RESUMO
Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores Dopaminérgicos/biossíntese , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Feminino , Células HEK293 , Xenoenxertos , Humanos , Células MCF-7 , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Receptores Dopaminérgicos/genética , Transdução de SinaisRESUMO
An assessment of the three part differential provided by the Coulter STKR blood counter showed good correlation when compared with an 800 cell manual differential. Satisfactory flagging of eosinophilia, basophilia, and the presence of immature cells was found. The use of variables derived from the STKR in conjunction with interpretive reporting and user-defined flagging enabled this department to reduce considerably the numbers of films requiring manual differential counts.
Assuntos
Contagem de Células Sanguíneas/instrumentação , Células Sanguíneas/anormalidades , Humanos , Contagem de LeucócitosRESUMO
An evaluation of the Coulter VCS (volume, conductivity, light scatter) automated differential counter demonstrated satisfactory correlations with manual 800-cell differential counts for neutrophils, lymphocytes, monocytes and eosinophils. For the detection of abnormal cells, 12.2% of samples gave false-negative results on the VCS, and 13.4% gave false-positive results. However, only 0.8% of the false-negatives would be expected to be picked up by a standard 100-cell manual differential count. Carry-over accorded to manufacturer's specifications and throughput was 60 samples/h. Reference normal ranges have been established and the instrument's precision and performance with leucopenic and neonatal blood samples assessed.
