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Procalcitonin has been investigated as a marker for bowel ischemia. This study examined the role of procalcitonin in predicting failure of non-operative management (NOM) in bowel obstructions. Patients with bowel obstructions at a single center from August 2022 to January 2023 were prospectively enrolled (n = 79). Lactic acid (LA) and procalcitonin were collected after surgical consultation. The primary outcome was success or failure of NOM. Univariate analysis, multivariable logistic regression, and performance measures of procalcitonin and LA in predicting bowel ischemia was performed. Of 79 patients included, 48 (61%) required operative intervention during index admission. There were no significant differences in demographics, comorbidities, procalcitonin, nor LA between groups. Time from last bowel movement was associated with failure of NOM (OR 1.03 [95% CI 1.01-1.06]; P = .008), though initial procalcitonin or LA was not. Procalcitonin >.3 ng/mL had acceptable sensitivity in screening for bowel ischemia.
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RATIONALE: Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). OBJECTIVE: We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. METHODS: Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting ß-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. MEASUREMENTS AND MAIN RESULTS: Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. CONCLUSION: Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.
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Corticosteroides , Asma , Mastócitos , Doença Pulmonar Obstrutiva Crônica , Células Th2 , Humanos , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Biomarcadores , Broncodilatadores/uso terapêutico , Quimioterapia Combinada , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Células Th2/efeitos dos fármacos , Células Th2/metabolismoRESUMO
Crohn's disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions. We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment. We applied hierarchical clustering of enrichment scores derived from gene set variation analysis of signatures representative of various immunological processes and activated cell types, to a colonic biopsy dataset that included healthy volunteers, Crohn's disease and ulcerative colitis patients. Patient stratification at baseline or after anti-TNF treatment in clinical responders and non-responders was queried. Signatures with significantly different enrichment scores were identified using a general linear model. Comparisons to healthy controls were made at baseline in all participants and then separately in responders and non-responders. Fifty-nine percent of the signatures were commonly enriched in both conditions at baseline, supporting the notion of a disease continuum within ulcerative colitis and Crohn's disease. Signatures included T cells, macrophages, neutrophil activation and poly:IC signatures, representing acute inflammation and a complex mix of potential disease-driving biology. Collectively, identification of significantly enriched signatures allowed establishment of an inflammatory bowel disease molecular activity score which uses biopsy transcriptomics as a surrogate marker to accurately track disease severity. This score separated diseased from healthy samples, enabled discrimination of clinical responders and non-responders at baseline with 100% specificity and 78.8% sensitivity, and was validated in an independent data set that showed comparable classification. Comparing responders and non-responders separately at baseline to controls, 43% and 70% of signatures were enriched, respectively, suggesting greater molecular dysregulation in TNF non-responders at baseline. This methodological approach could facilitate better targeted design of clinical studies to test therapeutics, concentrating on patient subsets sharing similar underlying pathobiology, therefore increasing the likelihood of clinical response.
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Biologia Computacional/métodos , Doenças Inflamatórias Intestinais , Transcriptoma/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Análise por Conglomerados , Colo/química , Colo/metabolismo , Monitoramento de Medicamentos , Fármacos Gastrointestinais/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/classificação , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Infliximab/uso terapêuticoRESUMO
BACKGROUND: For large international research consortia, such as those funded by the European Union's Horizon 2020 programme or the Innovative Medicines Initiative, good data coordination practices and tools are essential for the successful collection, organization and analysis of the resulting data. Research consortia are attempting ever more ambitious science to better understand disease, by leveraging technologies such as whole genome sequencing, proteomics, patient-derived biological models and computer-based systems biology simulations. RESULTS: The IMI eTRIKS consortium is charged with the task of developing an integrated knowledge management platform capable of supporting the complexity of the data generated by such research programmes. In this paper, using the example of the OncoTrack consortium, we describe a typical use case in translational medicine. The tranSMART knowledge management platform was implemented to support data from observational clinical cohorts, drug response data from cell culture models and drug response data from mouse xenograft tumour models. The high dimensional (omics) data from the molecular analyses of the corresponding biological materials were linked to these collections, so that users could browse and analyse these to derive candidate biomarkers. CONCLUSIONS: In all these steps, data mapping, linking and preparation are handled automatically by the tranSMART integration platform. Therefore, researchers without specialist data handling skills can focus directly on the scientific questions, without spending undue effort on processing the data and data integration, which are otherwise a burden and the most time-consuming part of translational research data analysis.
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Bases de Dados Factuais , Gestão do Conhecimento , Biologia de Sistemas , Pesquisa Translacional Biomédica/métodos , Animais , Células Cultivadas , Simulação por Computador , Modelos Animais de Doenças , Humanos , Modelos Biológicos , Proteômica , Software , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Asma/complicações , Epitélio/fisiopatologia , Refluxo Gastroesofágico/patologia , Obesidade/complicações , Asma/genética , Asma/fisiopatologia , Proteínas de Sinalização Intercelular CCN/genética , Estudos de Casos e Controles , Endoscopia Gastrointestinal , Refluxo Gastroesofágico/diagnóstico , Expressão Gênica , Humanos , Obesidade/fisiopatologia , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
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Remodelação das Vias Aéreas/genética , Asma/imunologia , Eosinófilos/imunologia , Metaloproteinase 10 da Matriz/genética , Metaloproteinase 10 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Adulto , Asma/patologia , Biópsia , Brônquios/patologia , Estudos de Coortes , Eosinofilia/imunologia , Matriz Extracelular/genética , Feminino , Humanos , Imuno-Histoquímica , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fatores de Transcrição SOX/metabolismo , TranscriptomaRESUMO
GOAL: Computed tomography angiography (CTA) is a well-tolerated, noninvasive study of the intracranial vascular circulation; however, contrast-induced nephropathy (CIN) has been reported in 5%-7% of patients undergoing CTA. Limited studies have evaluated the risks of CIN in patients undergoing CTA. Our study was designed to evaluate the prevalence and risk factors for CIN in patients with ischemic stroke who receive a CTA. MATERIALS AND METHODS: Single-center, nested, case-control study of patients with ischemic stroke who received a CTA between June 18, 2012 and January 1, 2016. Patients were grouped based on development of CIN. FINDINGS: A total of 209 patients were included in the final analysis (178 controls, 31 cases). The prevalence of CIN during the time period studied was 14.8% (95% confidence interval [CI]: 10.2-20.2). A higher proportion of patients who developed CIN had a history of diabetes mellitus (37 [20.56%] versus 15 [48.39%]; P = .0009) and reported taking no medications prior to admission (35 [19.44%] versus 11 [35.48%]; P = .0458). However, a lower proportion of patients who developed CIN had a history of smoking (59 [32.78] versus 3 [9.68]; P = .0091). After statistical adjustment, only a history of diabetes (odds ratio [OR] 4.15 [95% CI: 1.765, 9.754), taking no medications prior to admission (OR 3.56 [95% CI: 1.417, 8.941]) and a self-reported history of smoking (OR 0.204 [95% CI: 0.057, 0.721]) remained associated with the development of CIN. CONCLUSIONS: Those patients with a history of diabetes mellitus or not taking medications prior to admission should be monitored closely for the development of contrast-induced nephropathy CIN.
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Angiografia Cerebral/efeitos adversos , Angiografia por Tomografia Computadorizada/efeitos adversos , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Angiografia Cerebral/métodos , Meios de Contraste/administração & dosagem , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/terapia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prevalência , Terapia de Substituição Renal , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Tennessee/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.
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Doença/genética , Biologia de Sistemas/métodos , Biomarcadores/metabolismo , Análise por Conglomerados , Reações Falso-Positivas , Aprendizado de Máquina , Controle de QualidadeAssuntos
Colite Ulcerativa , Informação de Saúde ao Consumidor , Doença de Crohn , Exercício Físico , Adulto , Colite Ulcerativa/fisiopatologia , Colite Ulcerativa/psicologia , Doença de Crohn/fisiopatologia , Doença de Crohn/psicologia , Exercício Físico/fisiologia , Exercício Físico/psicologia , Feminino , Humanos , Masculino , Relações Médico-Paciente , Padrões de Prática MédicaRESUMO
BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1ß protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.
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Asma/imunologia , Perfilação da Expressão Gênica , Receptores de Interleucina-1/imunologia , Escarro/imunologia , Regulação para Cima/imunologia , Adulto , Animais , Asma/patologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Células Th2/imunologia , Células Th2/patologiaRESUMO
Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects.After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets.We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R, CCR3 and TSLPR), TAC2 (characterised by interferon-, tumour necrosis factor-α- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1â s. Gene-protein coexpression networks from TAC1 and TAC2 extended this molecular classification.We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.
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Asma/genética , Eosinófilos/imunologia , Escarro , Células Th2/imunologia , Transcriptoma , Corticosteroides/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Asma/imunologia , Biomarcadores , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Interleucina-13/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Fenótipo , Reino UnidoRESUMO
RATIONALE: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. OBJECTIVES: Using transcriptomic profiling of airway tissues, we sought to define the molecular phenotypes of severe asthma. METHODS: The transcriptome derived from bronchial biopsies and epithelial brushings of 107 subjects with moderate to severe asthma were annotated by gene set variation analysis using 42 gene signatures relevant to asthma, inflammation, and immune function. Topological data analysis of clinical and histologic data was performed to derive clusters, and the nearest shrunken centroid algorithm was used for signature refinement. MEASUREMENTS AND MAIN RESULTS: Nine gene set variation analysis signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper cell type 2 cytokines and lack of corticosteroid response (group 1 and group 3). Group 1 had the highest submucosal eosinophils, as well as high fractional exhaled nitric oxide levels, exacerbation rates, and oral corticosteroid use, whereas group 3 patients showed the highest levels of sputum eosinophils and had a high body mass index. In contrast, group 2 and group 4 patients had an 86% and 64% probability, respectively, of having noneosinophilic inflammation. Using machine learning tools, we describe an inference scheme using the currently available inflammatory biomarkers sputum eosinophilia and fractional exhaled nitric oxide levels, along with oral corticosteroid use, that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSIONS: This analysis demonstrates the usefulness of a transcriptomics-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target T-helper cell type 2-mediated inflammation and/or corticosteroid insensitivity.
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Corticosteroides/imunologia , Asma/genética , Brônquios/patologia , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Adulto , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Biomarcadores/análise , Biópsia , Testes Respiratórios , Broncoscopia/instrumentação , Broncoscopia/métodos , Estudos de Coortes , Resistência a Medicamentos/genética , Resistência a Medicamentos/imunologia , Eosinófilos/citologia , Eosinófilos/imunologia , Feminino , Perfilação da Expressão Gênica/instrumentação , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Escarro/citologia , Escarro/imunologia , Células Th2/citologia , Células Th2/imunologiaRESUMO
BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. METHODS: Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. RESULTS: Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. CONCLUSION: Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
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Asma , Escarro , Adulto , Idoso , Algoritmos , Asma/classificação , Asma/genética , Asma/metabolismo , Biomarcadores/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Proteômica , Índice de Gravidade de Doença , Escarro/citologia , Escarro/metabolismoRESUMO
RATIONALE: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy. OBJECTIVES: To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences. METHODS: Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis. MEASUREMENTS AND MAIN RESULTS: A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids. CONCLUSIONS: Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study. Clinical trial registered with www.clinicaltrials.gov (NCT01982162).
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Corticosteroides/uso terapêutico , Asma/sangue , Asma/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Corticosteroides/sangue , Adulto , Análise por Conglomerados , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Transcriptoma/efeitos dos fármacosRESUMO
BACKGROUND: The application of sunscreen is a critical component of a sun-safe strategy, however the possibility of unexpected, adverse outcomes resulting from long-term use of sunscreens containing nanoparticles of titanium dioxide (TiO2) and zinc oxide (ZnO) has not yet been examined. Here, immune-competent hairless mice were exposed over a 36-week period to weekly topical applications of sunscreens containing nanoparticles of ZnO or TiO2, or no metal oxide nanoparticles, with or without subsequent exposure to ultraviolet radiation (UVR). Control groups received no sunscreen applications, with or without UVR. RESULTS: Mice exposed to UVR in the absence of sunscreen developed statistically significant incidences of histologically-diagnosed malignant and benign skin neoplasms, whereas no statistically significant adverse biological outcomes were found in mice treated with the sunscreens containing ZnO or TiO2 nanoparticles. Elevated levels of Ti were detected in the livers of mice treated with sunscreen containing TiO2 nanoparticles compared to untreated control, but total Zn concentrations did not significantly alter in any major organs except for the skin of mice treated with ZnO sunscreen. Exposure to UVR did not have a significant impact on examined tissue concentrations of Zn or Ti. Few to no transcriptional changes were found in ZnO or TiO2-treated groups, but mice treated with the sunscreen containing only organic filters showed substantial gene disregulation. CONCLUSIONS: Taken together with previous work, this long-term study provided no basis to avoid the use of sunscreens containing metal oxide nanoparticles.
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Nanopartículas Metálicas/toxicidade , Modelos Animais , Protetores Solares/toxicidade , Titânio/toxicidade , Óxido de Zinco/toxicidade , Animais , Perfilação da Expressão Gênica , Fígado/metabolismo , Camundongos , Camundongos Pelados , Protetores Solares/química , Distribuição Tecidual , Titânio/farmacocinética , Raios Ultravioleta , Óxido de Zinco/farmacocinéticaRESUMO
Pericapsular fibrotic overgrowth (PFO) is a problem that thwarts full implementation of cellular replacement therapies involving encapsulation in an immunoprotective material, such as for the treatment of diabetes. Mesenchymal stem cells (MSCs) have inherent anti-inflammatory properties. We postulated that coencapsulation of MSCs with the target cells would reduce PFO. A hepatoinsulinoma cell line (HUH7) was used to model human target cells and was coencapsulated with either human or mouse MSCs at different ratios in alginate microcapsules. Viability of encapsulated cells was assessed in vitro and xenografted either intraperitoneally or subcutaneously into C57BL/6 mice. Graft retrieval was performed at 3 weeks posttransplantation and assessed for PFO. Coencapsulation of human MSCs (hMSCs) or mouse MSCs (mMSCs) with HUH7 at different ratios did not alter cell viability in vitro. In vivo data from intraperitoneal infusions showed that PFO for HUH7 cells coencapsulated with hMSCs and mMSCs in a ratio of 1:1 was significantly reduced by â¼30% and â¼35%, respectively, compared to HUH7 encapsulated alone. PFO for HUH7 cells was reduced by â¼51% when the ratio of mMSC/HUH7 was increased to 2:1. Implanting the microcapsules subcutaneously rather than intraperitoneally substantially reduced PFO in all treatment groups, which was most significant in the mMSC/HUH7 2:1 group with a â¼53% reduction in PFO compared with HUH7 alone. Despite the reduced PFO reaction to the individual microcapsules implanted subcutaneously, all microcapsule treatment groups were contained in a vascularized fibrotic pouch at 3 weeks. The presence of MSCs in microcapsules retrieved from these fibrotic pouches improved graft survival with significantly higher cell viabilities of 83.1 ± 0.6% and 79.1 ± 0.8% seen with microcapsules containing mMSC/HUH7 at 2:1 and 1:1 ratios, respectively, compared to HUH7 alone (51.5 ± 0.7%) transplanted subcutaneously. This study showed that coencapsulation of MSCs with target cells has a dose-dependent effect on reducing PFO and improving graft survival when implanted either intraperitoneally or subcutaneously in a stringent xenotransplantation setting.
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Sobrevivência de Enxerto , Células-Tronco Mesenquimais/citologia , Transplante Heterólogo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Células Imobilizadas/citologia , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Implantes Experimentais , Camundongos , Células-Tronco Multipotentes/citologia , Cavidade Peritoneal/citologia , Tela Subcutânea/patologiaRESUMO
U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.
Assuntos
Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/epidemiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Hipersensibilidade Imediata , Masculino , Pediatria , Estudos Prospectivos , Qualidade de Vida , Sons Respiratórios/diagnóstico , Índice de Gravidade de Doença , Espirometria , Inquéritos e QuestionáriosRESUMO
U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12â months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/complicações , Fumar/efeitos adversos , Adulto , Ansiedade/epidemiologia , Asma/tratamento farmacológico , Asma/epidemiologia , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Depressão/epidemiologia , Europa (Continente) , Feminino , Refluxo Gastroesofágico/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/análise , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Fumar/epidemiologia , Espirometria , Inquéritos e Questionários , Biologia de SistemasRESUMO
BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airway inflammation. However, the role of obesity in severe asthma remains unclear. Thus, our objective was to explore the association between obesity (defied by BMI) and severe asthma. METHODS: Data from the British Thoracic Society Difficult Asthma Registry were used to compare patient demographics, disease characteristics, and health-care utilization among three BMI categories (normal weight: 18.5-24.99; overweight: 25-29.99; obese: 30) in a well-characterized group of adults with severe asthma. RESULTS: The study population consisted of 666 patients with severe asthma; the group had a median BMI of 29.8 (interquartile range, 22.5-34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% vs 40.4% and 34.5% in the overweight and normal-weight groups, respectively), steroid burst therapy, and short-acting b 2 -agonist use per day. Significant differences were seen with gastroesophageal reflux disease (53.9% vs 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor use. Bone density scores were higher in the obese group, while pulmonary function testing revealed a reduced FVC and elevated carbon monoxide transfer coefficient. Serum IgE levels decreased with increasing BMI and the obese group was more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Patients with severe asthma display particular characteristics according to BMI that support the view that obesity-associated severe asthma may represent a distinct clinical phenotype.
Assuntos
Asma/etiologia , Asma/fisiopatologia , Índice de Massa Corporal , Obesidade/complicações , Fenótipo , Índice de Gravidade de Doença , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Asma/tratamento farmacológico , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Testes de Função Respiratória , Sociedades Médicas , Reino UnidoRESUMO
Liver toxicity is a side effect observed with some herbal treatments, including Piper methysticum. The possible mechanisms responsible include inflammation subsequent to activation of liver macrophages and oxidative damage. Hepatotoxicity of the pharmacologically active component of Piper methysticum (kavalactones) was tested in isolated, perfused livers from rats which were pretreated with the macrophage intoxicant gadolinium chloride. Perfusions without kavalactones in gadolinium chloride pretreated and untreated livers were included as negative controls. Serial liver lobe biopsies were collected to measure temporal changes in available (reduced) hepatic glutathione. There were no statistically significant changes in reduced glutathione over the course of perfusion in any experimental group. Liver damage was observed using electron microscopy. Hepatic sinusoids displayed extensive damage to the endothelium in kavalactone-perfused, rat livers. This damage was significantly reduced by pre-treatment with gadolinium chloride. Hence liver macrophages may be a factor in liver injury induced by Piper methysticum. Characterisation and modulation of the liver macrophage response may enable the development of strategies to avoid these hepatic side effects.