Abstract 12681: Implication of Aurora Kinase B in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Objective: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by a progressive remodelling of pulmonary arteries (PAs). This leads to an elevation in PA pressure and resistance, leading to right heart failure and death. Nowadays, it is recognized that PA smooth muscle cells (PASMCs) are key actors in the histopathological changes in PAH. As seen in cancer cells, PASMCs exhibit a pro-proliferative and anti-apoptotic cancer-like phenotype, sustained by an important metabolic switch known as Warburg effect. Aurora kinase B (AURKB) is strongly involved in cell proliferation, apoptosis and metabolism by controlling cell cycle activation and mitochondrial functions. Previous research has shown that AURKB is overexpressed in various human cancers and its inhibition repressed tumor progression both in vivo and in vitro, suggesting that it could be a novel therapeutic target in PAH. We thus hypothesized that AURKB is upregulated in PAH and contributes to PAH-PASMCs proliferation and resistance to apoptosis, inhibition of which may reverse PA remodeling. Methods/Results: Using Western blot (WB), we demonstrated a FOXM1-dependent upregulation of AURKB in PASMCs isolated from PAH patients compared to controls (p<0.05 ; n=8-14). Similar results were found in the monocrotaline (MCT) and sugen-hypoxia (Su/Hx) rat models (p<0.05 ; n=11-22). In vitro, we found that pharmacological inhibition of AURKB significantly decreases PAH-PASMC proliferation (EdU incorporation, Ki67 labeling) as well as resistance to apoptosis (Annexin V assay) (p<0.05 ; n=6). We also demonstrated that inhibition of AURKB decreases pro-survival factors such as Survivin and PLK1 and increases apoptosis and cell cycle arrest factors including P21, P27, and P53 (WB; p<0.05 ; n=6). As expected, inhibition of AURKB in PAH-PASMCs was associated with a dose-dependent decrease of phosphohistone H3 expression, a well-known target of AURKB (p<0.05 ; n=6). The therapeutic potential of Barasertib, a clinically available and specific AURKB inhibitor, is currently investigated in both MCT and Su/Hx models. Conclusion: Our preliminary data suggests the contribution of AURKB in PA remodeling and the great potential of using AURKB inhibitors to reverse PAH development.
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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) | 0.004 | 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".