Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha

All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure‐specific “dissolvasome,” also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the heteromeric RTR complex consists of RMI1, RMI2, the Bloom's syndrome gene product (BLM), and topoisomerase 3A (TOP3A) proteins. Here, we describe the identification and characterization of two deleterious mutations in the zebrafish top3a gene that reveal an unexpected tissue‐specific requirement of top3a function in developing thymocytes. Deficiency in top3a activates a p53‐dependent check‐point but does not affect VDJ recombination. Our results suggest that TOP3A could be a candidate gene involved in human primary immunodeficiency syndromes.     

Pyrosequencing analysis of BRCA1 methylation level in breast cancer cells

BRCA1 and BRCA2 genes are crucial for double-strand break repair by homologous recombination, and mutations in these genes are responsible for most familial breast carcinomas. Cells with inactivating mutations of the BRCA1 or BRCA2 tumor suppressor genes are sensitive to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Already in 2010, it has been predicted, that BRCA1 hypermethylation might be sensitive to PARP1 inhibitor. However, till today, a statistically significant proof has been missing, and the effectiveness of PARP1 inhibitors for breast cancer caused by BRCA1 promoter hypermethylation remained elusive. Pyrosequencing has been proposed as an optimal method to investigate the methylation status of the BRCA1 genes. Here, we show for the first time that BRCA1 CpG island hypermethylation is sensitive to PARP1 inhibitors. In clinical settings, this might improve treatment response and provide a more personalized therapy for breast cancer patients. Furthermore, the determination of methylation status of BRCA1 and other genes of the BRCA/homologous recombination (HR) pathway may be an important predictive classifier of response to PARP inhibitor therapy.     

Relevance of cellular and serum carbonic anhydrase IX in primary breast cancer

Background

Carbonic anhydrase IX (CAIX) is involved in pH homeostasis, growth and survival of tumor cells. Besides the membranous form of CAIX, a soluble form is detectable in serum (s-CAIX). Overexpression of CAIX in tumors offers the opportunity for therapeutic strategies such as CAIX targeting antibodies. The aim of this study was to examine the relationships of CAIX mRNA expression and s-CAIX levels with clinicopathological parameters and survival of patients with primary breast cancer.

Methods

Tumor tissue of 169 primary breast cancer patients was analyzed for RNA expression by microarray analysis (Affymetrix HG-U133A). Concentration of s-CAIX was determined by ELISA in blood samples of 140 patients.

Results

In tumor tissue, CAIX mRNA signal intensities (MAS5 values) ranged from 34 to 2,513. Higher CAIX expression was associated with younger age (</≥50 years p = 0.040), negative hormone receptors (estrogen receptor p = 0.004; progesterone receptor p = 0.022) and positive nodal status (p = 0.001) as well as with shorter disease-free survival (p = 0.031). Concentrations of s-CAIX ranged from 56 to 1,500 pg/ml. There was no correlation between s-CAIX and CAIX mRNA levels as well as clinicopathological characteristics or outcome.

Conclusion

In contrast to reported immunohistochemical studies, we performed RNA-based tissue analyses of CAIX expression and, for the first time, analyzed CAIX serum levels in primary breast cancer. The correlations between CAIX RNA expression and prognostic factors and patient outcome support a biologic role of CAIX in early breast cancer. A role of s-CAIX in primary breast cancer is not supported by our findings.     

Clinical nurse specialists shaping policies and procedures via an evidence-based clinical practice council

In the practice of nursing, organizations with progressive evidence-based practice programs implement structures and processes whereby nurses are engaged in the review of existing research and in the development of clinical practice documents to better align nursing practices with the best available scientific knowledge. At our academic hospital system, clinical nurse specialists (CNSs) took the lead to help transform a traditional nursing policy and procedure committee into a hospital-wide, staff-represented Clinical Practice Council (CPC) that ensures evidence-based nursing practices are reflected in the organization's nursing practice documents for the provision of patient care. Clinical nurse specialists function as mentors and cochairs who are dedicated to ensuring that nursing practice is supported by the latest evidence and committed to guiding staff nurses to continually move their practice forward. The success of the CPC is due to the leadership and commitment of the CNSs. This article describes the structure, process, and outcomes of an effective CPC where CNSs successfully engage frontline clinicians in promoting nursing care that is evidence based. Clinical nurse specialist leadership is increasingly made visible as CNSs effectively involve staff nurses in practice reforms to improve patient outcomes.     

Prognostic value of intercellular adhesion molecule (ICAM)-1 expression in breast cancer

Purpose  

The intercellular adhesion molecule (ICAM)-1 is expressed on many cell types including endothelial cells and different cancer cell entities. Experimental data strongly indicate that ICAM-1 can activate intracellular signalling pathways in cancer cells leading to enhanced cell motility, invasion and metastasis. Yet, little is known about the role of ICAM-1 expression during malignant progression in breast cancer patients.