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Characteristics, phenotypes, mechanisms and management of severe asthma

Chinese Medical Journal 2022年第10期135卷 1141-1155页

作者： Kian Fan Chung Piers Dixey Hisham Abubakar-Waziri Pankaj Bhavsari Pujan H.Patel Sujuan Guo Yang Ji National Heart&Lung Institute Imperial College LondonLondon SW36LYUK Royal Brompton&Harefield NHS Hospitals LondonUK Department of Respiratory Medicine University of Hong Kong Shenzhen HospitalShenzhenGuangdong 518053China.

Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ’’uncontrolled’ or which remains ’’uncontrolled’ despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.

关键词： Severe asthma Biologic therapies Eosinophils Neutrophils Corticosteroid insensitivity Type 2-high inflammation

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Murine studies and expressional analyses of human cardiac pericytes reveal novel trajectories of SARS-CoV-2 Spike protein-induced microvascular damage

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3211-3214页

作者： Elisa Avolio Prashant K.Srivastava Jiahui Ji Michele Carrabba Christopher T.W.Tsang Yue Gu Anita C.Thomas Kapil Gupta Imre Berger Costanza Emanueli Paolo Madeddu Bristol Medical School Translational Health SciencesUniversity of BristolBristolUK National Heart&Lung Institute Imperial CollegeLondonUK School of Biochemistry University of BristolBristolUK

Dear Editor,The Coronavirus disease 2019(COVID-19)pandemic has caused over 670 million cases and 6.7 million deaths worldwide,many of which are attributed to cardiovascular complications.Virus-induced endothelial dama... 详细信息

关键词： damage cardiovascular cardiac

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Human mitochondrial DNA diseases and Drosophila models

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Journal of Genetics and Genomics 2019年第4期46卷 201-212页

作者： Zhe Chen Fan Zhang Hong Xu national heart Lung and Blood InstituteNational Institute of Health

Mutations that disrupt the mitochondrial genome cause a number of human diseases whose phenotypic presentation varies widely among tissues and individuals. This variability owes in part to the unconventional genetics of mitochondrial DNA(mtDNA), which includes polyploidy, maternal inheritance and dependence on nuclear-encoded factors. The recent development of genetic tools for manipulating mitochondrial genome in Drosophila melanogaster renders this powerful model organism an attractive alternative to mammalian systems for understanding mtDNA-related diseases. In this review, we summarize mtDNA genetics and human mtDNA-related diseases. We highlight existing Drosophila models of mtDNA mutations and discuss their potential use in advancing our knowledge of mitochondrial biology and in modeling human mitochondrial disorders. We also discuss the potential and present challenges of gene therapy for the future treatment of mtDNA diseases.

关键词： Mitochondrial DNA mtDNA disease mtDNA genetics Drosophila model

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Monkeypox claims new victims: the outbreak in men who have sex with men

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Infectious Diseases of Poverty 2022年第4期11卷 91-93页

作者： Xiaoning Liu Zheng Zhu Yun He Jia Wen Lim Bethany Lane Hui Wang Qiaoli Peng Liqin Sun Hongzhou Lu Department of Infectious Diseases National Clinical Research Center for Infectious DiseasesThe Third People's Hospital of ShenzhenShenzhen 518112GuangdongChina National Heart&Lung Institute Faculty of MedicineImperial College LondonLondonUK School of Nursing Fudan UniversityShanghaiChina Fudan University Centre for Evidence-Based Nursing:A Joanna Briggs institute Centre of Excellence ShanghaiChina NYU Rory Meyers College of Nursing New York UniversityNew YorkNYUSA St Bartholomew's Hospital LondonUK

Monkeypox has a very prominent regional epidemic.It has been confined to Western and Central African countries.Sporadic cases found in countries outside Africa generally have a history of sojourn in endemic areas.However,the recent multinational outbreak of monkeypox cases in Europe in early May 2022 has revealed a changing epidemiological trend,those confirmed cases had no sojourn history in endemic areas and with a high proportion of cases involving men who have sex with men(MSM).Among the MSM cases,many of them presented atypical clinical manifestations of monkeypox and with other sexually transmitted diseases co-infection.Combined with the high social interactivity in this community,there is likely a higher risk of monkeypox transmission in this population.Establishing an infectious disease surveillance system,maintaining highly vigilant regarding the transmission of monkeypox in MSM,and responding promptly are necessary and effective measures to contain the outbreak.

关键词： Monkeypox Men have sex with men Public health Infectious diseases

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“病理影像化”:基于组织学特征的磁共振成像在体识别心肌纤维化

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Science Bulletin 2023年第9期68卷 864-867页

作者：陆敏杰朱乐怡 Sanjay K.Prasad 赵世华 Department of Magnetic Resonance Imaging Fuwai HospitalState Key Laboratory of Cardiovascular DiseaseChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Key Laboratory of Cardiovascular Imaging(Cultivation) Chinese Academy of Medical SciencesBeijing 100037China Cardiovascular Magnetic Resonance Unit Royal Brompton HospitalLondon SW36NPUK National Heart&Lung Institute Imperial CollegeLondon W21PGUK

Myocardial fibrosis,characterized by the excessive deposition of extracellular matrix proteins,is an important underlying mechanism for adverse outcomes in many cardiovascular diseases[1].Multiple modalities have been developed to identify and quantify myocardial fibrosis non-invasively.Cardiac magnetic resonance(CMR)imaging provides the gold standard for the assessment of cardiac structure and function.

关键词：磁共振成像心肌纤维化组织学特征影像化

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mRNA delivery in cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1348-1357页

作者： Yichen Zhong Shi Du Yizhou Dong Division of Pharmaceutics&Pharmacology College of PharmacyThe Ohio State UniversityColumbusOH 43210USA Department of Radiation Oncology Department of Biomedical EngineeringCenter for Clinical and Translational ScienceComprehensive Cancer CenterDorothy M.Davis Heart&Lung Research InstituteCenter for Cancer EngineeringCenter for Cancer MetabolismPelotonia Institute for Immune-OncologyThe Ohio State UniversityColumbusOH 43210USA Icahn Genomics institute Precision Immunology InstituteDepartment of Oncological SciencesTisch Cancer InstituteFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA

Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.

关键词： Cancer immunotherapy Lipid nanoparticles Lipid—polymer hybrid nanoparticles Messenger RNA mRNA delivery Polymeric nanoparticles Protein/peptide-mediated nanoparticles

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血红素氧化酶基因启动子GT序列变量与冠状动脉支架术后再狭窄

血红素氧化酶基因启动子GT序列变量与冠状动脉支架术后再狭窄

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中华医学会心血管病分会第八次全国心血管病学术会议

作者：李萍 Mohamed A.Elrayess Abuzeid H.Gomma Jutta Palmen Emma Hawe Kim M.Fox Steve E.Humphries 江西医学院二附院心内科 Centre for Cardiovascular Genetics BHF laboratories University College London National Heart&Lung Institute and Royal Brompton Hospital National Heart&Lung Institute and Royal Brompton Hospitab

目的血管平滑肌细胞可表达血红素氧化酶(HO),后者是降解血红素成为胆红素、亚铁及一氧化碳的限速酶。血管平滑肌来源的一氧化碳已证实能抑制血管平滑肌增殖。研究表明Ⅰ型HO基因启动子部位的GT重复序列长短变量可影响该基因的转录水平,...

目的血管平滑肌细胞可表达血红素氧化酶(HO),后者是降解血红素成为胆红素、亚铁及一氧化碳的限速酶。血管平滑肌来源的一氧化碳已证实能抑制血管平滑肌增殖。研究表明Ⅰ型HO基因启动子部位的GT重复序列长短变量可影响该基因的转录水平,较短GT重复序列能使该基因转录活性增加,因而对多个疾病的发生具有保护作用。本研究的目的为观察GT重复序列长短变量差异对冠脉支架置入术后再狭窄的影响。方法187例成功行冠脉支架置入术的患者,6个月随访时约27.8%管腔再狭窄超过50%。用PCR和DNA测序仪确定HO基因启动子部位的GT重复次数。高敏法测定术前及术后24、48小时血浆中的白介素6和C反应蛋白水平。结果各基因型组间术后IL-6和CPR水平以及再狭窄情况无差异,但携带较短GT序列者(n=120)术前基础IL-6值比非短GT序列携带者(n=67)低大约33.3%(P=0.0008)。结论尽管未能说明HO-1基因多态能影响支架置入术后的炎性水平及再狭窄情况,但它和基础IL6浓度的关系提示,短GT序列可能保护动脉粥样的炎症过程。

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Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA

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Genomics, Proteomics & Bioinformatics 2017年第3期15卷 177-186页

作者： Iain M.Dykes Costanza Emanueli School of Clinical Sciences University of Bristol national heart and lung institute Imperial College London

Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA （lncRNA）, a heteroge- neous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA （miRNA） pathways, lncRNA has been shown to act as both a source and an inhi- bitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying com- plexes by directing them to specific loci.

关键词： Long non-coding RNA MicroRNA Transcriptional regulation Epigenetics Post-transcriptionalregulation

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Atg7 in development and disease： panacea or Pandora＇s Box？

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Protein & Cell 2015年第10期6卷 722-734页

作者： Jianhua Xiong Center for Molecular Medicine National Heart Lung and Blood Institute National Institutes of Health Bethesda MD 20892USA

Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG （autophagy-related） protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an Ellike activating enzyme facilitating both microtubule-associated protein light chain 3 （LC3）- phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.

关键词： autophagy Atg7 mouse model,development disease

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BMPR2 spruces up the endothelium n pulmonary hypertension

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Protein & Cell 2015年第10期6卷 703-708页

作者： Jianhua Xiong Center for Molecular Medicine National Heart Lung and Blood Institute National Institutes of Health Bethesda MD 20892USA

Pulmonary hypertension （PH） is a potentially lethal disorder because of a dearth of effective therapeutic options （Schermuly et al., 2011; Mehari et al., 2014）. Pulmonary arterial hypertension （PAH） is a major type of PH that is defined by a mean pulmonary arterial pressure higher than 25 mm Hg at rest or 30 mm Hg during exercise （Kovacs et al., 2009）.

关键词： Pulmonary Hypertension Pulmonary Arterial Hypertension Idiopathic Pulmonary Arterial Hypertension Monocrotaline Bone Morphogenetic Protein Ligand

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