Phosphoinositide-3 kinase antagonism does not reverse steroid insensitivity in severe asthma
Bibliographic record
Abstract
Introduction: Response to glucocorticosteroid (GCS) therapy in asthma is assessed by reduction in eosinophil counts. Phosphoinositide-3 kinase (PI3K) pathway may contribute to GCS insensitivity in severe asthma. Aims and objectives: The effect of PI3K antagonism was evaluated on GCS induced eosinophil apoptosis as a mechanism of GCS insensitivity. Methods: Blood eosinophils, isolated from 7 healthy subjects (HS) and 18 asthmatics, were incubated with increasing concentrations of dexamethasone (0.1, 1 and 10uM) and a pan-PI3K antagonist (LY294002 at 1 and 2uM). Cell viability was assessed using PrestoBlue cell viability assay, Trypan Blue exclusion test and PE-Annexin-V/7-AAD apoptosis detection (flow cytometry). Results: In HS, a time-dependent increase in eosinophil apoptotic% was observed (1.9% at baseline, 25.7% at 16h and 31% at 24h) (p=0.06, p=0.005 respectively). Dexamethasone 10uM increased it to 40.1% at 16h (p=0.03). Dexamethasone induced eosinophil apoptosis was less in severe asthmatics (34.2%) vs. to mild-to-moderate asthmatics (46.7%) (p=0.05) suggesting steroid insensitivity (Fig. 1A). This was not reversed by co-incubation with LY294002 2uM (39.9% vs. 53.3%) (p=0.04) (Fig. 1B). Conclusions: Evaluating dexamethasone-induced apoptosis in blood eosinophil can assess GCS sensitivity ex vivo. Severe asthmatics demonstrate GCS insensitivity, which was not reversed by a pan-PI3K antagonist.
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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) | 0.001 | 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) | 0.003 | 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".