Bibliographic record
Abstract
Protein degradation is a highly regulated process that is required for maintaining cellular homeostasis, and its deregulation is associated with development of a number of diseases including cancer. Neddylation is a posttranslational modification that involves conjugation of the ubiquitin-like protein NEDD8 (neural precursor cell expressed, developmentally downregulated) to target proteins such as oncoproteins and tumor suppressors to regulate their functions through a cascade of enzymes including NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligases (E3). 1 As such, the neddylation pathway presents an attractive oncogenic target for development of anticancer therapies. The main cellular substrates for neddylation include components of the Cullin-RING E3 ligase (CRL), which is the largest multicomponent ubiquitin ligase family regulating the turnover of multiple tumor suppressor proteins such as p21, p27, and NF-Kappa-B Inhibitor Alpha, among others (Fig. 1A). 2 In an elegant study, Hua et al systematically investigated the effectiveness of the NAE inhibitor, MLN4924, against glioblastoma (GBM) in vitro and in vivo. MLN4924 is a newly developed small molecule inhibitor of the neddylation pathway that specifically inhibits NAE by binding to its active site and hindering its enzymatic activity. 3 Several other groups have shown that treatment of cancer cells with MLN4924 results in induction of DNA damage response, cell cycle arrest, apoptosis, or senescence. 4,5 MLN4924 is currently under investigation in several phase 1/2 clinical trials for multiple solid tumor types and hematologic malignancies. 6 The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against GBM. Analysis of overall survival of GBM patients, as well as correlation with expression of global protein neddylation, indicated that higher global protein neddylation correlates with poor patient survival. They also found that GBM tumors generally express higher levels of NEDD8 and neddylation enzymes such as NAE1/UBA3 and UBC12 compared with adjacent normal brain tissue, with recurrent GBM tumors displaying even
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".