Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Nature ; 607(7917): 97-103, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35255492

RESUMEN

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.


Asunto(s)
COVID-19 , Enfermedad Crítica , Genoma Humano , Interacciones Huésped-Patógeno , Secuenciación Completa del Genoma , Transportadoras de Casetes de Unión a ATP , COVID-19/genética , COVID-19/mortalidad , COVID-19/patología , COVID-19/virología , Moléculas de Adhesión Celular , Cuidados Críticos , Enfermedad Crítica/mortalidad , Selectina E , Factor VIII , Fucosiltransferasas , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno/genética , Humanos , Subunidad beta del Receptor de Interleucina-10 , Lectinas Tipo C , Mucina-1 , Proteínas del Tejido Nervioso , Proteínas de Transferencia de Fosfolípidos , Receptores de Superficie Celular , Proteínas Represoras , SARS-CoV-2/patogenicidad , Galactósido 2-alfa-L-Fucosiltransferasa
2.
Nat Med ; 30(1): 279-289, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38200255

RESUMEN

The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.


Asunto(s)
Glioblastoma , Medicina de Precisión , Humanos , Genómica , Oncogenes , Mutación de Línea Germinal/genética
3.
Bioanalysis ; 8(6): 487-95, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26916197

RESUMEN

The 9th GCCClosed Forum was held just prior to the 2015 Workshop on Recent Issues in Bioanalysis (WRIB) in Miami, FL, USA on 13 April 2015. In attendance were 58 senior-level participants, from eight countries, representing 38 CRO companies offering bioanalytical services. The objective of this meeting was for CRO bioanalytical representatives to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues selected at this year's closed forum include CAPA, biosimilars, preclinical method validation, endogenous biomarkers, whole blood stability, and ELNs. A summary of the industry's best practices and the conclusions from the discussion of these topics is included in this meeting report.


Asunto(s)
Biomarcadores/análisis , Biosimilares Farmacéuticos/análisis , Evaluación Preclínica de Medicamentos/métodos , Biomarcadores/sangre , Registros Electrónicos de Salud , Laboratorios , Sociedades Médicas , Estudios de Validación como Asunto
4.
Bioanalysis ; 7(24): 3107-24, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26635247

RESUMEN

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5 day, week-long event - A Full Immersion Bioanalytical Week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS and LBA approaches, including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 3 discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Part 1 (small molecule bioanalysis using LCMS) and Part 2 (hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in volume 7, issues 22 and 23 of Bioanalysis, respectively.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Bioensayo , Biomarcadores/análisis , Biofarmacia/organización & administración , Biotecnología/organización & administración , Humanos
5.
AAPS J ; 16(1): 83-8, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24242296

RESUMEN

The L2 Global Harmonization Team on large molecule specific assay operation for protein bioanalysis in support of pharmacokinetics focused on the following topics: setting up a balanced validation design, specificity testing, selectivity testing, dilutional linearity, hook effect, parallelism, and testing of robustness and ruggedness. The team additionally considered the impact of lipemia, hemolysis, and the presence of endogenous analyte on selectivity assessments as well as the occurrence of hook effect in study samples when no hook effect had been observed during pre-study validation.


Asunto(s)
Técnicas de Química Analítica/normas , Guías de Práctica Clínica como Asunto , Proteínas/análisis , Estudios de Validación como Asunto
6.
Bioanalysis ; 6(23): 3113-20, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25529880

RESUMEN

Recent guidelines on bioanalytical method validation have recommended to investigate matrix effects in special matrices such as hemolytic and hyperlipidemic plasma. However, these guidelines were not clear on how to implement these recommendations. The European Bioanalysis Forum has discussed this topic in depth and has asked for feedback from member companies. Those discussions have resulted in more specific guidance on how to define hemolytic and hyperlipidemic plasma, how to validate bioanalytical methods for these matrices and how to deal with hemolytic and hyperlipidemic study samples. These recommendations are presented in this manuscript.


Asunto(s)
Técnicas de Laboratorio Clínico/métodos , Hemólisis , Hiperlipidemias , Europa (Continente) , Humanos , Reproducibilidad de los Resultados
7.
Bioanalysis ; 4(15): 1883-94, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22943619

RESUMEN

Biomarkers have become increasingly important in drug development and many bioanalysts are getting involved. Consequently, different views on how to approach the bioanalysis of biomarkers have been published or are being developed. The European Bioanalysis Forum has intensively discussed this topic since 2010 and is ready with their recommendation on method establishment and bioanalysis of biomarkers. Acknowledging that the challenges step outside the bioanalytical laboratory is a cornerstone of our recommendation. The importance of integrating all scientific aspects, from purely analytical aspects, all the way to understanding the biology and effects of the biomarker, prior to embarking on method establishment or sample analysis, cannot be underestimated. Close and iterative interactions with the teams requesting the data is imperative to develop a bioanalytical strategy that combines science, analytical performance and regulations. The European Bioanalysis Forum developed a straightforward decision tree to help the scientific community in developing a bioanalytical strategy for any biomarker in drug development.


Asunto(s)
Biomarcadores Farmacológicos/análisis , Descubrimiento de Drogas/normas , Animales , Biomarcadores Farmacológicos/metabolismo , Europa (Continente) , Estudios de Evaluación como Asunto , Regulación Gubernamental , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA