Abstract 15328: Investigating the Role of Endothelial Breast Cancer Susceptibility Gene 2 in Doxorubicin-Induced Cardiotoxicity
Bibliographic record
Abstract
Background: Doxorubicin (DOX) is a chemotherapeutic drug used to treat various malignancies including breast cancer. However, DOX use is limited by DOX-induced cardiotoxicity (DIC), which carries a poor prognosis and is frequently fatal. Accumulating evidence indicates a central role of oxidative stress, DNA damage, inducing cellular inflammation and apoptosis as common pathways during DIC. BRCA2 functions to maintain genome-wide stability by promoting DNA damage repair and also has anti-oxidative and anti-inflammatory roles. Thus, the pathways of DIC; DNA damage, oxidative stress, inflammation and endotheliotoxiciy; are specifically regulated by BRCA2. However, the role of endothelial BRCA2 in the mechanisms driving DIC remain unknown. Hypothesis: We hypothesize that endothelial cell-specific loss-of BRCA2 exacerbates and prevents DOX- induced DNA damage, inflammation, endotheliotoxicity, and cardiomyocyte death promoting DIC. Methods and Results: To understand the effect of DOX on BRCA2 expression in vitro , we cultured Human Umbilical Vein Endothelial Cells (HUVECs) and performed time and dose experiments and extracted RNA and protein to perform qPCR and immunoblot, respectively, for BRCA2. DOX inhibited BRCA2 expression in HUVECs at transcript and protein levels. We also measured the expression of pro-apoptotic p53, which appear to be up-regulated by DOX in a dose/time-dependent manner. We also have generated and characterized endothelial cell-specific BRCA2 knockout mice (BRCA2 endo ) using the Cre-Lox P method. DOX treatment to BRCA2 endo mice induced significant weight loss in comparison to wild-type (WT) mice. Echocardiography done on DOX-treated BRCA2 endo and WT mice showed significantly reduced cardiac function in BRCA2 endo mice compared to WT mice. Our qPCR data performed on RNAs extracted from DOX-treated BRCA2 endo and WT mice demonstrated significantly increased expression of heart failure markers in the heart of BRCA2 endo mice compared to WT mice. Conclusion: Our studies’ will provide a novel mechanism for DIC by elucidating the roles of endotheliotoxicity and determining whether BRCA2’s function is a critical factor for restorative DNA damage repair and recovery of endothelial cell function following DOX treatment.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.003 | 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".