MB-81THE GD3 ACETYLATION PATHWAY AS A POTENTIAL THERAPEUTIC TARGET FOR PAEDIATRIC MEDULLOBLASTOMA
Bibliographic record
Abstract
Medulloblastoma survivors frequently suffer from low quality of life as a result of aggressive treatment. New treatments are urgently needed to reduce down-stream sequelae. GD3, an oncofoetal ganglioside is re-expressed in medulloblastoma and when accumulated causes mitochondrially-mediated apoptosis. 9-O-acetyl GD3 (GD3A), its acetylated form, has been shown to protect cells from GD3-mediated apoptosis. In three medulloblastoma cell lines RES256, UW402 and CHLA-01-Med expression of GD3 (56.7%, 61.3% and 45.1%) and GD3A (84.5%, 74.4% and 79.4%) was confirmed. Sialate-O-acetylesterase (SIAE), the human endogenous deacetylation enzyme of GD3A is significantly down-regulated in medulloblastoma tissue (p < 0.001), shown by genome-wide transcriptional analysis. In order to evaluate this pathway as a potential therapeutic target we used an inducible SIAE over-expression approach in RES256 cells. Upon over-expression of SIAE we show a significant increase in GD3 expression (p < 0.05), and a significant increase in depolarisation of the mitochondrial membrane potential (p < 0.05). These changes were not seen on induction of expression of a catalytic mutant SIAE-S127A or vector controls. Induction of SIAE over-expression in combination with etoposide treatment resulted in a significant reduction in IC50 (5.2 mM to 3.3 mM; p < 0.0001, n = 2). In SIAE-S127A expressing cells there was also a significant reduction in IC50, (3.5 mM to 2.4 mM; p < 0.01 n = 2). IC50 values for empty vector control could not be determined. Our preliminary results suggest that SIAE over-expression leads to a collapse of the mitochondrial membrane potential in RES256 cells. Additionally, these results suggest that SIAE over-expression may sensitise cells to chemotherapeutics, potentially reducing side-effects.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".