嵌合抗原受体T细胞治疗的现状与展望

肿瘤严重威胁着人类健康,当前肿瘤传统的治疗方法有手术治疗、化疗、放疗和靶向药物治疗等。近年来,肿瘤免疫治疗,尤其是嵌合抗原受体（chimeric antigen receptor,CAR） T细胞免疫疗法在基础研究与临床应用中蓬勃发展,并在治疗血液系统恶性肿瘤方面取得了巨大成功。然而,大量研究显示,细胞免疫治疗后可出现不同程度的毒副反应,且部分患者缓解后再次复发。因此,了解细胞治疗面临的挑战与局限性,寻找解决的办法,对继续发挥细胞免疫疗法的潜能具有重要意义。本文就免疫细胞的CAR结构、病毒载体的选择、细胞治疗面临的挑战及前景进行综述。     

胰腺癌早期检测的生物标志物（英文）

胰腺癌症是最难诊断和治疗的恶性肿瘤之一,其特点是发病隐匿、进展迅速、预后差。目前,手术治疗仍然是首选治疗方法。然而由于缺乏早期症状,大约70%的患者在确诊时已经出现局部扩散或远端转移,从而无法进行手术治疗。由此看来,早期检测是提高患者治疗效果和预后的有效途径。临床上使用的成像方法 （CT、MRI、EUS等）通常无法检测早期病变,并且很容易受到操作员的影响。常规临床标志物如CA19-9、CA125、CA242和CEA受到限制,其敏感性或特异性不令人满意。因此,寻找新的具有高敏感性和特异性的标志物是实现胰腺癌早期检测的关键。近年来,对生物标志物的广泛研究主要集中在遗传学、转录组学和蛋白质组学上。特别是由microRNA(miRNA)、long non-coding RNA(lncRNA)和circRNA(circRNA)组成的非蛋白质编码RNA(non-protein coding RNA,ncRNA)为胰腺癌的早期检测提出了许多新思路。然而,其中绝大多数仍处于实验室研究阶段。而一项成熟的生物标志物研究应该整合基因组学、转录组学、蛋白质组学或代谢组学的数据,并结合患者的个体特征（如体重指数...     

非侵入物理疗法——红光照射改善脂多糖诱发小鼠抑郁样行为

目的 抑郁的发生机制不清及药物的临床疗效不佳,导致其成为世界难题。已有研究发现甲醛的气态暴露或液态腹腔注射都可直接诱发小鼠抑郁样行为,而内源甲醛是否参与抑郁的发生尚不清楚。本研究探索脂多糖（lipopolysaccharide,LPS）是否通过刺激内源甲醛产生而诱发小鼠抑郁的分子机制;并观察非侵入物理疗法——630 nm红光照射是否能激活甲醛脱氢酶而降解甲醛,从而改善小鼠抑郁样行为。方法 雄性成年C57BL/6J小鼠随机分组：a.对照组,腹腔注射磷酸缓冲液（phosphate buffer solution,PBS）;b.抑郁模型组,按浓度梯度腹腔注射LPS;c.红光干预组,按浓度梯度腹腔注射LPS后并定时进行630 nm全身红光照射。采用旷场实验（open field test,OFT）、糖水偏爱（suorose preference test,SPT）、悬尾实验（tail suspension test,TST）、强迫游泳（forced swimming test,FST）等方法,评估小鼠的抑郁样行为;用甲醛荧光（Na-FA,特异甲醛荧光探针）定量法及整脑甲醛荧光成像法,检测小鼠脑...     

褪黑素调节烟草丁香假单胞菌抗性的功能研究

为分析褪黑素(N-乙酰-5-甲氧基色胺)在植物先天免疫中的功能及调控机理,研究以病原菌丁香假单胞杆菌(Pseudomonas syringae pv.tomato DC3000,Pst DC3000)—烟草互作系统为模型,检测了病原菌侵染对烟草褪黑素相关基因表达的影响,并探讨了褪黑素对植物叶片病原菌生长以及气孔开度和活性氧自由基(reactive oxygen species,ROS)含量的影响以及调控机理。结果表明:(1)Pst DC3000处理提高了烟草褪黑素合成(NtSNAT1)和受体(NtPMTR1)基因表达,且外源褪黑素处理降低了叶片中的病原菌含量。(2)与野生型植物相比,过表达大豆GmSNAT1基因显著提高了转基因烟草中内源褪黑素含量和NtPMTR1的表达,且转基因烟草叶片中的Pst DC3000菌落数显著下降。(3)外源褪黑素和细菌鞭毛蛋白多肽flg22处理诱导了野生型和转基因烟草保卫细胞中ROS产生和气孔关闭,且转基因植物对褪黑素和flg22诱导的气孔关闭和ROS产生比野生型烟草更加敏感。综上所述,研究表明褪黑素可能通过受体NtPMTR1介导的信号途径促进保卫细胞ROS产生,诱导气孔关闭,从而降低病原菌Pst DC3000的入侵。     

Novel (E)-3-(3-Oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides as Histone Deacetylase Inhibitors: Design,Synthesis and Bioevaluation

Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides ( 4 a – i , 7 a – g ) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a – i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a – g in all biological assays. Compounds 7 e – f were found to be the most active HDAC inhibitors with IC₅₀ of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC₅₀ values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.     

Characterization of the 16S rRNA- and membrane-binding domains of Streptococcus pneumoniae Era GTPase: structural and functional implications.

Era is a highly conserved GTPase essential for bacterial growth. The N-terminal part of Era contains a conserved GTPase domain, whereas the C-terminal part of the protein contains an RNA- and membrane-binding domain, the KH domain. To investigate whether the binding of Era to 16S rRNA and membrane requires its GTPase activity and whether the GTPase domain is essential for these activities, the N- and C-terminal parts of the Streptococcus pneumoniae Era - Era-N (amino acids 1-185) and Era-C (amino acids 141-299), respectively - were expressed and purified. Era-C, which had completely lost GTPase activity, bound to the cytoplasmic membrane and 16S rRNA. In contrast, Era-N, which retained GTPase activity, failed to bind to RNA or membrane. These results therefore indicate that the binding of Era to RNA and membrane does not require the GTPase activity of the protein and that the RNA-binding domain is an independent, functional domain. The physiological effects of the overexpression of Era-C were assessed. The Escherichia coli cells overexpressing Era and Era-N exhibited the same growth rate as wild-type E. coli cells. In contrast, the E. coli cells overexpressing Era-C exhibited a reduced growth rate, indicating that the overexpression of Era-C inhibits cell growth. Furthermore, overexpression of era-N and era-C resulted in morphological changes. Finally, purified Era and Era-C were able to bind to poly(U) RNA, and the binding of Era to poly(U) RNA was significantly inhibited by liposome, as the amount of Era bound to the RNA decreased proportionally with the increase of liposome in the assay. Therefore, this study provides the first biochemical evidence that both binding sites are overlapping. Together, these results indicate that the RNA- and membrane-binding domain of Era is a separate, functional entity and does not require the GTPase activity or the GTPase domain of the protein for activity.     

Neurobiological mechanisms of the meridian and the propagation of needle feeling along the meridian pathway

The present experiments attempt to find the meridian phenomenon and how the needle feeling propagates along the given meridian channels. The neurobiological mechanisms of the meridian were studied with neuroelectrical recording from the motor neurons and CB-HRP retrograde histochemistry technique in both rats and cats. The results demonstrated that most, but not all, of alpha motor neurons supplying a muscle group of a given meridian were selectively activated by afferent inputs originating not only from homonymous or heterogeneous, but synergistic muscle, but also from the skin nerve overlying the muscle group of the homonymous meridian. However, the afferent inputs from the heterogeneous meridian have very weak or no effect. On the other hand, the labeled motor neurons supplying a given meridian muscles form a discrete longitudinal column with a definite bound in the lateral ventral horn. There are oriented dendro-dendristes projections between the labeled motor neurons.The characteristics of both sel