O-090 Foxo3 Is Activated In High-risk Neuroblastoma And Contributes To Chemotherapy-resistance And Angiogenesis
Bibliographic record
Abstract
Background FOXO transcription factors control programmed cell death, stress resistance and longevity in normal and malignant cells. We investigated the expression, subcellular localization and phosphorylation of FOXO3 in tumour sections of post chemotherapy neuroblastoma (NB) patients and analysed the effects of FOXO3 in cultured NB cells. Methods Paraffin-embedded sections from patients were analysed for FOXO3 expression, localization and phosphorylation. Effects of chemotherapeutics on FOXO3 subcellular shuttling were assessed by live cell fluorescence imaging in ECFP-FOXO3 transgenic cells. To study how FOXO3 modulates survival we generated cell lines expressing a conditional PKB-independent FOXO3 allele (FOXO3(A3)ERtm) that can be activated by 4OH-tamoxifen and studied the effects of FOXO3-activation in vitro by clonagenic survival and propidium iodide FACS-analyses and in vivo by xenograft transplantation into nude mice. Results We found that FOXO3 was localised in the nucleus in tumour sections from high-risk NB patients. FOXO3 nuclear localization and phosphorylation significantly correlated with reduced patient survival. The chemotherapeutics etoposide and doxorubicin led to rapid nuclear accumulation and increased phosphorylation of FOXO3. After low activation of FOXO3 increased clonagenic survival was observed in NB8/FOXO3 cells in combination with chemotherapeutic drugs whereas NB15/FOXO3 cells underwent spontaneous apoptosis. When transplanting NB15/FOXO cells into nude mice, basal FOXO3 activity induced angiogenesis of NB tumours in vivo, whereas full activation eradicated the tumour. Conclusions The combined data suggest that FOXO3 is activated in high risk NB tumours and depending on the level of its activation, contributes to chemotherapy resistance and tumour angiogenesis or acts as a tumour suppressor.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".