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1.
Acta Paediatr ; 111(3): 620-627, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34773288

RESUMEN

AIM: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. METHODS: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. RESULTS: Sputum data were available in 48 children (acute asthma; n = 18, stable asthma; n = 17, healthy controls; n = 13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. CONCLUSION: Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.


Asunto(s)
Asma , Esputo , Adolescente , Asma/diagnóstico , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Eosinófilos , Humanos
2.
BMC Pulm Med ; 19(1): 144, 2019 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-31395050

RESUMEN

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1ß, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.


Asunto(s)
Asma/inmunología , Asma/metabolismo , Citocinas/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Área Bajo la Curva , Biomarcadores/metabolismo , Niño , Progresión de la Enfermedad , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la Enfermedad , Esputo/inmunología , Esputo/metabolismo
3.
J Allergy Clin Immunol ; 140(3): 730-737, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28412391

RESUMEN

BACKGROUND: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. OBJECTIVE: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. METHODS: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. RESULTS: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-ß, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. CONCLUSION: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.


Asunto(s)
Dermatitis Atópica/sangre , Dermatitis Atópica/clasificación , Adulto , Alérgenos/inmunología , Asma/sangre , Asma/epidemiología , Biomarcadores/sangre , Comorbilidad , Citocinas/sangre , Dermatitis Atópica/epidemiología , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Rinitis/sangre , Rinitis/epidemiología
4.
Am J Respir Cell Mol Biol ; 50(5): 985-94, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24325475

RESUMEN

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Células Epiteliales/efectos de los fármacos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Interleucina-13/metabolismo , Animales , Células Epiteliales/metabolismo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones SCID , Terapia Molecular Dirigida , Regulación hacia Arriba/efectos de los fármacos
5.
Am J Respir Crit Care Med ; 188(6): 657-63, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23590263

RESUMEN

RATIONALE: The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.


Asunto(s)
Asma/inmunología , Eosinofilia/inmunología , Interleucina-5/inmunología , Obesidad/inmunología , Mucosa Respiratoria/inmunología , Esputo/inmunología , Asma/complicaciones , Asma/metabolismo , Biomarcadores/metabolismo , Índice de Masa Corporal , Eosinofilia/complicaciones , Eosinofilia/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Humanos , Interleucina-5/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Mucosa Respiratoria/metabolismo , Índice de Severidad de la Enfermedad , Esputo/metabolismo
9.
Pharm Stat ; 10(6): 494-507, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22162336

RESUMEN

Biomarkers play an increasingly important role in many aspects of pharmaceutical discovery and development, including personalized medicine and the assessment of safety data, with heavy reliance being placed on their delivery. Statisticians have a fundamental role to play in ensuring that biomarkers and the data they generate are used appropriately and to address relevant objectives such as the estimation of biological effects or the forecast of outcomes so that claims of predictivity or surrogacy are only made based upon sound scientific arguments. This includes ensuring that studies are designed to answer specific and pertinent questions, that the analyses performed account for all levels and sources of variability and that the conclusions drawn are robust in the presence of multiplicity and confounding factors, especially as many biomarkers are multidimensional or may be an indirect measure of the clinical outcome. In all of these areas, as in any area of drug development, statistical best practice incorporating both scientific rigor and a practical understanding of the situation should be followed. This article is intended as an introduction for statisticians embarking upon biomarker-based work and discusses these issues from a practising statistician's perspective with reference to examples.


Asunto(s)
Biomarcadores/análisis , Descubrimiento de Drogas/estadística & datos numéricos , Humanos , Medicina de Precisión/métodos , Medicina de Precisión/estadística & datos numéricos , Proyectos de Investigación/estadística & datos numéricos , Pruebas de Toxicidad/estadística & datos numéricos
10.
Sci Rep ; 8(1): 53, 2018 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-29311660

RESUMEN

The global increase in Diabetes Mellitus (DM) has led to an increase in DM-Chronic Kidney Disease (DM-CKD). In this cross-sectional observational study we aimed to define phenotypes for patients with DM-CKD that in future may be used to individualise treatment We report 4 DM-CKD phenotypes in 220 patients recruited from Imperial College NHS Trust clinics from 2004-2012. A robust principal component analysis (PCA) was used to statistically determine clusters with phenotypically different patients. 163 patients with complete data sets were analysed: 77 with CKD and 86 with DM-CKD. Four different clusters were identified. Phenotypes 1 and 2 are entirely composed of patients with DM-CKD and phenotypes 3 and 4 are predominantly CKD (non-DM-CKD). Phenotype 1 depicts a cardiovascular phenotype; phenotype 2: microvascular complications with advanced DM-CKD; phenotype 3: advanced CKD with less anaemia, lower weight and HbA1c; phenotype 4: hypercholesteraemic, younger, less severe CKD. We are the first group to describe different phenotypes in DM-CKD using a PCA approach. Identification of phenotypic groups illustrates the differences and similarities that occur under the umbrella term of DM-CKD providing an opportunity to study phenotypes within these groups thereby facilitating development of precision/personalised targeted medicine.


Asunto(s)
Nefropatías Diabéticas/diagnóstico , Fenotipo , Comorbilidad , Estudios Transversales , Citocinas/metabolismo , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/metabolismo , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Neovascularización Patológica
11.
Allergy Asthma Immunol Res ; 9(2): 177-181, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28102063

RESUMEN

Aspergillus fumigatus sensitization and culture in asthma are associated with disease severity and lung function impairment, but their relationship with airway inflammation is poorly understood. We investigated the profile of 24 sputum inflammatory mediators in A. fumigatus culture-positive or-negative moderate-to-severe asthmatics. Fifty-two subjects were recruited from a single center. A. fumigatus was cultured from 19 asthmatics. Asthma control, symptom score, lung function, and sputum cell count were not significantly different between the asthmatics with and without a positive A. fumigatus culture. All of the sputum mediators were numerically increased in subjects with a positive versus negative sputum A. fumigatus culture. Sputum TNF-R2 was significantly elevated (P=0.03) and the mediator that best distinguished A. fumigatus culture-positive from culture-negative subjects (receiver-operator characteristic area under the curve 0.66 [95% CI: 0.51 to 0.82, P=0.045]). A. fumigates-positive culture in moderate-to-severe asthma is associated with increased inflammatory sputum mediators.

12.
Clin Cancer Res ; 23(13): 3416-3427, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28069723

RESUMEN

Purpose: To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy.Experimental Design: The EC50 value of the mGITRL-FP was compared with an anti-GITR antibody in an in vitro agonistic cell-based reporter assay. We assessed the impact of dose, schedule, and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared with an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models. Combination of the mGITRL-FP with antibodies targeting PD-L1, PD-1, or CTLA-4 was analyzed in mice bearing CT26 tumors.Results: The mGITRL-FP had an almost 50-fold higher EC50 value compared with an anti-murine GITR antibody. Treatment of CT26 tumor-bearing mice with mGITRL-FP-mediated significant antitumor activity that was dependent on isotype, dose, and duration of exposure. The antitumor activity could be correlated with the increased proliferation of peripheral CD8+ and CD4+ T cells and a significant decrease in the frequency of intratumoral Tregs. The combination of mGITRL-FP with mOX40L-FP or checkpoint inhibitor antagonists enhanced antitumor immunity above that of monotherapy treatment.Conclusions: These results suggest that therapeutically targeting GITR represents a unique approach to cancer immunotherapy and suggests that a multimeric fusion protein may provide increased agonistic potential versus an antibody. In addition, these data provide, for the first time, early proof of concept for the potential combination of GITR targeting agents with OX40 agonists and PD-L1 antagonists. Clin Cancer Res; 23(13); 3416-27. ©2017 AACR.


Asunto(s)
Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Melanoma Experimental/inmunología , Proteínas de Fusión Oncogénica/administración & dosificación , Factores de Necrosis Tumoral/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Modelos Animales de Enfermedad , Proteína Relacionada con TNFR Inducida por Glucocorticoide/administración & dosificación , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/inmunología , Ratones , Ligando OX40 , Proteínas de Fusión Oncogénica/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Factores de Necrosis Tumoral/agonistas , Factores de Necrosis Tumoral/genética
13.
Mol Cancer Res ; 1(11): 826-35, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14517345

RESUMEN

Comparative two-dimensional proteome analysis was used to identify proteins differentially expressed in multiple clinical normal and breast cancer tissues. One protein, the expression of which was elevated in invasive ductal and lobular breast carcinomas when compared with normal breast tissue, was arylamine N-acetyltransferase-1 (NAT-1), a Phase II drug-metabolizing enzyme. NAT-1 overexpression in clinical breast cancers was confirmed at the mRNA level and immunohistochemical analysis of NAT-1 in 108 breast cancer donors demonstrated a strong association of NAT-1 staining with estrogen receptor-positive tumors. Analysis of the effect of active NAT-1 overexpression in a normal luminal epithelial-derived cell line demonstrated enhanced growth properties and etoposide resistance relative to control cells. Thus, NAT-1 may not only play a role in the development of cancers through enhanced mutagenesis but may also contribute to the resistance of some cancers to cytotoxic drugs.


Asunto(s)
Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Etopósido/farmacología , Mama/citología , Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Especificidad de Órganos , Proteómica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Tumorales Cultivadas , Regulación hacia Arriba
14.
Chem Biol ; 22(11): 1442-1452, 2015 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-26548614

RESUMEN

The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro. MMP-8 degraded human IL-13 most efficiently in vitro and ex vivo in human IL-13 transgenic mouse bronchoalveolar lavage. Hence, MMP-8 is a therapeutic protease lead against IL-13 for inflammatory conditions whereby reported genetic and genomics data suggest an involvement of MMP-8. This work describes the first exploitation of human enzyme promiscuity for therapeutic applications, and reveals both starting points for protease-based therapies and potential new regulatory networks in inflammatory disease.


Asunto(s)
Interleucina-13/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Animales , Dominio Catalítico , Línea Celular , Quimiocina CCL2/metabolismo , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Dermatitis Atópica/terapia , Electroforesis en Gel de Poliacrilamida , Humanos , Interleucina-6/metabolismo , Cinética , Metaloproteinasa 8 de la Matriz/química , Metaloproteinasa 8 de la Matriz/genética , Metaloproteinasa 8 de la Matriz/metabolismo , Metaloproteinasas de la Matriz/química , Ratones , Ratones Transgénicos , Ingeniería de Proteínas , Proteolisis , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
15.
PLoS One ; 6(6): e21253, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21712985

RESUMEN

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.


Asunto(s)
Progresión de la Enfermedad , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/fisiopatología , MicroARNs/metabolismo , Anciano , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/patología , Pulmón/citología , Pulmón/patología , Pulmón/fisiología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estudios Retrospectivos , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Adulto Joven
16.
Can Respir J ; 17(6): 275-81, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21165349

RESUMEN

BACKGROUND: Epidemics of hospitalization for chronic obstructive pulmonary disease (COPD) occur annually during the Christmas holidays, and COPD exacerbations commonly coincide with respiratory viral infections. OBJECTIVE: To compare the incidence and determinants of COPD exacerbations occurring between the Christmas holiday period and the remainder of the winter season. METHODS: Seventy-one subjects with COPD of mixed severity faxed daily symptom diaries to a computer monitoring system from December 1, 2006, to April 30, 2007. Possible exacerbations prompted a home visit for assessment, spirometry and specimen collection for virological testing. RESULTS: Study subjects submitted a total of 95.4% of possible daily symptom diary sheets by fax. Of 114 possible COPD exacerbations detected using the faxed diaries, 110 met the Anthonisen criteria for true exacerbations. A total of 47 exacerbations (mean 6.7/week) occurred during the Christmas holiday period, while 63 exacerbations (mean 4.3/week) occurred during the remainder of winter. Of the Christmas period exacerbations and of those in the balance of winter, 21 (44%) and 20 (32%), respectively, coincided with respiratory viral infections. CONCLUSIONS: The incidence of COPD exacerbations during the Christmas period was greater than during the rest of winter in 2006/2007 and peaked immediately before Christmas - in contrast to hospital presentation for COPD, which peaked during the Christmas week. No clear role of respiratory viral infections in the increased rate of exacerbations during the Christmas period was established in the present study. COPD patients were highly compliant with daily symptom reporting using faxed daily diaries, which permitted nearly complete detection of all exacerbations that occurred at incidence.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Estaciones del Año , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Incidencia , Masculino , Estudios Prospectivos , Factores de Riesgo
17.
Mol Oncol ; 3(1): 24-32, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19383364

RESUMEN

Biomarker measurements have become an essential component of oncology drug development, particularly so in this era of targeted therapies. Such measurements ensure that clinical studies are testing our biological hypotheses and can help make the difficult decisions required to choose which drugs to stop developing or de-prioritise. For those drugs taken forward, biomarker measurements may also help choose the appropriate dose, schedule and patient population. In this review we discuss the intrinsic properties of biological sample based efficacy measurements and how these relate to their implementation in oncology drug development by way of points to consider and examples.


Asunto(s)
Biomarcadores , Diseño de Fármacos , Animales , Química Farmacéutica/métodos , Industria Farmacéutica/métodos , Humanos
18.
Proteomics Clin Appl ; 3(3): 394-407, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26238755

RESUMEN

Proteomics is increasingly being applied to the human plasma proteome to identify biomarkers of disease for use in non-invasive assays. 2-D DIGE, simultaneously analysing thousands of protein spots quantitatively and maintaining protein isoform information, is one technique adopted. Sufficient numbers of samples must be analysed to achieve statistical power; however, few reported studies have analysed inherent variability in the plasma proteome by 2-D DIGE to allow power calculations. This study analysed plasma from 60 healthy volunteers by 2-D DIGE. Two samples were taken, 7 days apart, allowing estimation of sensitivity of detection of differences in spot intensity between two groups using either a longitudinal (paired) or non-paired design. Parameters for differences were: two-fold normalised volume change, α of 0.05 and power of 0.8. Using groups of 20 samples, alterations in 1742 spots could be detected with longitudinal sampling, and in 1206 between non-paired groups. Interbatch gel variability was small relative to the detection parameters, indicating robustness and reproducibility of 2-D DIGE for analysing large sample sets. In summary, 20 samples can allow detection of a large number of proteomic alterations by 2-D DIGE in human plasma, the sensitivity of detecting differences was greatly improved by longitudinal sampling and the technology was robust across batches.

19.
Clin Chem ; 51(10): 1796-803, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16099942

RESUMEN

BACKGROUND: Our objectives were to identify serum marker proteins in rats that might serve as sensitive indicators of hepatomegaly, hepatocellular necrosis, or hepatobiliary injury and to use them to analyze data from a collaborative proteomics project. METHODS: In each of 4 studies comprising the collaborative project, rats were given 1 of 4 compounds that target the liver through different mechanisms. Sera and liver samples were collected by terminal bleeds at 1 of 3 postdose time points. Sera were depleted of major secretory proteins and then separated into protein features by 2-dimensional gel electrophoresis (2DGE). Liver specimens were also processed and subjected to 2DGE. Protein spots that significantly increased or decreased in quantity after drug treatment were recovered, digested, analyzed by mass spectroscopy, and compared with available databases for identification. Criteria for further consideration were (a) temporal expression (i.e., increase or decrease at early, fulminant, or recovery periods), (b) known biological function, (c) probable hepatic origin, and (d) any previous association with toxicity in published studies. Markers that changed significantly at the early time point were important because of their potential sensitivity for signaling minimal damage. RESULTS: Vitamin D-binding protein, paraoxonase, cellular retinol-binding protein, malate dehydrogenase, F-protein, and purine nucleoside phosphorylase were identified as empirically confirmed serum markers for hepatic effects in drug-treated rats. CONCLUSION: Proteomics can be applied for the identification and confirmation of peripheral biomarkers for altered liver function after toxicant exposure.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Hipertrofia/sangre , Hepatopatías/sangre , Proteómica/métodos , 1-Naftilisotiocianato , Acetaminofén/toxicidad , Animales , Biomarcadores/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertrofia/inducido químicamente , Hipertrofia/patología , Hepatopatías/patología , Masculino , Metilcelulosa/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Fenobarbital/administración & dosificación , Fenobarbital/toxicidad , Pirimidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Sensibilidad y Especificidad
20.
Proteomics ; 4(6): 1802-10, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15174146

RESUMEN

Ductal morphogenesis in the mouse mammary gland occurs mainly postnatally and is driven by specialized structures at the ends of the developing ducts, the terminal end buds (TEBs), which later regress once ductal growth is complete. To identify proteins that are specifically associated with migration of TEBs we developed a novel method of isolating TEBs, which eliminated the mammary stroma. The protein expression profile of the TEBs was then compared with that of isolates taken from the 4th inguinal mammary gland of adult virgin mice using two-dimensional (2-D) gel electrophoresis and mass spectrometry (MS) analysis (matrix-assisted laser desorption/ionization and quadrupole time of flight). Following construction of an integrated protein expression database, 44 protein features which showed differential expression levels between the two sets were chosen for MS analysis. Of these, 24 gave protein annotations whereas the other 20 produced unidentified peptides. Fourteen unequivocal proteins were identified from these 24, whereas the remaining 10 matched more than one protein within a single 2-D gel feature. Several of the identified proteins were associated with the cytoskeleton and have previously been reported in axonal growth cones, suggesting that they may influence cell shape and motility within the advancing TEBs, in a similar fashion to migrating axons.


Asunto(s)
Axones/química , Conos de Crecimiento/química , Glándulas Mamarias Animales/química , Proteínas/análisis , Proteoma/análisis , Animales , Western Blotting , Electroforesis en Gel Bidimensional , Femenino , Inmunohistoquímica , Queratinas/metabolismo , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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