The effects of fenretinide, a vitamin a derivative, on phenotypes of cystic fibrosis
Notice bibliographique
Résumé
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR). Individuals are usually diagnosed in infancy and are burdened with extensive medical treatments throughout their lives. The treatments currently available attempt to preserve lung function by addressing bacterial infections and physiological defects of the CF lung. There are many CF phenotypes not addressed by current therapies such as high levels of inflammation, high oxidative/nitrosative stress, abnormal levels of polyunsaturated fatty acids (PUFA) and defects in ceramide. Based on our preliminary studies, we hypothesized that fenretinide could address these gaps in CF treatment. Our previous studies demonstrated the protective effects of fenretinide, a derivative of vitamin A, in CF mice. The drug treatment in CF mice improved clearance of lung infections and normalized the levels of ceramide, which were abnormally low in CF. In this thesis, we show that the abnormal levels of PUFAs, arachidonic acid (AA) and docosahexaenoic acid (DHA), are associated with the defects in ceramide in CF patients. Fenretinide treatment in CF mice improved the PUFA imbalance systemically and in CF-related organs, lung, ileum, pancreas and liver. The drug also reduced the expression of inflammatory genes, IL-1β and S100A8, in the lung of CF mice. Fenretinide had prolonged normalizing effects on PUFA and ceramide levels in mice with one dose improving the lipids up to 90 hours after treatment. It also reduced the levels of malondialdehyde, a marker of lipid peroxidation, and nitrotyrosine, a marker of nitrosative stress. High levels of lipid peroxidation and nitrosative stress were correlated with greater defects in lipids. Lipids from leukocytes isolated from CF patients responded to fenretinide treatment in similar ways with a reduction in AA, and increased DHA and ceramide. Lipid peroxidation also decreased in CF cells. We also tested different formulations of the drug in monkeys and demonstrated a drug effect in yet another animal species. CF patients periodically experience worsening of their pulmonary symptoms and these events are called pulmonary exacerbations (PEx). These events impact the progression of lung disease however they are nearly impossible to prevent. We followed a cohort of CF patients during stable disease to evaluate markers associated with the risk of a future PEx. We determined that at stable disease, a worse clinical picture and a lower score on the patient's quality of life assessment were related to a higher risk of a PEx. After treatment for PEx, patients with high levels of inflammation had rapidly re-exacerbated. We discovered that the aggressive treatments used during PEx decreased inflammatory markers but also improved the defects in PUFA by decreasing AA and increasing DHA. Additionally, treatments for PEx reduced the levels of malondialdehyde and nitrotyrosine, however they are not feasible for chronic use unlike fenretinide. Fenretinide has been used in long-term cancer prevention trials. The reported side-effects were minimal and reversible with short drug-free intervals. The results in this thesis show the impact of fenretinide on improving lipid defects, reducing inflammation and normalizing high levels of lipid peroxidation and nitrosative stress. These phenotypes are not currently addressed in routine CF therapy thus fenretinide is a good candidate for future clinical trials.
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 | 0,000 |
| 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 | 0,001 |
| 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 ».