Abstract 1646: Molecular pathways associated with Reolysin and gemcitabine synergy in ras-mutated human HCT116 cells
Notice bibliographique
Résumé
Abstract Reolysin, a type 3 reovirus, is a ubiquitous double-stranded RNA virus that exhibits selective oncolytic activity in ras-activated tumor cells and is non-pathogenic in humans. Our laboratory has previously demonstrated that Reolysin (reo) is synergistic when used in combination with gemcitabine (gem) and other commonly used cytotoxic agents against human colon carcinoma cells in vitro and in vivo. To determine the molecular pathways associated with gem/reo synergy, we exposed HCT116 cells, a human colon carcinoma cell line, to gem, reo, or the combination for 24, 48, 72 and 96 hrs in triplicate. The drug concentrations used were those found to be synergistic in previous in vitro studies (24 pfu/cell reo and/or 4nM gem). We harvested the cells, extracted RNA and performed microarray analysis using the HU133 2.0 plus array (Affymetrix). Gene expression data analysis was performed using GeneSpring GX 7.3.1 (Agilent Technologies). Raw intensity data were imported and preprocessed using the RMA algorithm. Data was then transformed, chips were normalized to the 50th percentile and raw data were filtered with a 2 fold minimum gene expression cutoff. Each experiment was run in triplicate and gene expression levels were averaged among replicates. We performed a 2-way ANOVA to test for time and treatment effects. The genes presenting the most significant treatment effects (160 genes, p<0.01) were uploaded to Ingenuity IPA 6.5 (Ingenuity Systems) for further pathway analysis. The top three canonical pathways significantly affected by the combination treatment were interferon signaling, antigen presentation and the protein ubiquitination pathways. These data suggest that the combination of gem and reo stimulates the immune system to increase surveillance/recognition of cancer cells. Further analyses were performed comparing the combination of gem/reo to gem alone. Approximately 300 genes were significantly (2 fold change, p<0.01) up or down-regulated in the combination therapy compared to gem alone. The combination of gem/reo downregulated PI3Kinase signaling while upregulating IKB signaling. The downstream effects of IKB upregulation are antiviral and stress responses. Single agent gemcitabine has proven to be inactive in colon cancer, yet HCT116 cells treated with a combination of gem and reo proved to be an effective pre-clinical therapy in these experiments. This enhanced preclinical efficacy is potentially due to an enhancement of tumor surveillance by the immune system. Clinical trials with Reolysin in combination with other chemotherapeutic drugs are ongoing. Understanding the mechanisms associated with cytotoxic synergy will allow us to better select drug combinations for specific tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1646.
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 | 0,001 |
| 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) | 0,002 | 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 ».