偏倚,使用Kaplan-Meier生存分...目的探讨亚肺叶切除和肺叶切除在原发浸润性肺腺癌中的预后效果。方法通过HIS系统(Hospital Information System)选择肿瘤大小在0~2cm的原发浸润性肺腺癌患者作为研究对象。通过倾向性匹配分析来消除潜在的偏倚,使用Kaplan-Meier生存分析比较亚肺叶切除组和肺叶切除组的总体生存时间。结果共纳入了154例肿瘤大小为0~2cm的浸润性肺腺癌患者,其中肺段切除31例,肺叶切除123例,3年生存时间的分析的结果显示:肺段切除的预后和肺叶切除相似(OS:HR,1.29(0.13-12.81),P=0.81);154例浸润性腺癌患者术后10例出现并发症,其中肺段切除组1例(3.2%)出现持续漏气(超过7d);肺叶切除组出现9例,2例出现持续漏气,1例出现肺部感染,2例出现皮下气肿,1例出现胸腔积液。基于年龄、性别、吸烟史、慢性病史、肿瘤大小及淋巴结清扫数目等变量进行倾向性匹配分析获得28对肺段切除和肺叶切除病例,两组的近期总体生存时间无明显统计学差异性(OS:HR,2.50(0.12-52.20),P=0.38)。结论肺段切除可作为早期原发浸润性肺腺癌的可选治疗方法。展开更多
基金supported by The National Key R&D Program (2022YFC2303700,China)the Ningxia Hui Autonomous Region Key Research and Development Project (2022BEG02042,China)+3 种基金the National Natural Science Foundation of China (82030108,81803351)Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University (KF-202304,China)the China Postdoctoral Science Foundation (2018M641122,China)the National Major Scientific and Technological Special Project for Significant New Drugs Development (2018ZX09711002-013-004,2018ZX09735-001,China)。
文摘Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.
基金Project (2005CB623904) supported by the National Basic Research Program of ChinaProject (30770586) supported by the National Natural Science Foundation of China+1 种基金Project (31011120049) supported by the Australia-China special fund, International Science Linkages Program co-supported by the Department of Innovation, Industry, Science and Research of Australia, and the Ministry of Science and Technology and National Science Foundation of ChinaProject (2010ZDKG-96) supported by the major Subject of "13115" Programs of Shaan’xi Province, China
文摘A layer of porous film containing Ca and P was prepared by the micro-arc oxidation method on the surface of a novel near β biomedical Ti-3Zr-2Sn-3Mo-25Nb alloy, and then NH2- active group was introduced to the films by activation treatment. The phase composition, surface micro-topography and elemental characteristics of the micro-arc oxidation films were investigated with XRD, SEM, EDS and XPS, and the osteoinduction of the micro-arc oxidation films was tested using the simulated body fluid immersion, the in-vitro osteoblast cultivation test and animal experiment. The results show that the oxide layer is a kind of porous ceramic intermixture and contains Ca and P. The films in the simulated body fluid can induce apatite formation, resulting in excellent bioactivity. The cell test discovers that osteoblasts can grow well on the surface of micro-arc oxidation films. And the Ti-3Zr-2Sn-3Mo-25Nb biomedical alloy coated with active porous calcium-phosphate films shows better osteoinduction in vivo.
基金This work was supported by State Key Laboratory of Natural and Biomimetic Drugs,Peking University。
文摘Accurate characterization of the interactions between biomolecules not only provides fundamental insights into cellular processes but also paves the way for drug discovery and development. With recent increases in throughput and sensitivity, biophysical technologies have become prominent tools for studying biomolecular interactions. Biophysical techniques that can reduce costs, shorten detection time, simplify the complexity of the system under analysis, and simultaneously provide high-quality data content are particularly favored. Here, we summarize the qualitative and quantitative analysis of biomolecular interactions using Micro Scale Thermophoresis(MST), as well as extend the application of MST functions to explore thermodynamics, enzyme kinetics and protein folding-unfolding processes. MST has emerged as a simple and powerful biophysical approach for identifying and quantifying binding events based on the movement of molecules along microscopic temperature gradients. The advantages of MST over other competitive biophysical techniques include freedom from immobilization, rapid analysis times, lower sample consumption, and the ability to analyze binding affinities in cell lysates. This article discusses the instrumental setups, principles, experimental workflows, and examples of MST application in practice.
基金The work was supported by grants from the Science and Technology Planning Project of Anhui Province,China(No.1604a0802071)the Major Science and Technology Projects of Anhui Province,China(No.18030801126)。
文摘To the Editor:Umbilical cord blood transplant(UCBT)serves as an alternative option for treating patients with B cell acute lymphoblastic leukemia(ALL),in the absence of a compatible donor.However,disease recurrence presents a difficult challenge.Chimeric antigen receptor(CAR)-T cell therapy is a promising approach for treating patients with relapsed/refractory ALL.Among the intensive investigations of infusion of CAR-T cells after transplant,few focus on patients who were administered CAR-T therapy after they relapsed subsequently to UCBT.Here,we report the response rate,toxicity,and survival of CD19 CAR-T cells administered to 10 children and young adults with relapsed acute B lymphoblastic leukemia(B-ALL)after UCBT.Between April 2018 and September 2019,11 patients with relapsed B-ALL after UCBT were enrolled,including three females and eight males,the median age was 10 years(range 7-22 years)and median weight was 35.0 kg(range 21.0-72.0 kg).Patient 10 was excluded because of unsuccessful cell culture.
基金supported by the National Key Research and Development Project(Grant No.2019YFC1708900)the National Natural Science Foundation of China(Grant No.21772005)+1 种基金National Major Scientific and Technological Special Project for Significant New Drugs Development(2019ZX09204-001,China)Beijing Municipal Natural Science Foundation(7202088,7172118,China)
文摘Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve depolarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this study,several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening,among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed,synthesized and compound 42(IC;=0.79μmol/L)was finally obtained.Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca;concentration.Subsequently,the analgesic effect was investigated by intragastric administration in pain models.Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury.Through homology modeling and molecular dynamics,the binding site was predicted to be located near the calcium-binding region betweenα6 andα8.Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.
基金Partially supported by the National Natural Science Foundation of China (No.10271010)the Natural Science Foundation of Beijing and a Project of Science and Technology of Beijing Education Committee.
文摘Abstract Comparison is made between the MINQUE and simple estimate of the error variance in the normal linear model under the mean square errors criterion, where the model matrix need not have full rank and the dispersion matrix can be singular. Our results show that any one of both estimates cannot be always superior to the other. Some sufficient criteria for any one of them to be better than the other are established. Some interesting relations between these two estimates are also given.
文摘目的探讨亚肺叶切除和肺叶切除在原发浸润性肺腺癌中的预后效果。方法通过HIS系统(Hospital Information System)选择肿瘤大小在0~2cm的原发浸润性肺腺癌患者作为研究对象。通过倾向性匹配分析来消除潜在的偏倚,使用Kaplan-Meier生存分析比较亚肺叶切除组和肺叶切除组的总体生存时间。结果共纳入了154例肿瘤大小为0~2cm的浸润性肺腺癌患者,其中肺段切除31例,肺叶切除123例,3年生存时间的分析的结果显示:肺段切除的预后和肺叶切除相似(OS:HR,1.29(0.13-12.81),P=0.81);154例浸润性腺癌患者术后10例出现并发症,其中肺段切除组1例(3.2%)出现持续漏气(超过7d);肺叶切除组出现9例,2例出现持续漏气,1例出现肺部感染,2例出现皮下气肿,1例出现胸腔积液。基于年龄、性别、吸烟史、慢性病史、肿瘤大小及淋巴结清扫数目等变量进行倾向性匹配分析获得28对肺段切除和肺叶切除病例,两组的近期总体生存时间无明显统计学差异性(OS:HR,2.50(0.12-52.20),P=0.38)。结论肺段切除可作为早期原发浸润性肺腺癌的可选治疗方法。
