Abstract 17213: Crizotinib Exacerbates the Severity of Pah in a Preclinical Rat Model
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy histologically associated with remodeling of distal pulmonary arteries and right ventricular failure that is drug-induced in approximately 10% of cases. Recently, PAH induced by chemotherapeutic agents such as RTK inhibitors (e.g. dasatinib) has been described. Crizotinib is a new MET inhibitor increasingly used for the treatment of ALK-positive non-small cell lung carcinoma. Interestingly, crizotinib has been shown to induce endothelial cells (EC) dysfunction (e.g. inhibition of EC survival and angiogenesis) and is symptomatically associated with dyspnea and peripheral oedema in many patients, which are cardinal symptoms of PAH. We thus hypothesized that chronic administration of crizotinib exacerbates PAH. Material and results: We observed a significant increase of mortality rate in PAH rats (Sugen/hypoxia model) treated with daily oral administration of crizotinib (100mg/kg/d for 2 weeks) compared to rats treated with vehicle (6/group; p<0.05). Furthermore, we demonstrated that crizotinib treatment was associated with increases in right ventricular systolic pressure, mean pulmonary arterial pressure and pulmonary vasculature resistance; and decreases in cardiac output and stroke volume (right heart catheterizations in closed chest) compared to vehicle-treated rats with Sugen-induced PAH (4 PAH+crizotinib; 6 PAH+vehicle, 5 PAH and 3 control rats; p<0.05). Histologically, crizotinib administration significantly increased pulmonary arteries wall thickness as well as right ventricular fibrosis (p<0.05). Finally, crizotinib increased macrophage accumulation and size within the lungs of PAH rats (p<0.05). Conclusion: We documented for the first time that crizotinib treatment markedly increases vascular remodeling and macrophage activation with concomitantly marked PAH exacerbation in Sugen rats. This study could have major clinical relevance in the management of patients treated with crizotinib.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".