31 research outputs found
DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer
Background
Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood.
Methods
Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group).
Results
Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression.
Conclusions
BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain
Impact of Imiglucerase Supply Shortage on Clinical and Laboratory Parameters in Norrbottnian Patients with Gaucher Disease Type 3
Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients
Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain
Investigation of tool life in reducing hot rolled tube ends
W artykule przedstawiono wyniki badań eksploatacyjnych narzędzi do obciskania końcówek rur. Badano narzędzia ze stali narzędziowych i węglików spiekanych. Stwierdzono wyraźny wzrost trwałości po zastosowaniu narzędzi z węglików. Dominującym mechanizmem zużycia narzędzi jest ścieranie. Badania wykazały, że korzystniejsze jest zastosowanie węglików twardszych gatunku G40 niż węglików bardziej elastycznych gatunku G50.The paper presents the results service investigation of tube end reducing tools. The tools under investigation had been made of tool steels and sintered carbides. It has been found that the tool life significantly increases when carbide tools are applied. The prevailing mechanism of tool wear is abrasion. The investigation has shown that the application of harder carbides of grade G40 is more advantageous than the more elastic carbides of grade G50