Pharmacotherapeutic strategies for critical asthma syndrome: a look at the state of the art

ABSTRACT

Introduction

‘Critical Asthma Syndrome’ (CAS) is an umbrella term proposed to include several forms of asthma, responsible for acute and life-threatening exacerbations. CAS requires urgent and adequate supportive and pharmacological treatments to prevent serious outcomes.     

体外转染Cyclin A2基因对原代大鼠心肌细胞增殖的影响

目的探讨体外转染细胞周期素A2(Cyclin A2)基因对原代大鼠心肌细胞增殖的影响,为心脏再生提供细胞学依据。方法 SD乳鼠12只,分离、培养、鉴定原代乳鼠心肌细胞并分为3组,实验组:转染带有强化绿色荧光蛋白(GFP)和Cyclin A2基因的重组腺病毒(Ad-Cyclin A2-GFP);空病毒组:转染不含目的基因带有GFP的重组腺病毒(Ad-Null-GFP);阴性对照组:未做转染处理,仅加入等量的培养基。利用GFP示踪技术,评估原代心肌细胞转染效率;转染后的细胞继续体外培养3~5d,利用免疫荧光技术分别检测Cyclin A2、磷酸化组蛋白H3(H3P)、心肌肌钙蛋白-T(c Tn T)。结果 1.荧光GFP示踪表明原代心肌细胞的转染效率高达(97±0.74)%;2.免疫荧光标记显示,空病毒组和对照组结果相似;心肌细胞特异性标记蛋白c Tn T分布于细胞质,原代心肌细胞纯度高达(95±0.62)%;心肌细胞Cyclin A2主要在胞核内聚集,少数分布于细胞质。H3P为核蛋白在细胞核内分布。3.转染Cyclin A2后,实验组H3P阳性率明显高于空病毒组和对照组,差异具有统计学意义(P0.05);实验组可见大量多核细胞,以双核为主,伴少量3核细胞。结论腺病毒作为转染载体对原代心肌细胞有很好的侵染效率;Cyclin A2超表达促进原代心肌细胞形成双核。     

低密度脂蛋白在2型糖尿病骨质疏松中的作用研究进展

2型糖尿病及骨质疏松已成为我国最主要的慢性代谢性疾病。2型糖尿病常伴有血脂紊乱，常表现为低密度脂蛋白升高，而越来越多的研究表明血脂通过不同的方式影响骨代谢，其机制可能是通过抑制骨髓间充质干细胞成骨分化，通过RANK/RNAKL/OPG信号通路及炎症反应调节破骨细胞等方式调节骨代谢。     

Dissecting the biological heterogeneity of HER2-positive breast cancer

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.     

利用耳甲腔型小耳畸形残耳皮瓣及软骨改善再造耳颅耳沟效果观察

目的探讨对先天性耳甲腔型小耳畸形患者行全扩张法全耳再造术后，利用残耳皮瓣改善再造耳颅耳沟的效果。方法回顾分析 2012 年 1 月—2017 年 1 月收治的 150 例先天性耳甲腔型小耳畸形患者。其中男 92 例，女 58 例；年龄 6.5～35.0 岁，平均 11.1 岁。采用一期扩张器埋置、二期全扩张法全耳再造术后发现上部颅耳沟浅显；于 6～12 个月后行三期再造耳修整。将残耳垂通过“Z”字改型转移以再造耳垂。在残耳上部作蒂在轮屏切迹的残耳上部皮瓣，弧形切开松解并加深上部颅耳沟，将上部残耳皮瓣向颅耳沟创面旋转推进缝合以覆盖创面；将带皮下组织蒂的残耳软骨组织瓣插入支架底部形成的腔隙内，并缝合固定，以增加支架的高度；耳甲腔区其余残耳皮瓣用以覆盖耳甲腔创面。结果术后拆线时 1 例患儿皮瓣远端出现直径约 0.5 cm 的表皮水疱，经换药 2 周后愈合；其余患者皮瓣成活良好。患者均获随访，随访时间 6～12 个月，平均 9.6 个月。再造耳上部颅耳沟均明显加深，再造耳支架高度不同程度增加，双耳对称性佳，耳甲腔无明显挛缩变小，再造耳外观满意。再造耳上部表面毛发明显减少，耳周发际线上移。结论采用耳甲腔型小耳畸形的残耳皮瓣及残耳软骨瓣转移，不仅可加深颅耳沟，而且可增加上部支架的高度，术后颅耳沟变形较轻，再造耳与正常耳廓的对称性更佳。     

藿香正气汤抑制新型冠状病毒复制过程的有效成分及机制初探＊

目的 收集藿香正气汤的主要活性成分，通过分子对接及网络药理学探讨其防控新型冠状病毒肺炎（COVID-19）的有效成分及治疗机制。方法 通过基于配体-蛋白质相互作用的计算方法，以瑞德西韦为对照，探索藿香正气汤潜在治疗COVID-19的成分，并选出对接较好成分进行药理学机制预测，初探其药理学机制。结果 本研究筛选出5种与新冠病毒3CLpro结合能力强于瑞德西韦的小分子成分。网络药理学初步预测抗病毒途径可能是通过PI3K-Akt 信号通路影响病毒复制。结论 成分C1-C5与3CLpro结合良好，推测其可能是潜在的3CLpro的抑制剂，为抗病毒天然药物的开发提供了理论依据。     

Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils

Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b⁺ cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.