BackgroundRecent studies have shown that androgen displays an inhibitory effect on breast cancer cell lines that express androgen receptor (AR) but not estrogen receptor (ER) and progesterone receptor (PR). We have previously reported that approximately 1/3 of ER negative high grade invasive ductal carcinomas express AR. Thus, AR can serve as a potential therapeutic target for this group of patients.AimHere we investigated AR expression patterns in 980 consecutive breast carcinomas.ResultsWe found that (1) AR was expressed more frequently (77%) than ER (61%) and PR (60%) in breast carcinomas; (2) AR expression was associated with ER and PR expression (P < 0.0001), small tumor size (P = 0.0324) and lower Ki-67 expression (P = 0.0013); (3) AR expression was found in 65% of ER negative tumors; (4) AR expression was associated with PR and Ki-67 in ER negative tumors, but not in ER positive tumors; (5) AR expression was higher in ER positive subtypes (Luminal A, Luminal B and Luminal HER2 subtypes, 80%–86%) and lower in ER negative subtypes [HER2, triple negative (TN), and TN EFGR positive subtypes; 52%–66%], with over 50% of TN tumors expressing AR.ConclusionMore breast carcinomas express AR than ER and PR, including significant numbers of ER negative and TN tumors, for which AR could serve as a potential therapeutic target.
Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. Heme oxygenase-1 (HO-1), the key enzyme in heme degradation, is highly expressed after ICH, but its role is still unclear. In this study, we used an HO-1 inducer and inhibitor to test the role of HO-1 in different stages of ICH in vivo and in vitro. In the early stage of ICH, high HO-1 expression worsened the outcomes of mice subjected to the collagenase-induced ICH model. HO-1 increased brain edema, white matter damage, neuronal death, and neurobehavioral deficits. Furthermore, elevated HO-1 increased inflammation, oxidative stress, matrix metalloproteinase-9/2 activity, and iron deposition. In the later stage of ICH, long-term induction of HO-1 increased hematoma absorption, angiogenesis, and recovery of neurologic function. We conclude that HO-1 activation mediates early brain damage after ICH but promotes neurologic function recovery in the later stage of ICH.
Developing new strategies to treat cerebral ischemic-reperfusion injury will require a better understanding of the mechanisms that underlie vascular permeability. In this study we examined the temporal expression of Src and angiogenic factors in rat brain after focal cerebral ischemia and reperfusion and analyzed the relationships among those factors. We also investigated the effect of Src inhibitor PP1 in ischemic reperfusion. Rats were subjected to middle cerebral artery occlusion for 90 min followed by reperfusion with or without PP1 treatment. Src mRNA increased at 3 h after reperfusion and then gradually declined. Phosphorylation of Src at Y418 displayed a biphasic increase. Phosphorylation increased as early as 3 h and peaked at 6 h; after decreasing, it peaked again at 3 to 7 days. Increases in Src mRNA and phosphorylation correlated positively with levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), and negatively with levels of angiopoietin-1 (Ang-1) and zonula occludens-1 (ZO-1). Changes in the expression of these factors correlated with the progress of vascular permeability, especially early after reperfusion. Hence, dynamic temporal changes in Src Y418 phosphorylation may modulate vascular permeability after cerebral ischemia and reperfusion. PP1 effectively decreased Src Y418 phosphorylation and the expression of VEGF and Ang-2 and increased the expression of Ang-1 and ZO-1. It also reduced cerebral infarct size and neurologic dysfunction. Therefore, Src may represent a new therapeutic target for reducing tissue damage caused by increased vascular permeability.
This histopathologic case-control study was designed to characterize the dynamic changes in protein expression of nuclear factor-kappa B (NF-κB)/p65 subunit, macrophage inflammatory protein-2 (MIP-2), and matrix metalloproteinase-9 (MMP-9) in postmortem brains of patients with and without intracerebral hemorrhage (ICH). Thirty-six human brains from patients with ICH and six control brains were included in this study. We found that expression levels of NF-κB/p65, MIP-2, and MMP-9 were each upregulated on the injured side of the hippocampus at times ranging from 2 hr to 5 days post-ICH. Interestingly, the expression of all three markers was also upregulated on the uninjured side of the hippocampus and in the cerebellum, although to a lesser extent. These data suggest that inflammation occurs early and persists for several days after ICH in humans and could be involved in the progression of ICH-induced secondary brain damage.
Intracerebral hemorrhage (ICH) can cause secondary brain damage through inflammation-related pathways. Thrombin and one of its receptors, protease activated receptor-1 (PAR-1); matrix metalloproteinase (MMP)-9; and aquaporin (AQP)-4 are stroke-related inflammatory mediators that have been implicated in ICH pathology. To further characterize the inflammatory response after ICH, we studied the temporal profile of the expression of these inflammatory mediators and assessed their potential correlation with brain edema formation after brain hemorrhage in rats. ICH was modeled by infusing autologous blood into the striatum. Then mRNA and protein expression was assessed over the course of 5 days. We found that the mRNA and/or protein expression of thrombin, PAR-1, AQP-4, and MMP-9 was upregulated between 2 h and 5 days after ICH. Each reached a maximal level at day 2, except for AQP-4 protein, which peaked at day 5. Brain water content after ICH presented a similar trend; it was increased at 2 h, peaked at day 2, and then decreased but remained elevated at day 5. Our data provide novel evidence that upregulation of these selected inflammatory mediators occurs very early and persists for several days after ICH, and that temporal patterns of expression of thrombin and AQP-4 are associated with brain edema formation. These findings have important implications for efforts to reduce secondary brain damage after ICH.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.