AKT/mTOR and MAPK Inhibition Improves Childhood RASopathic Cardiomyopathy
Bibliographic record
Abstract
All articles of this category Background: RASopathies are a spectrum of pleomorphic syndromic disorders and caused by germline mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway. They cause progressive RASopathy-associated cardiomyopathy (RAS-CM) for which no preventive or curative therapies exist. Young infants presenting with heart failure suffer from high mortality. RAS-CM presenting later in life is morbid with increased risk for sudden cardiac death or cardiac transplantation. Animal studies and limited case reports have suggested that small molecule inhibitors of target of rapamycin (mTOR) or mitogen-activated protein kinase kinase (MEK), pathways activated in certain RASopathies, are beneficial. The aim of this study is to report on 25 patients from Europe and North America with progressive and/or life-threatening RAS-CM in whom we initiated off-label or compassionate inhibition of mTOR or MEK after exhaustion of standard therapies. Method: This study was done by retrospective data collection. Results: Over a follow-up period of 296 patient-months (median, 5.5 months; range, 1.5–50), we observed increased transplant-free survival in critically ill patients <6 months of age treated with mTORi and/or MEKi as compared with that from natural history studies (75 vs. 39%, p = 0.031). Freedom from surgical intervention was 52% (11 of 21 patients in whom surgical outflow tract resection was indicated), and clinically meaningful improvement (greater than 20% from baseline) in 50% or more of preselected cardiac outcome variables occurred in 18 of 25 patients (72%) undergoing mTORi and/or MEKi treatment. No life-threatening adverse events related to mTORi or MEKi occurred. Conclusion: These data suggest that selected RASopathy patients may benefit from mechanism-informed therapeutics guided by the biological understanding of cardiac pathology in this disease spectrum. Publication History Article published online: 12 February 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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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) | 0.002 | 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".