Transient expression of factor VIII and a chronic high-fat diet induces ER stress and late hepatocyte oncogenesis
Bibliographic record
Abstract
Liver-directed gene therapy using adeno-associated virus (AAV) for delivery of therapeutic transgenes has posed particular challenges over the past 25 years, and there are no FDA-approved products to date. Reasons include lack of efficacy or toxicity or both, despite acceptable efficacy and toxicology results in animals, including non-human primates. The experience with AAV-mediated gene therapy for hemophilia is a case in point. The clotting factor VIII gene was cloned in 1984, but production of the full-length recombinant protein is challenging. Despite this, two therapeutic recombinant factor VIII proteins were approved and marketed by 1993. A subsequent B-domain deleted (BDD) version of factor VIII (FVIII) proved more efficient to manufacture in cell lines than full-length FVIII. However, it was later recognized that high levels of FVIII expression are responsible for an endoplasmic reticulum (ER) stress response in cells. 1 Malhotra J.D. Miao H. Zhang K. Wolfson A. Pennathur S. Pipe S.W. Kaufman R.J. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA. 2008; 105: 18525-18530https://doi.org/10.1073/pnas.0809677105 Crossref PubMed Scopus (546) Google Scholar With the enigmatic toxicity seen in AAV-factor VIII gene therapy trials, all of which use the BDD factor VIII, investigation redoubled into whether an ER stress response may be responsible for the variable and diminishing levels of factor VIII observed in the clinical trials.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.009 | 0.006 |
| Insufficient payload (model declined to judge) | 0.002 | 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".