A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity

Introduction: There is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis. Methods: We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets. Results: In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like (BD-L). Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-/ER- primary tumors as compared with HER2+/ER + and HER2-/ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. Conclusions: A BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway

Investigating the Corrosion Behaviour and Electrochemical Properties of Intermetallic Matrix Composites

In the realm of advanced materials, intermetallic matrix composites (IMC) have garnered significant attention due to their potential for high-temperature applications and superior mechanical properties. This research delves into the corrosion behaviour and electrochemical characteristics of selected IMCs to elucidate their performance in aggressive environments. Employing potentiodynamic polarization tests and electrochemical impedance spectroscopy (EIS) , the study provides a comprehensive analysis of the corrosion kinetics and mechanisms inherent to these materials. The results indicate that the microstructural features, including the distribution of secondary phases and the nature of the matrix, play a pivotal role in determining the corrosion resistance. Furthermore, the presence of certain alloying elements was found to impart passivation capabilities, thereby enhancing the overall corrosion resistance. The EIS data revealed distinct time constants, suggesting multiple electrochemical processes at the interface. This study not only advances our understanding of the corrosion behaviour of IMCs but also underscores the importance of microstructural engineering in tailoring their electrochemical properties. The insights garnered hold profound implications for the design and application of IMCs in industries where corrosion resistance is paramount