Abstract 7178: Neuronal cells derived from iPSCs cell to evaluate neurotoxicity after 48 or 72 hours in high-through put screening format
Bibliographic record
Abstract
Abstract Neurotoxicity is a major concern in central nervous system drug discovery and a frequent cause of attrition in clinical trials or approved drug withdrawal. Neuropathy is a side effect defined by the injury of peripheral nerves causing a loss of sensation/motion. Drug development pipelines typically involve testing in cell lines followed by animal investigations with translation to humans. The induced pluripotent stem cells (iPSCs) have widened new model systems to study adverse toxicities. With evolution in regulatory guidance the use of human- iPSC-derived tissue provides high-throughput access and a more relevant testing environment. Neuropathy is one of the most chemotherapy adverse effects. In this study we have screened 8 compounds. Bortezomib (proteasome inhibitor), gemcitabine (approved ovarian cancer treatment), ivermectin (parasitic diseases treatment), flavopiridol (approved CDKs inhibitors), SNS-032 (approved CDKs inhibitor), mefloquine (anti-malaria drug), digitonin (nonionic detergent) and tamoxifen (hormone receptor-positive breast cancer treatment). These molecule toxicities were tested on neuronal-derived iPSCs Dopaneurone, GABAneurone, Glutaneurone, Motorneurone, Microglya and Astrocytes in high throughput screening. For the project, cells were plated in 384 well/plates. DMSO tolerance was performed (up to 10%). Drugs were added, then, after 48h or 72h, total protease and protease activities were measured using CytoTox-GloTM. Compounds were tested at 7 concentrations (from 10−4 to 10−9M).In this study we have validated cell culture and the assay conditions. The signal window range was good after 48h and 72h of treatment. No toxicity was found until 10% DMSO. A specific neurotoxicity signature was measurable for each drug tested. Digitonin, our positive control, induced toxicity in all IPSCs after 48h and 72h of incubation. On the contrary, Tamoxifen, our negative control, did not induce any neurotoxicity. The other molecules generated a signature of severe to mild neurotoxicity. These results are in agreement with their known adverse side-effects. In conclusion, this panel is a good tool to anticipate possible neurotoxicity within the 3Rs respect. It can be used in early drug de-risking or neuroprotection screening, with the aim of preventing/reducing/curing neuropathy in at-risk populations. Citation Format: Fabienne Sabatier, Justine Chaigne, Maryse Martin, Rodolphe Barbeau, Luisa Houssin, Stephane Bonnin, Alastair King, Vanessa Jahnke. Neuronal cells derived from iPSCs cell to evaluate neurotoxicity after 48 or 72 hours in high-through put screening format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7178.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.010 | 0.006 |
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".