Tumour initiated purinergic signalling promotes cardiomyocyte RBFOX1 degradation and cardiotoxicity from DNA damaging anticancer agents
Bibliographic record
Abstract
It is well established tumour cells secrete signalling factors affecting distant normal tissues. What remains unresolved is whether these factors initiate a signalling cascade rendering terminally differentiated cardiomyocytes susceptible to apoptosis, a feature of chemotherapy-induced cardiotoxicity (CIC). Here we show in MANTICORE trial cancer patients, cumulative baseline plasma levels of the nucleoside inosine and its derivative hypoxanthine predict cardiotoxicity. We found the Zn2+ finger transcription factor ZNF281 increases synthesis and release of inosine and hypoxanthine, which bind the A2A receptor on cardiomyocytes, activating CAMKIIδ which phosphorylates the postnatal mRNA splicing factor RBFOX1, resulting in its caspase-dependent degradation. RBFOX1 loss reverts cardiomyocytes to a less mature state with open chromatin and susceptibility to DNA damage, apoptosis or CIC, when treated with DNA intercalating or alkylating anticancer agents. These findings suggest cumulative inosine and hypoxanthine levels may be a biomarker predicting patient susceptibility to DNA damaging anti-cancer agents. Chemotherapy-induced cardiotoxicity (CIC) is an adverse condition associated with several DNA damaging chemotherapeutics. Here, the authors discover that tumour ZNF281-mediated increase of purinergic signalling factors inosine and hypoxanthine promotes RBFOX1 degradation in cardiomyocytes, increasing the risk for developing CIC.
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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) | 0.001 | 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".