Pharmacological inhibition of PDGF-C/neuropilin-1 interaction: A novel strategy to reduce melanoma metastatic potential.

Activation of neuropilin-1 (NRP-1) by platelet derived growth factor (PDGF)-C sustains melanoma invasiveness. Therefore, in the search of novel agents capable of reducing melanoma spreading, PDGF-C/NRP-1 interaction was investigated as a potential druggable target. Since the PDGF-C region involved in NRP-1 binding is not yet known, based on the sequence and structural homology between PDGF-C and vascular endothelial growth factor-A (VEGF-A), we hypothesized that the NRP-1 b1 domain region involved in the interaction with VEGF-A might also be required for PDGF-C binding. Hence, this region was selected from the protein crystal structure and used as target in the molecular docking procedure. In the following virtual screening, compounds from a DrugBank database were used as query ligands to identify agents potentially capable of disrupting NRP-1/PDGF-C interaction. Among the top 45 candidates with the highest affinity, five drugs were selected based on the safety profile, lack of hormonal effects, and current availability in the market: the antipsychotic pimozide, antidiabetic gliclazide, antiallergic cromolyn sodium, anticancer tyrosine kinase inhibitor entrectinib, and antihistamine azelastine. Analysis of drug influence on PDGF-C in vitro binding to NRP-1 and PDGF-C induced migration of human melanoma cells expressing NRP-1, indicated gliclazide and entrectinib as the most specific agents that were active at clinically achievable and non-toxic concentrations. Both drugs also reverted PDGF-C ability to stimulate extracellular matrix invasion by melanoma cells resistant to BRAF inhibitors. The inhibitory effect on tumor cell motility involved a decrease of p130Cas phosphorylation, a signal transduction pathway activated by PDGF-C-mediated stimulation of NRP-1.

Cultural adaptations of psychological interventions for prevalent sleep disorders and sleep disturbances: A systematic review of randomized controlled trials in the United States.

Psychological interventions for sleep-wake disorders have medium-to-large effect sizes, however whether behavioral randomized controlled trials (RCTs) targeted underserved populations or addressed contextual and cultural factors is unknown. We conducted a systematic review to: (a) examine sociodemographic characteristics of behavioral RCTs for prevalent sleep-wake disorders and sleep disturbances that targeted undeserved adults, (b) identify types of cultural adaptations (surface-level, deep-level), and (c) describe intervention effectiveness on primary sleep outcomes. Overall, 6.97% of RCTs (56 studies) targeted underserved groups (veterans, women, racial/ethnic minorities, low socioeconomic status, disability status); 64.29% made surface-level and/or deep-level cultural adaptations. There was a lack of racial/ethnic, socioeconomic, sexual orientation, and linguistic diversity. Most cultural adaptations were made to behavioral therapies, and cognitive behavioral therapy for insomnia (CBT-I). Surface-level cultural adaptations to the delivery modality and setting were most common. Deep-level cultural adaptations of the content and core intervention components were also typical. Intervention effectiveness varied by type of adapted intervention and participant population. RCTs of adapted CBT-I interventions among participants with a definite sleep disorder or sleep disturbance showed consistent significant reductions in adverse sleep outcomes versus control. These findings have important implications for the use of cultural adaptations to address behavioral sleep medicine disparities.