6 research outputs found
Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2
Vascular endothelial growth factor (VEGF)-induced receptor phosphorylation
is the crucial step for initiating downstream signaling pathways that lead to
angiogenesis or related pathophysiological outcomes. Our previous studies have
shown that the neurotransmitter dopamine could inhibit VEGF-induced
phosphorylation of VEGF receptor 2 (VEGFR-2), endothelial cell proliferation,
migration, microvascular permeability, and thus, angiogenesis. In this study,
we address the mechanism by which VEGFR-2 phosphorylation is regulated by
dopamine. Here, we demonstrate that D2 dopamine receptor (D2DR) colocalizes
with VEGFR-2 at the cell surface. Dopamine pretreatment increases the
translocation and colocalization of Src-homology-2-domain-containing protein
tyrosine phosphatase (SHP-2) with D2DR at the cell surface. Dopamine
administration leads to increased VEGF-induced phosphorylation of SHP-2 and
this increased phosphorylation parallels the increased phosphatase activity of
SHP-2. Active SHP-2 then dephosphorylates VEGFR-2 at Y951, Y996 and Y1059, but
not Y1175. We also observe that SHP-2 knockdown impairs the dopamine-regulated
inhibition of VEGF-induced phosphorylation of VEGFR-2 and, subsequently, Src
phosphorylation and migration. Our data establish a novel role for SHP-2
phosphatase in the dopamine-mediated regulation of VEGFR-2
phosphorylation
Substance use disorders: diagnosis and management for hospitalists
Substance use disorder is a significant health concern. Hospitalists manage patient with various forms of substance use disorder on a daily basis. In this review, we have tried to synthesize evidence together to give a brief, yet succinct, review of commonly encounters disorders; alcohol intoxication and withdrawal, opioid intoxication and withdrawal, cocaine intoxication and methamphetamine intoxication. We describe clinical features, diagnosis and management, which would serve as a great resource for hospitalist when managing these complicated patients
Evidence for Cytogenetic and Fluorescence In Situ Hybridization Risk Stratification of Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies
Overall survival (OS) has improved with increasing use of novel agents in multiple myeloma (MM). However, the disease course remains highly variable, and the heterogeneity largely reflects different genetic abnormalities. We studied the impact of the Mayo risk-stratification model of MM on patient outcome in the era of novel therapies, evaluating each individual component of the model—fluorescence in situ hybridization (FISH), conventional cytogenetics (CG), and the plasma cell labeling index—that segregates patients into high- and standard-risk categories. This report consists of 290 patients with newly diagnosed MM, predominantly treated with novel agents, who were risk-stratified at diagnosis and were followed up for OS. Of these patients, 81% had received primarily thalidomide (n=50), lenalidomide (n=199), or bortezomib (n=79) as frontline or salvage therapies. Our retrospective analysis validates the currently proposed Mayo risk-stratification model (median OS, 37 months vs not reached for high- and standard-risk patients, respectively; P=.003). Although the FISH or CG test identifies a high-risk cohort with hazard ratios of 2.1 (P=.006) and 2.5 (P=.006), respectively, the plasma cell labeling index cutoff of 3% fails to independently prognosticate patient risk (hazard ratio, 1.4; P=.41). In those stratified as standard-risk by one of the 2 tests (FISH or CG), the other test appears to be of additional prognostic significance. This study validates the high-risk features defined by FISH and CG in the Mayo risk-stratification model for patients with MM predominantly treated with novel therapies based on immunomodulatory agents