p53 Loss Mitigates Early Volume Deficits in the Brains of Irradiated Young Mice
Notice bibliographique
Résumé
PurposePediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomic development.Methods and MaterialsMice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7 Gy (IR; n = 30) or 0 Gy (sham; n = 28) at 16 days of age. In vivo magnetic resonance imaging was performed before irradiation and at 4 time points after irradiation, until 3 months posttreatment, followed by ex vivo magnetic resonance imaging and immunohistochemistry. The role of p53 in development was assessed at 6 weeks of age in another group of untreated mice (n = 37).ResultsNeuroanatomic development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through 2 stages: an early volume loss within 1 week and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth; thus, p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared with WT-IR mice.ConclusionsAlthough p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiation therapy. This early preservation alone was insufficient to normalize brain development on the whole, but regions reliant on neurogenesis exhibited a significant benefit. Pediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomic development. Mice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7 Gy (IR; n = 30) or 0 Gy (sham; n = 28) at 16 days of age. In vivo magnetic resonance imaging was performed before irradiation and at 4 time points after irradiation, until 3 months posttreatment, followed by ex vivo magnetic resonance imaging and immunohistochemistry. The role of p53 in development was assessed at 6 weeks of age in another group of untreated mice (n = 37). Neuroanatomic development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through 2 stages: an early volume loss within 1 week and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth; thus, p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared with WT-IR mice. Although p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiation therapy. This early preservation alone was insufficient to normalize brain development on the whole, but regions reliant on neurogenesis exhibited a significant benefit.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
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 | 0,001 | 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 | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| 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.
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 tête enseignante, 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 ».