Functional Assessment of the Mitochondrial Pathway of Caspase Activation in Patients with Acute Myeloid Leukemia (AML).
Notice bibliographique
Résumé
Abstract Chemotherapeutic agents used in the treatment of AML such as cytarabine and etoposide can induce caspase activation through the mitochondrial pathway. Blocks in this pathway can render cells resistant to these agents and may contribute to poor patient outcomes. To explore the frequency of defects in this pathway, the functional integrity of the downstream portion of the mitochondrial pathway of caspase activation was assessed in cytosolic lysates from patients with newly diagnosed (n=29) or relapsed (n=11) AML who had >80% blasts in their peripheral blood. Lysates were stimulated with cytochrome c and dATP (cy c/dATP) and hydrolysis of Ac-DEVD-AFC by effector caspases was measured over time. The specificity of the assay was tested by pretreating lysates with the BIR3 domain of XIAP (a caspase-9 inhibitor) or Crm A (a caspase-8 inhibitor). Pretreatment with BIR3, but not CrmA protein, inhibited cy c/dATP-induced effector caspase activation. In contrast, Crm A, but not BIR3 inhibited recombinant caspase-8-induced effector caspase activation, demonstrating the specificity of the assay. Cy c/dATP-induced effector caspase activation correlated with etoposide-induced apoptosis. Samples with the highest increases in effector caspase activation had the greatest sensitivity to etoposide (R2=0.69, p=0.006). To relate the functional status of the mitochondrial pathway to patient outcome, mitochondrial pathways were divided into intact and blocked based on the increase in effector caspase activity in normal mobilized peripheral blood mononuclear stem cells (PBSC) stimulated with cy c/dATP. AML samples with increases in effector caspases ≥ PBSC were deemed to have intact pathways, while AML samples with increases in effector caspases < PBSC were deemed to have blocked pathways. With this division, 8/11 (73%) samples from patients with relapsed disease had a blocked mitochondrial pathway vs 7/29 (24%) samples from patients with newly diagnosed disease (p = 0.009 by Fisher Exact test). In the 22 patients who completed induction chemotherapy, functional defects in caspase activation did not predict response, as 3/13 (23%) responders and 2/9 (22%) nonresponders had a blocked pathway (p = 1.0 by Fisher Exact test). Defects in the mitochondrial pathway of caspase activation may be due to blocks above or below the level of effector caspases. To distinguish between these possibilities, effector caspases were directly activated by stimulating lysates with recombinant active caspase-8. Data were dichotomized based on caspase-8-induced activation of effector caspases in lysates of PBSC. Active caspase-8 failed to activate effector caspases in 13/15 (87%) samples with a blocked mitochondrial pathway. In contrast, active caspase-8 failed to activate effector caspase in 3/27 (11%) samples with an intact mitochondrial pathway (p<0.0001 by Fisher Exact test). These results suggest that most samples with a blocked mitochondrial pathway had a distal defect in caspase activation. In conclusion, functional defects in the distal portion of the mitochondrial pathway of caspase activation were observed more frequently in patients with relapsed AML than newly diagnosed disease. Future studies with longitudinal samples are required to determine whether defects in relapsed patients were present at diagnosis or emerged at relapse. Nonetheless, for patients with blocked pathways, therapeutic strategies that overcome these distal blocks or induce cell death through caspase-independent mechanisms could be useful.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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) | 0,001 | 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.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».