Decreased P2 Waveform Reflects Impaired Brain Executive Function Induced by 12 h of Low Homeostatic Sleep Pressure: Evidence From an Event-Related Potential Study

Homeostatic sleep pressure can cause cognitive impairment, in which executive function is the most affected. Previous studies have mainly focused on high homeostatic sleep pressure (long-term sleep deprivation); thus, there is still little related neuro-psycho-physiological evidence based on low homeostatic sleep pressure (12 h of continuous wakefulness) that affects executive function. This study aimed to investigate the impact of lower homeostatic sleep pressure on executive function. Our study included 14 healthy young male participants tested using the Go/NoGo task in normal resting wakefulness (10:00 am) and after low homeostatic sleep pressure (10:00 pm). Behavioral data (response time and accuracy) were collected, and electroencephalogram (EEG) data were recorded simultaneously, using repeated measures analysis of variance for data analysis. Compared with resting wakefulness, the participants&#39; response time to the Go stimulus was shortened after low homeostatic sleep pressure, and the correct response rate was reduced. Furthermore, the peak amplitude of Go-P2 decreased significantly, and the peak latency did not change significantly. For NoGo stimulation, the peak amplitude of NoGo-P2 decreased significantly (p &lt; 0.05), and the peak latency was significantly extended (p &lt; 0.05). Thus, the P2 wave is likely related to the attention and visual processing and reflects the early judgment of the perceptual process. Therefore, the peak amplitude of Go-P2 and NoGo-P2 decreased, whereas the peak latency of NoGo-P2 increased, indicating that executive function is impaired after low homeostatic sleep pressure. This study has shown that the P2 wave is a sensitive indicator that reflects the effects of low homeostatic sleep pressure on executive function, and that it is also an important window to observe the effect of homeostatic sleep pressure and circadian rhythm on cognitive function.</p

Discovery of a New Series of Naphthamides as Potent VEGFR‑2 Kinase Inhibitors

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a new series of naphthamides as potent inhibitors of VEGFR-2. Among these compounds, <b>14c</b> exhibited high VEGFR-2 inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with IC₅₀ values of 1.5 and 0.9 nM, respectively. Kinase selectivity profiling revealed that <b>14c</b> was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-β, and RET. Furthermore, <b>14c</b> effectively blocked tube formation of HUVEC at nanomolar level. Overall, <b>14c</b> might be a promising candidate for the treatment of cancer

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood–brain barrier and exhibits potent activity against glioblastoma

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380)