Abstract 980: Preclinical evaluation of mps1 inhibition in uterine leiomyosarcoma
Notice bibliographique
Résumé
Abstract Background: Uterine leiomyosarcoma (Ut-LMS) is the commonest malignant mesenchymal tumor arising from the uterus. It is aggressive and the prognosis is dismal. To-date, no specific oncogenic drivers have been identified. Conventional adjuvant therapy and immunotherapy are ineffective and treatment largely remains surgical. MPS1 kinase is vital in spindle assembly checkpoint which safeguards the faithful segregation of chromosomes. Its inactivation leads to mitotic defects and induces mitotic catastrophe. Compare with normal tissue, MPS1 has shown to be overexpressed in Ut-LMS. Method: The Ut-LMS cell lines SK-UT-1 and SKN were treated with a MPS1 inhibitor. RT-qPCR was performed to analyze mRNA expression levels of Spindle Assembly Checkpoint-related genes. Cells were seeded in 96-well plates and treated with MPS1 inhibitor for 4 days. Sulforhodamine B stain was used to labelled viable cells. IC50 of different cell lines was determined by SRB assay. Cell cycle analysis was done after 2 days treatment by propidium iodide staining. Apoptosis study was done after 3 days treatment by AnnexinV/PI apoptotic assay. Flow cytometry was used to analyze PI assay and AnnexinV/PI apoptotic assay. Immunofluorescence staining of centromere, α-tubulin and DAPI was used to label kinetochore, mitotic spindles and DNA. Cells with chromosome missegregation were counted in treated and non-treated samples. Ut-LMS cell lines SKN was injected subcutaneously in Balb/c nude mice and MPS1 inhibitor was administrated through oral gavage daily, tumor weight was record and tumor size was estimated by caliper. Results: The Spindle Assembly Checkpoint-related genes MPS1, CDC20, MAD2L1, BUB1, BUB1B, and KNL1 were found to be overexpressed. SRB assays had shown that there was growth inhibition of both cell lines in a concentration-dependent manner with IC50 values ranged between 40-65 nM. An increase in aneuploidy cells was demonstrated by PI assay, which suggested that MPS1 inhibitor disrupted cell cycle and induced aneuploidy. The inhibitor also induced apoptosis as demonstrated an increase in AnnexinV+/PI+ cells. Chromosome missegregation was demonstrated in double-thymidine block synchronized anaphase cells with immunofluorescence staining. Micronuclei were also identified in tetraploid cells. In a preliminary in vivo study, MPS1 inhibitor was shown to reduce tumor growth in xenograft models. Conclusion: Our preclinical results indicated that MPS1 inhibitor was an effective treatment in Ut-LMS as a single agent by causing chromosome missegregation, mitotic catastrophe, genomic instability and cell death. Further evaluation of its use in combination with other pharmacological agents is in progress. Citation Format: Ho Shing Wong, Hok Yeung H. Lee, Ka Yu Tse, Tak Wah Mak, Philip PC Ip. Preclinical evaluation of mps1 inhibition in uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 980.
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) | 0,001 | 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) | 0,005 | 0,001 |
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 ».