Vesicular stomatitis virus and BCL-2 inhibitor combination therapy for the treatment of chronic lymphocytic leukemia
Bibliographic record
Abstract
Chronic lymphocytic leukemia (CLL) is a cancer of the white blood cells (B cell lymphocytes).It is an indolent disorder that results in the accumulation of CD5+ B cells.In CLL, resistance to cell death is attributed to the overexpression of several key pro-survival proteins (i.e.B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia-1 (Mcl-1)) that belong to the apoptotic Bcl-2 family of proteins.Bcl-2 and Mcl-1 overexpression deregulates both the apoptotic and autophagic signaling pathways and contributes to tumorigenesis.Oncolytic virotherapy has emerged as a novel anti-cancer therapy for the treatment of a variety of malignant disorders.Oncolytic virus (OV) Vesicular stomatitis virus (VSV)-AV1 takes advantage of genetic defects present within cancerous cells and preferentially targets and kills them.Normal cells are spared the cytotoxic effects of viral lysis and are left unharmed.CLL cells are largely resistant to VSV oncolysis due to an elevated protein expression level of Bcl-2 and Mcl-1 as well as the inhibitory interactions Bcl-2 and Mcl-1 form with proapoptotic and pro-autophagic proteins.It is a common approach to use combination therapy to overcome limitations with single agent treatment.In the studies presented within, VSV-AV1 treatment was combined with small-molecule Bcl-2 inhibitors as a means to overcome resistance to oncolytic virtotherapy observed in CLL patients.In the first strategic approach, we combined low-dose amounts of the pan-Bcl-2 inhibitor, Obatoclax, with VSV-AV1 and examined the effect on the apoptotic signaling pathway.Obatoclax and VSV-AV1 synergistically enhanced cell death in primary CLL cells.The combination therapy induced intrinsic apoptotic signaling through the activation of caspases-3 and -9 cleavage.Inhibitory complexes between Bcl-2:Bax and Mcl-1:Bak were disrupted as well.
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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) | 0.001 | 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".