前列腺素E1降低心脏瓣膜置换术患者心肌细胞NF-κB活性及血浆TNF-α水平

目的：评价前列腺素E1（PGE1）对心脏瓣膜置换术患者心肌细胞核转录因子κB（NF‐κB）活性和血浆肿瘤坏死因子α（T N F‐α）水平的影响。方法择期行体外循环下心脏瓣膜置换术的患者40例,年龄32～67岁,体质量指数17～28 kg／m2,美国麻醉师协会（ASA）分级Ⅱ或Ⅲ级,纽约心脏病协会（NYHA）分级Ⅱ或Ⅲ级。采用随机数字表法,将患者分为2组（n＝20）：对照组（C组）和PGE1组（P组）。麻醉诱导后P组静脉输注PGE120 ng · kg －1· min－1,至手术结束,C组给予等容量生理盐水。于体外循环前（T0,基础值）、体外循环开始后30 min（T1）、体外循环结束时（T2）、体外循环结束后12 h（T3）、体外循环结束后24 h（T4）抽取动脉血,检测血浆TNF‐α水平;于T0和T2时取右心耳组织,观察组织病理学变化,并用蛋白免疫印迹法（Western blot）检测NF‐κB活性。结果与C组比较,P组T1～T4时血浆 TNF‐α水平下降（P＜0．05）,T2时心肌病理学损伤明显减轻,心肌细胞NF‐κB活性下降（P＜0．05）。结论 PGE1可减轻心脏瓣膜置换术患者心肌损伤,其机制与抑制心肌细胞NF‐κB活性,减少血浆TNF‐α水平有关。     

氦－氖激光血管内照射治疗慢性乙肝临床观察

应用氦－氖激光血管内照射（ＩＬＩＢ）方法治疗１８例慢性乙型肝炎患者，结果显示丙氨酸转氨酶（ＡＬＴ）、过氧化脂质（ＬＰＯ）降低，Ｐ＜０．０１；而总超氧化物歧化萌（ＳＯＤ）、锰超氧化物歧化酶（ＭｎＳＯＤ）、铜锌超氧化物歧化酶（ＣｕＺｎＳＯＤ）增高，同时５０％～６０％的病人ＨＢｅＡｇ、ＨＢＶＤＮＡ转阴，且与患者临床症状好转相符合。结果还显示Ｔ淋巴细胞亚群ＣＤ８（Ｔｓ／Ｔｃ）、大颗粒淋巴细胞（ＬＧＬ）提高（Ｐ＜０．０５～０．０１），然而ＴＨ亚群变动不显著（Ｐ＞０．０５），提示ＩＬＩＢ具有免疫调节及抗病毒感染的作用。文中还讨论了ＩＬＩＢ治疗慢性乙型肝炎效应的机理，为乙型肝炎的治疗提供了一个新的方法。     

肾移植术后受者CD4+CD28nullT淋巴细胞的表达和阿托伐他汀的干预作用

目的 探讨肾移植术后受者CD4+CD28nullT淋巴细胞的表达和阿托伐他汀的干预作用.方法 采用流式细胞仪检测35例肾移植术后3年以上无明显排斥反应受者以及20例健康人外周血CD4+CD28nullT淋巴细胞数量.对21例合并高脂血症的患者,给予阿托伐他汀20 mg/d干预3月后再次检测外周血CD4+CD28nullT淋巴细胞数量的变化.结果 与健康人相比,肾移植术后受者外周血CD4+CD28nullT淋巴细胞表达明显增加(P＜0.01),通过阿托伐他汀干预后其表达可以明显下降(P＜0.01).结论 肾移植术后受者外周血CD4+CD28nullT淋巴细胞表达增加可能是移植后心血管事件风险增加的重要因素之一,阿托伐他汀可以抑制其作用.     

原发性胆汁性肝硬化-自身免疫性肝炎重叠综合征临床病理研究

目的探讨并比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)及原发性胆汁性肝硬化-自身免疫性肝炎重叠综合征(AIH-PBC重叠综合征)的临床、生化及病理特征。方法对具有肝穿刺标本的14例AIH-PBC重叠综合征、26例Ⅰ型AIH和29例PBC(Scheuer分期Ⅰ、Ⅱ期)患者进行比较,重点分析AIH-PBC重叠综合征的临床表现、生化特点及病理特点。结果 3组患者的性别、年龄及临床特点无显著差异;AIH-PBC重叠综合征血清碱性磷酸酶(ALP)、γ-谷氨酰转肽酶(GGT)、抗线粒体抗体(AMA)、AMA-M2阳性率明显高于AIH组(P<0.05);而丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、γ-球蛋白、免疫球蛋白IgG以及抗核抗体(ANA)或抗平滑肌抗体(SMA)阳性率明显高于PBC(P<0.05或P<0.01)。肝组织学示界面炎/碎屑样坏死、小叶内炎症及胆管病变。结论 AIH-PBC重叠综合征临床、血清学及组织病理学表现出AIH和PBC双重特征,不同于单纯的PBC和AIH。     

HLA-DM基因遗传多态性对系统性红斑狼疮易感性的影响

目的　探索 HL A- DM等位基因频率与基因型分布对系统性红斑狼疮 （SL E）易感性的影响。方法　用多聚酶链反应 -限制性片断长度多态性 （PCR- RFL P）确定 DM的基因型 ,用病例对照研究的方法探索 DM与 SL E的关联性。结果　检测到的 7种 DMA与 DMB等位基因和 4 2种单体型在 SL E组与正常对照组分布一致。DMB* 0 10 2 / 0 10 3基因型在对照组的分布频率明显高于 SL E组 （P <0 .0 5 ） ,但校正后差异无显著性 ,其余 13种基因型在两组差异均无显著意义。结论　 HL A-DM基因的遗传多态性对 SL E的发病没有直接影响     

海星甾醇抗实验性心律失常的作用

目的：研究海星甾醇C01对实验性心律失常的拮抗作用。方法：麻醉大鼠股静脉快速iv5?Cl2诱发室颤（VF）,记录大鼠的VF发生和死亡数,小鼠尾静脉ivCaCl2-Ach混合液（10ml/kg）诱发小鼠房颤（扑）,记录房颤（扑）的发生率;麻醉大鼠冠脉结扎再灌注诱发心律失常,记录结扎5min和再灌期各时间点的心律失常发生率,并比较ST段的变化,电刺激致家兔室颤,记录室颤阈值。结果：海星甾醇C801显著降低了CaCl2诱发VF的发生率,抑制小鼠房颤（扑）的发生,对大鼠结扎期 再灌期各个时间点都有显著的抗心律失常的作用,减轻结扎造成的心肌缺血及再灌所致的心肌损伤,中高剂量组可显著提高家兔室颤阈值,降低VF的发生。结论：C01能对抗多个性和房性心律失常的实验模型,提示C01具有广泛的抗心律失常作用。     

Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report

Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points

• The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
• The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
• The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.

     

Central nervous system diseases related to pathological microglial phagocytosis

Microglia are important phagocytes of the central nervous system (CNS). They play an important role in protecting the CNS by clearing necrotic tissue and apoptotic cells in many CNS diseases. However, recent studies have found that microglia can phagocytose parts of neurons excessively, such as the neuronal cell body, synapse, or myelin sheaths, before or after the onset of CNS diseases, leading to aggravated injury and impaired tissue repair. Meanwhile, reduced phagocytosis of synapses and myelin results in abnormal circuit connections and inhibition of remyelination, respectively. Previous studies focused primarily on the positive effects of microglia phagocytosis, whereas only a few studies have focused on the negative effects. In this review, we use the term "pathological microglial phagocytosis" to refer to excessive or reduced phagocytosis by microglia that leads to structural or functional abnormalities in target cells and brain tissue. The classification of pathological microglial phagocytosis, the composition, and activation of related signaling pathways, as well as the process of pathological phagocytosis in various kinds of CNS diseases, are described in this review. We hypothesize that pathological microglial phagocytosis leads to aggravation of tissue damage and negative functional outcome. For example, excessive microglial phagocytosis of synapses can be observed in Alzheimer's disease and schizophrenia, leading to significant synapse loss and memory impairment. In Parkinson's disease, ischemic stroke, and traumatic brain injury, excessive microglial phagocytosis of neuronal cell bodies causes impaired gray matter recovery and sensory dysfunction. We therefore believe that more studies should focus on the mechanism of pathological microglial phagocytosis and activation to uncover potential targets of therapeutic intervention.     

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.