A sensitive and specific assay to characterize plasma kallikrein activity in plasma from patients with hereditary angioedema
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Résumé
Introduction Plasma kallikrein (PKa) activity is increased in the plasma of patients with hereditary angioedema (HAE) and has been implicated in other kallikrein-kinin system (KKS)–mediated diseases. Exogenous substrates commonly used in PKa assays can be cleaved by multiple plasma proteases, which reduce assay specificity and sensitivity for PKa. We describe a sensitive and specific assay to detect PKa activity in plasma as a candidate biomarker for HAE. Methods PKa activity was measured in plasma samples from patients with HAE with decreased C1 inhibitor (C1INH) levels or activity who were not receiving prophylactic medications for HAE (HAE-C1INH; n = 25), from individuals with a presumptive diagnosis of HAE with normal C1INH (HAE-nC1INH; n = 3), and from age-matched controls without HAE ( n = 57). Samples were analyzed at baseline and after 6 h of cold incubation at 4 °C. Amidolytic activity was measured in the absence and presence of a PKa-specific inhibitor (KV999272). Specific PKa (sPKa) activity was quantified by the subtraction of amidolytic activity not inhibited by KV999272 from the total measured amidolytic activity. Results In control plasma, sPKa activity was 0.69 ± 0.07 nmol/min/mL at baseline and 0.88 ± 0.11 nmol/min/mL after 6 h of cold incubation (mean ± SEM, p = 0.0062); the 95th percentile of sPKa activity was 1.87 nmol/min/mL at baseline and 3.07 nmol/min/mL after cold incubation. In plasma from patients with HAE-C1INH, sPKa activity was 3.43 ± 0.64 nmol/min/mL at baseline and 24.53 ± 8.92 nmol/min/mL after 6 h of cold incubation ( p = 0.023). sPKa activity in HAE-C1INH plasma samples was above the 95th percentile for control plasma with assay sensitivity of 84% and specificity of 95%. The area under the receiver operating characteristic curve was 0.98 ( p < 0.0001). sPKa activity in all plasma samples from patients with HAE-nC1INH was above the 95th percentile for control plasma after 6 h of cold incubation. Conclusion We developed a specific PKa assay that can detect low levels of PKa activity in plasma and can differentiate patients with HAE-C1INH from controls without HAE with high sensitivity and specificity. Using this assay, we demonstrated that sPKa activity is elevated during the intercritical period in patients with HAE-C1INH and in those with HAE-nC1INH compared with controls when measured after 6 h of cold incubation. This sensitive and specific PKa assay could be useful to characterize PKa activity in plasma samples from patients with HAE and could potentially serve as a future candidate biomarker for HAE-nC1INH.
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Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
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