Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.
Background. This study investigates the long-term survival and durability of mitral procedures on patients undergoing surgical ventricular restoration.Methods. From 1992 to 2017, 109 patients underwent surgical ventricular restoration. Survival was determined from hospital records and the National Death Index. Preoperative demographics, clinical characteristics and features, operative technique, and follow-up echocardiography findings were analyzed using Cox regression and log-rank to determine variables influencing survival.Results. The mean age was 61.57 ± 12.81 years. There were 101 (93%) true and 8 (7%) pseudo-aneurysms. Concomitant surgeries included mitral valve (MV) repair (n [ 40, 37%), MV replacement (n [ 5, 5%), tricuspid valve repair (n [ 4, 4%), aortic valve replacement (n [ 3, 3%), coronary bypass grafting (n [ 76, 70%; 1.6 ± 1.3 grafts), and ventricular septal defect closure (n [ 5, 5%). Redosternotomies were performed in 12 patients (11%). Median duration of echocardiographic follow up was 2.9 years (interquartile range, 9.0) and was obtained in 59 patients
A 54 year old man was referred to the department of neurosurgery for frontal headache and vomiting. The patient was known in the department because of previous multiple surgery for a locally invasive pituitary prolactinoma (eight years, three years, and one year previously). The neurological examination revealed a frontal mass, which adhered to the dura, suggesting a meningioma. One year later, a left temporal metastasis was removed. Three months later, the patient died, with spinal metastases, of massive lung embolism. Histology revealed a progression of adenohypophyseal prolactinoma on neuroendocrine carcinoma, with an increase in proliferating indexes and modification of hormone production. This study documents a 10 year history of a rare prolactin producing pituitary carcinoma, which metastasised via liquoral flow.
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