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Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats. 伊伐卡夫托能减轻 hG551D 大鼠急性铜绿假单胞菌感染时的粘液负担、细菌负荷和炎症,但不能减轻慢性铜绿假单胞菌感染时的粘液负担、细菌负荷和炎症。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-11-04 DOI: 10.1186/s12931-024-03029-0
Johnathan D Keith, Mikayla Murphree-Terry, Gretchen Bollar, Ashley M Oden, Ian H Doty, Susan E Birket

Background: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.

Methods: We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.

Results: We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.

Conclusions: The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.

背景:新批准的高效调节疗法(HEMT)改变了 CF 患者的生活。虽然这些药物显著改善了肺功能和病情恶化率,但肺部的细菌种群并未根除。持续定植背后的机制尚不完全清楚:我们使用人源化大鼠来评估伊伐卡夫托治疗对感染结果的影响。hG551D大鼠在感染铜绿假单胞菌期间或之前接受伊伐卡夫托治疗。感染反应通过肺部细菌负荷和肺部粘液负荷进行评估:结果:我们发现,使用伊伐卡夫托治疗的hG551D大鼠在感染的急性期肺部细菌数量减少,但在感染的慢性期与药物对照组相比没有差异。同样,气道中的中性粒细胞百分比在急性期也有所减少,但在慢性期则没有减少。总体体重数据表明,使用伊伐卡夫托治疗后,hG551D大鼠在感染过程中的体重恢复情况明显更好。伊伐卡夫托对 G551D 突变的增效作用使短路电流测量结果与 WT 相同,甚至在感染的慢性阶段也是如此。尽管存在持续感染,但使用伊伐卡夫托治疗的 hG551D 大鼠在慢性感染期间出现粘液栓塞的气道数量较少:数据表明,与载体组相比,接受伊伐卡夫托治疗的 hG551D 大鼠在感染期间的疗效更好。尽管感染和炎症持续存在,但大鼠的体重增加、CFTR蛋白功能增强、粘液积聚减少。这些数据表明,在这种大鼠模型中,ivacaftor 可改善对感染的耐受性,而不是根除感染。
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引用次数: 0
Loss of interferon regulatory factor-1 prevents lung fibrosis by upregulation of pon1 expression. 干扰素调节因子-1的缺失可通过上调pon1的表达防止肺纤维化。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-11-01 DOI: 10.1186/s12931-024-02987-9
Aiyuan Zhou, Xiyan Zhang, Xinyue Hu, Tiao Li, Wenzhong Peng, Hang Yang, Dingding Deng, Chunheng Mo, Rongli Lu, Pinhua Pan

Background: Interferon regulatory factor-1 (IRF1) is a transcription factor that plays a significant role in various biological processes, including inflammatory injury, viral infection, cell death, and immune responses, and it has been extensively studied in the context of different lung diseases. However, the mechanism underlying its involvement in lung fibrosis remains largely unknown.

Methods: Wild type (WT) mice, IRF1 global-null mice (Irf1-/-) were subjected to a bleomycin-induced lung fibrosis model to enable examination of the role of IRF1 in lung fibrosis. Proteomic analysis of lung tissue from WT and Irf1-/- mice treated with saline or bleomycin was performed to explore the mechanism of IRF1 in regulating lung fibrosis.

Results: In the bleomycin-induced fibrosis mouse model, increased expression of IRF1 was observed. Irf1 knockout mice displayed decreased lung fibrosis relative to WT mice following treatment with bleomycin. The protein expression of fibronectin, as assessed by the Western blot analysis of lung tissues, was downregulated in Irf1-/- mice. We observed a similar reduction in collagen content using hydroxyproline detection. Histologically, there was less collagen deposition in the lungs of Irf1-/- mice compared with WT mice. Proteomics data revealed that IRF1 may be involved in lung fibrosis via the regulation of ferroptosis. We determined that paraoxonase 1(PON1), a poorly characterized protein in lung fibrosis, was upregulated in Irf1-/- mice following exposure to bleomycin. In vitro experiments revealed that IRF1 could regulate the level of GSH and MDA through PON1. We also determined that PON1 levels were lower in the plasma of IPF patients compared with healthy controls.

Conclusion: Our data highlight the importance of IRF1 in the fibrotic process, and PON1 may be a potential mediator of IRF1 in the progression of lung fibrosis.

背景:干扰素调节因子-1(IRF1)是一种转录因子,在炎症损伤、病毒感染、细胞死亡和免疫反应等多种生物过程中发挥着重要作用,它在不同肺部疾病中的作用已被广泛研究。然而,它参与肺纤维化的机制在很大程度上仍然未知:方法:将野生型(WT)小鼠和IRF1全基因缺失小鼠(Irf1-/-)置于博莱霉素诱导的肺纤维化模型中,以研究IRF1在肺纤维化中的作用。对用生理盐水或博莱霉素处理的WT小鼠和Irf1-/-小鼠的肺组织进行了蛋白质组学分析,以探索IRF1调控肺纤维化的机制:结果:在博莱霉素诱导的肺纤维化小鼠模型中,观察到IRF1的表达增加。与WT小鼠相比,IRF1基因敲除小鼠在博莱霉素治疗后肺纤维化程度降低。通过对肺组织的 Western 印迹分析评估,Irf1-/-小鼠的纤维连接蛋白的蛋白表达下调。通过羟脯氨酸检测,我们观察到胶原蛋白含量也有类似的减少。从组织学角度看,与 WT 小鼠相比,Irf1-/- 小鼠肺部的胶原沉积较少。蛋白质组学数据显示,IRF1 可能通过调节铁氧化酶参与肺纤维化。我们发现,在暴露于博莱霉素后,Irf1-/-小鼠体内的对氧磷(paraoxonase)1(PON1)上调,而对氧磷(paraoxonase)1是一种在肺纤维化中特征不明显的蛋白质。体外实验显示,IRF1可通过PON1调节GSH和MDA的水平。我们还发现,与健康对照组相比,IPF 患者血浆中的 PON1 水平较低:我们的数据强调了IRF1在纤维化过程中的重要性,而PON1可能是IRF1在肺纤维化进展过程中的潜在介质。
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引用次数: 0
Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3. 参芪扶正注射液通过FOXO3影响FBXO22/p53轴,抑制乳酸诱导的NSCLC顺铂耐药。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-11-01 DOI: 10.1186/s12931-024-03013-8
Wei Bo, Xiaokai Wang, Ning Yu, Chun Wang, Chunying Liu

Background: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Cisplatin (DDP)-based combination chemotherapy is the main treatment of NSCLC. Due to resistance to DDP, 5-year overall survival rate of NSCLC patients is very low. Shenqifuzheng injection (SQFZ) is essential for lung cancer progression. However, whether SQFZ plays a role in DDP resistance in NSCLC and its molecular mechanism remains unclear.

Methods: Levels of FOXO3, FBXO22 and p53 in NSCLC tissues and cells were assessed by RT-qPCR and Western blot. Cell proliferation and apoptosis were analyzed utilizing CCK-8, Colony formation and Flow cytometry assays. Lactate (LA) levels were tested via ELISA. ChIP and Dual luciferase reporter assays validated regulatory relationship between FOXO3 and FBXO22. Immunoprecipitation assay evaluated p53 ubiquitination levels. The subcutaneous tumor model of nude mice was constructed. TUNEL staining detected apoptosis in tissues, and IHC assessed expression of Ki67, FOXO3, FBXO22 and p53.

Results: FOXO3 was decreased, whereas LA and FBXO22 were increased in NSCLC patients. LA led to a higher DDP resistance in A549/DDP cells, while SQFZ reversed this effect by upregulating FOXO3. Furthermore, FBXO22 was a downstream effecter of FOXO3 and FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. We next found SQFZ inhibited LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 axis. Finally, SQFZ regulated LA-mediated DDP resistance in NSCLC nude mice.

Conclusion: SQFZ influences LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 pathway, providing a promising agent for NSCLC treatment.

背景:非小细胞肺癌(NSCLC)占肺癌的 80%:非小细胞肺癌(NSCLC)占肺癌的 80%。以顺铂(DDP)为基础的联合化疗是治疗 NSCLC 的主要方法。由于对DDP产生耐药性,NSCLC患者的5年总生存率非常低。神曲扶正注射液(SQFZ)对肺癌的进展至关重要。然而,SQFZ是否在NSCLC的DDP耐药性中发挥作用及其分子机制仍不清楚:方法:通过RT-qPCR和Western blot评估NSCLC组织和细胞中FOXO3、FBXO22和p53的水平。利用 CCK-8、集落形成和流式细胞术分析细胞增殖和凋亡。通过 ELISA 检测乳酸(LA)水平。ChIP 和双荧光素酶报告实验验证了 FOXO3 和 FBXO22 之间的调控关系。免疫沉淀测定评估了 p53 泛素化水平。构建了裸鼠皮下肿瘤模型。TUNEL染色检测组织凋亡,IHC评估Ki67、FOXO3、FBXO22和p53的表达:结果:在NSCLC患者中,FOXO3减少,而LA和FBXO22增加。LA导致A549/DDP细胞对DDP的抗性增强,而SQFZ通过上调FOXO3逆转了这种效应。此外,FBXO22是FOXO3的下游效应器,FBXO22影响了p53的泛素化,从而逆转了SQFZ的抑制作用。接下来,我们发现SQFZ通过FOXO3/FBXO22/p53轴抑制LA诱导的NSCLC的DDP耐药性。最后,SQFZ调节了NSCLC裸鼠对LA介导的DDP耐药性:结论:SQFZ通过FOXO3/FBXO22/p53途径影响LA诱导的NSCLC DDP耐药性,为NSCLC治疗提供了一种有前景的药物。
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引用次数: 0
Patient-centered care in pulmonary fibrosis: access, anticipate, and act. 以患者为中心的肺纤维化护理:获取、预测和行动。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-11-01 DOI: 10.1186/s12931-024-02997-7
Delian E Hofman, Tonia Magrì, Catharina C Moor, Luca Richeldi, Marlies S Wijsenbeek, Yuko Waseda

Comprehensive care integrates individual patient needs and is highly valued for patients with pulmonary fibrosis (PF). The importance of a patient-centered care approach is rooted in the unpredictable progressiveness of the disease course in PF. The respiratory impairment associated with PF has a major impact on the quality of life for both patients and their caregivers. We believe that prioritizing patient preferences could improve the shared decision making process and may ultimately lead to better health outcomes. Despite the growing emphasis for this approach, it remains challenging to adopt it in clinical practice. In this review, we propose the comprehensive Triple A Care Model, consisting of the domains Access, Anticipate, and Act, which emphasizes core elements of patient-centered care for patients with PF. We will provide an overview of the unmet needs in care for patients with PF and elaborate on the current methods for delivering patient-centered care. The latest insights into symptom management and supportive measures and several approaches to improving access to care are discussed, in line with the most recent guidelines.

综合护理考虑了患者的个体需求,对肺纤维化(PF)患者具有很高的价值。以患者为中心的护理方法之所以重要,是因为肺纤维化的病程具有不可预测的进展性。与肺纤维化相关的呼吸障碍对患者及其护理人员的生活质量都有重大影响。我们认为,优先考虑患者的偏好可以改善共同决策过程,并最终带来更好的健康结果。尽管这种方法越来越受到重视,但在临床实践中采用这种方法仍具有挑战性。在这篇综述中,我们提出了全面的三A护理模式,由获取、预测和行动三个领域组成,强调了为 PF 患者提供以患者为中心的护理的核心要素。我们将概述心房颤动患者在护理方面尚未满足的需求,并详细介绍目前提供以患者为中心的护理的方法。我们还将讨论症状管理和支持性措施方面的最新见解,以及根据最新指南改善护理可及性的几种方法。
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引用次数: 0
Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice. 定量微计算机断层扫描生物标志物阐明了老年小鼠与年龄相关的肺纤维化。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-30 DOI: 10.1186/s12931-024-03006-7
Davide Buseghin, Andrea Grandi, Erica Ferrini, Gino Villetti, Roberta Ciccimarra, Nicola Sverzellati, Andrea Aliverti, Francesca Pennati, Franco Fabio Stellari

Background: Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.

Methods: A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.

Results: Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.

Conclusions: Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

背景:特发性肺纤维化(IPF)主要影响 60 岁以上的人群,目前主要通过年轻的小鼠模型进行研究。目前的治疗方法疗效有限,因此需要能更好地模拟老年患者群体的动物模型。为此,我们通过诱导老年小鼠肺纤维化,以纵向显微 CT 成像为主要读数,并特别关注动物福利:方法:给 18-24 个月大的雄性 C57Bl/6j 小鼠注射双倍博莱霉素,诱导肺纤维化。与幼鼠(8-12周大)的常用剂量相比,博莱霉素剂量降低至75%,从而使小鼠长期肺纤维化而不死亡,符合动物福利准则。诱导肺纤维化后,动物连续两周每天一次服用宁替达尼,并通过显微CT进行纵向监测,提供结构和功能生物标志物,然后进行死后组织学分析作为终点:结果:与年轻小鼠相比,老年小鼠的体积增大,组织密度和功能降低,炎症明显。这种脆弱性的增加迫使博莱霉素剂量减少到最低测试水平(2.5微克/只小鼠),从而诱发了较轻微但持续的纤维化,同时保护了动物福利。宁替达尼治疗可减少纤维化病变并改善肺功能:我们的数据确定了一种缩小博莱霉素剂量的治疗方法,它能在纤维化诱导和动物福利之间实现最佳权衡,而这正是在老年肺中进行抗纤维化药物试验的要求。在这种低严重程度的疾病模型中,Nintedanib显示出了显著的疗效,提示了潜在的患者分层策略。通过显微CT对肺部病理进行了定量评估,显示了临床试验中纵向终点的价值。
{"title":"Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice.","authors":"Davide Buseghin, Andrea Grandi, Erica Ferrini, Gino Villetti, Roberta Ciccimarra, Nicola Sverzellati, Andrea Aliverti, Francesca Pennati, Franco Fabio Stellari","doi":"10.1186/s12931-024-03006-7","DOIUrl":"10.1186/s12931-024-03006-7","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.</p><p><strong>Methods: </strong>A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.</p><p><strong>Results: </strong>Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.</p><p><strong>Conclusions: </strong>Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Six clinical phenotypes with prognostic implications were identified by unsupervised machine learning in children and adolescents with SARS-CoV-2 infection: results from a German nationwide registry. 通过无监督机器学习在感染 SARS-CoV-2 的儿童和青少年中识别出六种具有预后意义的临床表型:来自德国全国范围登记的结果。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-30 DOI: 10.1186/s12931-024-03018-3
Yanyan Shi, Ralf Strobl, Reinhard Berner, Jakob Armann, Simone Scheithauer, Eva Grill

Objective: Phenotypes are important for patient classification, disease prognostication, and treatment customization. We aimed to identify distinct clinical phenotypes of children and adolescents hospitalized with SARS-CoV-2 infection, and to evaluate their prognostic differences.

Methods: The German Society of Pediatric Infectious Diseases (DGPI) registry is a nationwide, prospective registry for children and adolescents hospitalized with a SARS-CoV-2 infection in Germany. We applied hierarchical clustering for phenotype identification with variables including sex, SARS-CoV-2-related symptoms on admission, pre-existing comorbidities, clinically relevant coinfection, and SARS-CoV-2 risk factors. Outcomes of this study were: discharge status and ICU admission. Discharge status was categorized as: full recovery, residual symptoms, and unfavorable prognosis (including consequential damage that has already been identified as potentially irreversible at the time of discharge and SARS-CoV-2-related death). After acquiring the phenotypes, we evaluated their correlation with discharge status by multinomial logistic regression model, and correlation with ICU admission by binary logistic regression model. We conducted an analogous subgroup analysis for those aged < 1 year (infants) and those aged ⩾ 1 year (non-infants).

Results: The DGPI registry enrolled 6983 patients, through which we identified six distinct phenotypes for children and adolescents with SARS-CoV-2 which can be characterized by their symptom pattern: phenotype A had a range of symptoms, while predominant symptoms of patients with other phenotypes were gastrointestinal (95.9%, B), asymptomatic (95.9%, C), lower respiratory tract (49.8%, D), lower respiratory tract and ear, nose and throat (86.2% and 41.7%, E), and neurological (99.2%, F). Regarding discharge status, patients with D and E phenotype had the highest odds of having residual symptoms (OR: 1.33 [1.11, 1.59] and 1.91 [1.65, 2.21], respectively) and patients with phenotype D were significantly more likely (OR: 4.00 [1.95, 8.19]) to have an unfavorable prognosis. Regarding ICU, patients with phenotype D had higher possibility of ICU admission than staying in normal ward (OR: 4.26 [3.06, 5.98]), compared to patients with phenotype A. The outcomes observed in the infants and non-infants closely resembled those of the entire registered population, except infants did not exhibit typical neurological/neuromuscular phenotypes.

Conclusions: Phenotypes enable pediatric patient stratification by risk and thus assist in personalized patient care. Our findings in SARS-CoV-2-infected population might also be transferable to other infectious diseases.

目的:表型对于患者分类、疾病预后和定制治疗非常重要。我们旨在确定感染 SARS-CoV-2 住院儿童和青少年的不同临床表型,并评估其预后差异:方法:德国儿科传染病学会(DGPI)登记处是一个全国性的前瞻性登记处,登记对象为德国因感染 SARS-CoV-2 而住院的儿童和青少年。我们采用分层聚类的方法进行表型识别,变量包括性别、入院时的 SARS-CoV-2 相关症状、入院前的合并症、临床相关的合并感染以及 SARS-CoV-2 风险因素。本研究的结果包括:出院情况和入住重症监护室情况。出院状态分为:完全康复、残留症状和预后不良(包括出院时已被确定为潜在不可逆的后遗症和与 SARS-CoV-2 相关的死亡)。获得表型后,我们通过多项式逻辑回归模型评估了它们与出院状态的相关性,并通过二元逻辑回归模型评估了它们与入住重症监护室的相关性。我们还对年龄较大的患者进行了类似的亚组分析:DGPI 登记了 6983 名患者,通过这些患者,我们确定了儿童和青少年 SARS-CoV-2 患者的六种不同表型,这些表型可根据症状模式来描述:表型 A 患者有一系列症状,而其他表型患者的主要症状是胃肠道症状(95.9%,B)、无症状(95.9%,C)、下呼吸道(49.8%,D)、下呼吸道和耳鼻喉(86.2%和 41.7%,E)以及神经系统(99.2%,F)。在出院状态方面,表型为 D 和 E 的患者出现残留症状的几率最高(OR:分别为 1.33 [1.11, 1.59] 和 1.91 [1.65, 2.21]),表型为 D 的患者预后不良的几率明显更高(OR:4.00 [1.95, 8.19])。在重症监护室方面,与表型为 A 的患者相比,表型为 D 的患者入住重症监护室的可能性高于普通病房(OR:4.26 [3.06,5.98])。除了婴儿没有表现出典型的神经/神经肌肉表型外,在婴儿和非婴儿中观察到的结果与所有登记人群的结果非常相似:表型有助于根据风险对儿科病人进行分层,从而帮助对病人进行个性化治疗。我们在 SARS-CoV-2 感染人群中的发现也可用于其他传染病。
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引用次数: 0
A novel Non-rodent animal model of hydrochloric acid-induced acute and chronic lung injury. 盐酸诱发急性和慢性肺损伤的新型非啮齿动物模型
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-29 DOI: 10.1186/s12931-024-03022-7
Pavel A Solopov, Ruben Manuel Luciano Colunga Biancatelli, Tierney Day, Christiana Dimitropoulou, John D Catravas

Hydrochloric acid is one of the most prevalent and hazardous chemicals. Accidental spills occur in industrial plants or during transportation. Exposure to HCl can induce severe health impairment, including acute and chronic pulmonary diseases. We have previously described the molecular, structural, and functional aspects of the development of chronic lung injury and pulmonary fibrosis caused by intratracheal instillation of HCl in mice. Although mouse models of human disease have many advantages, rodents are evolutionary far from human and exhibit significant anatomical and physiological differences. Genetic and anatomic similarities between rabbits and humans are significantly higher. Rabbit models of HCl-induced lung injury have been used sparsely to evaluate acute lung injury. In this study, for the first time, we utilized rabbits as a model of HCl-induced pulmonary fibrosis and chronic lung injury. We present molecular, histological, and functional evidence that demonstrate the utility of using this model for studying new pharmaceutics against pulmonary fibrosis.

盐酸是最常见的危险化学品之一。工业厂房或运输过程中会发生意外泄漏。接触盐酸会导致严重的健康损害,包括急性和慢性肺部疾病。我们以前曾描述过气管内灌注盐酸导致小鼠慢性肺损伤和肺纤维化的分子、结构和功能方面的发展。虽然人类疾病的小鼠模型有很多优点,但啮齿类动物在进化过程中与人类相差甚远,而且在解剖学和生理学方面也有显著差异。兔子与人类在遗传和解剖方面的相似性要高得多。HCl 诱导的肺损伤兔模型很少用于评估急性肺损伤。在本研究中,我们首次利用兔子作为 HCl 诱导的肺纤维化和慢性肺损伤的模型。我们提出了分子、组织学和功能方面的证据,证明了使用该模型研究抗肺纤维化新药的实用性。
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引用次数: 0
Automatic lung cancer subtyping using rapid on-site evaluation slides and serum biological markers. 利用现场快速评估切片和血清生物标记物自动进行肺癌亚型分析。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-29 DOI: 10.1186/s12931-024-03021-8
Junxiang Chen, Chunxi Zhang, Jun Xie, Xuebin Zheng, Pengchen Gu, Shuaiyang Liu, Yongzheng Zhou, Jie Wu, Ying Chen, Yanli Wang, Chuan He, Jiayuan Sun

Background: Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images.

Methods: The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen's kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff.

Results: The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257-0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756-0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026-0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714-0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians.

Conclusion: The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures.

Clinical trial number: Not applicable.

背景:快速现场评估(ROSE)在经支气管取样过程中发挥着重要作用,可提供术中细胞病理学评估。然而,细胞病理学家的短缺限制了它的广泛应用。本研究旨在开发一种深度学习模型,用于自动分析 ROSE 细胞学图像:方法:研究人员提出了分层多标签肺癌亚型分析(HMLCS)模型,该模型结合了ROSE切片的全切片图像和血清生物标记物,用于区分良性和恶性病变,并识别肺癌的不同亚型。研究人员于2019年7月至2020年11月期间回顾性收集了811张ROSE切片和配对的血清生物学标志物数据集,并随机划分数据集进行HMLCS模型的训练、验证和测试。计算曲线下面积(AUC)和准确率来评估模型的性能,计算科恩卡帕(κ)来衡量模型与注释之间的一致性。HMLCS 模型还与专业人员进行了比较:结果:HMLCS 模型在恶性/良性分类中的 AUC 值为 0.9540(95% 置信区间 [CI]:0.9257-0.9823),在恶性肿瘤亚型(非小细胞肺癌 [NSCLC]、小细胞肺癌 [SCLC] 或其他恶性肿瘤)中的 AUC 值为 0.9126(95% 置信区间 [CI]:0.8756-0.9365),在恶性肿瘤分类中的 AUC 值为 0.9297(95% CI:0.9026-0.9603)。在六级分类任务(良性、LUAD、LUSC、NSCLC-NOS、SCLC 或其他恶性肿瘤)中,该模型的 AUC 为 0.8721(95% CI:0.7714-0.9258),准确率为 0.7184。此外,该模型的注释κ值为0.6183,与细胞病理学家相当,优于训练有素的支气管镜医师和技术人员:HMLCS模型在肺部病变或胸腔内淋巴结病的多分类中表现出良好的性能,有望在经支气管取样过程中为标本的初步诊断提供实时反馈:临床试验编号:不适用。
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引用次数: 0
Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma. 在过敏性哮喘小鼠模型中,Kiss1 受体敲除会加剧气道高反应性和重塑。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03017-4
Nilesh Sudhakar Ambhore, Premanand Balraj, Ashish Kumar, Mohammad Irshad Reza, Yogaraj S Ramakrishnan, Jacob Tesch, Sahil Lohana, Venkatachalem Sathish

Background: In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R-/-) mice.

Methods: C57BL/6J WT (Kiss1R+/+) and Kiss1R-/- mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson's Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c.

Results: Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R-/- female mice. MA-challenged Kiss1R-/- mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R-/- mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR.

Conclusions: These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

背景:在哮喘中,性类固醇信号被认为是疾病病理生理学的关键调节因子。然而,性激素(尤其是雌激素)的矛盾作用表明,上游机制甚至独立于雌激素的机制在调节哮喘病理生理学方面发挥着重要作用。在此背景下,我们在之前的研究中探讨了吻肽(Kp)及其受体 Kiss1R 在体外调节人气道平滑肌细胞重塑和体内调节小鼠(野生型,WT)哮喘模型中气道高反应性(AHR)的信号传导。在本研究中,我们利用 Kiss1R 基因敲除(Kiss1R-/-)小鼠评估了内源性 Kp 在调节 AHR 和重塑中的作用:雌雄C57BL/6J WT(Kiss1R+/+)和Kiss1R-/-小鼠经鼻内注射混合过敏原(MA)和/或磷酸盐缓冲盐水(PBS)。我们使用 flexiVent 分析方法评估气道阻力 (Rrs)、弹性 (Ers) 和顺应性 (Crs)。然后进行支气管肺泡灌洗(BAL),以进行白细胞计数差异(DLC)和细胞因子分析。组织学染色采用苏木精和伊红(H&E)进行形态学分析,采用马森三色染色法(MT)进行胶原沉积分析。此外,还对肺部切片进行了免疫荧光(IF),以检测Ki-67、α-平滑肌肌动蛋白(α-SMA)和tenascin-c:结果:有趣的是,Kiss1R缺失会加剧MA挑战小鼠的肺功能和气道收缩力,对Kiss1R-/-雌性小鼠的影响更深。受到 MA 挑战的 Kiss1R-/- 小鼠的免疫细胞浸润和促炎细胞因子水平显著增加。重要的是,Kiss1R 的缺失加剧了 MA 攻击小鼠体内 Th2/Th17 偏向细胞因子的水平。此外,与 Kiss1R+/+ 小鼠相比,Kiss1R-/- 小鼠肺切片的组织学显示气道壁上的胶原沉积和气道细胞中的粘蛋白生成增加。此外,免疫荧光分析表明,Kiss1R 的缺失会显著加重气道重塑,进而导致 AHR:这些研究结果表明,在哮喘的病理生理学过程中,固有的 Kiss1R 信号在调节气道炎症、AHR 和重塑方面起着重要作用。
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引用次数: 0
Quantitative texture analysis using machine learning for predicting interpretable pulmonary perfusion from non-contrast computed tomography in pulmonary embolism patients. 利用机器学习进行定量纹理分析,从肺栓塞患者的非对比计算机断层扫描中预测可解释的肺灌注。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03004-9
Zihan Li, Meixin Zhao, Zhichun Li, Yu-Hua Huang, Zhi Chen, Yao Pu, Mayang Zhao, Xi Liu, Meng Wang, Kun Wang, Martin Ho Yin Yeung, Lisheng Geng, Jing Cai, Weifang Zhang, Ruijie Yang, Ge Ren

Background: Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis.

Methods: We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans.

Results: The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively.

Conclusions: This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases.

Clinical trial number: Not applicable.

背景:肺栓塞(PE)危及生命,需要及时、准确的诊断,但目前的成像方法,如计算机断层扫描肺血管造影术,存在局限性,尤其是对有碘造影剂禁忌症的患者。我们的目标是基于非对比胸部计算机断层扫描(CT),利用机器学习(ML)技术开发一种定量纹理分析管道,以发现与区域肺灌注(Q)生理和病理相关的强度和纹理特征,并合成体素Q替代物来协助PE诊断:我们回顾性地收集了疑似 PE 患者的 99mTc 标记大聚集白蛋白 Q-SPECT/CT 扫描图像,包括 76 例患者的内部数据集(64 例用于训练,12 例用于测试)和 49 例患者的外部测试数据集。从分割的肺部亚区提取定量 CT 特征,并进行两阶段特征选择。先验知识驱动的预选阶段筛选稳健、非冗余的灌注相关特征,而数据驱动的选择阶段则通过拟合 ML 模型进行分类,进一步筛选特征。最终的分类模型是用表现最好的 PE 相关特征组合训练出来的,在测试队列中根据曲线下面积(AUC)评估子区域级预测性。然后使用最终选定的特征图(FM)和模型得分图(MSM)合成体素Q代用值,以研究空间分布。斯皮尔曼相关系数(SCC)和骰子相似性系数(DSC)用于评估 FMs 或 MSMs 与 Q-SPECT 扫描之间的空间一致性:在内部测试中,最佳模型的 AUC 为 0.863,在外部测试队列中为 0.828。该模型确定了包含 14 个强度和纹理特征的组合,这些特征是非冗余的、稳健的,能够区分高功能和低功能肺区。内部测试队列的空间一致性评估显示,MSM 与参考 Q-SPECT 扫描之间的一致性为中度到高度一致,高功能区和低功能区的 SCC 中位数分别为 0.66,DSC 中位数分别为 0.86 和 0.64:这项研究验证了使用定量纹理分析和数据驱动的ML管道生成体素肺灌注替代物的可行性,为管理肺血管疾病提供了一种无辐射、可广泛使用的肺功能成像替代方法:临床试验编号:不适用。
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引用次数: 0
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Respiratory Research
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