Chymotrypsin B2 (CTRB2) Deletion Variant Induces Endoplasmic Reticulum Stress but Does not Increase Risk for Chronic Pancreatitis
Bibliographic record
Abstract
OBJECTIVES: CTRB2-del, a commonly occurring loss-of-function deletion variant in the CTRB2 gene encoding chymotrypsinogen B2 was shown to induce endoplasmic reticulum (ER) stress and increase risk for pancreatic cancer but not for chronic pancreatitis (CP). Since other digestive enzyme variants that cause misfolding and induce ER stress are strong risk factors for CP, the lack of association between CP and the CTRB2-del variant is surprising. The aim of the present study was to re-examine the biochemical and clinical characteristics of the CTRB2-del variant. METHODS: We performed experiments with AR42J cells transduced with adenoviral vectors and investigated disease association in Hungarian and German cohorts of CP cases. RESULTS: We found that the CTRB2-del protein was not secreted from AR42J cells but accumulated inside and induced significant ER stress. Curiously, epitope tagging CTRB2-del with a polyhistidine tail abolished its capacity to elicit ER stress even though the tagged construct remained defective in secretion and was retained intracellularly. Human genetic studies demonstrated similar carrier frequency of the CTRB2-del variant in CP cases and controls. CONCLUSIONS: We replicated the ER-stress causing effect of the CTRB2-del variant and confirmed the lack of association with CP. The observations also revealed that epitope-tagging may alter the cellular effects of the CTRB2-del protein. The lack of association between ER stress and CP risk in carriers of the CTRB2-del variant raises the possibility that ER stress is a marker of digestive enzyme misfolding but does not drive CP onset and/or progression.
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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 | 0.001 |
| 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 | 0.000 |
| 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".