Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8+ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME.

Angiogenesis depends on VEGF-mediated signaling. However, the regulatory mechanisms and functions of individual VEGF receptor 2 (VEGFR2) phosphorylation sites remain unclear. Here, we report that synaptic adhesion-like molecule 4 (SALM4) regulates a specific VEGFR2 phosphorylation site. SALM4 silencing in HUVECs and Salm4 knockout (KO) in lung endothelial cells (ECs) of Salm4 −/− mice suppressed phosphorylation of VEGFR2 tyrosine (Y) 1175 (Y1173 in mice) and downstream signaling upon VEGF-A stimulation. However, VEGFR2 phosphorylation at Y951 (Y949 in mice) and Y1214 (Y1212 in mice) remained unchanged. Knockdown and KO of SALM4 inhibited VEGF-A–induced angiogenic functions of ECs. SALM4 depletion reduced endothelial leakage, sprouting, and migratory activities. Furthermore, in an ischemia and reperfusion (I/R) model, brain injury was attenuated in Salm4 −/− mice compared with wild-type (WT) mice. In brain lysates after I/R, VEGFR2 phosphorylation at Y949, Y1173, and Y1212 were induced in WT brains, but only Y1173 phosphorylation of VEGFR2 was reduced in Salm4 −/− brains. Taken together, our results demonstrate that SALM4 specifically regulates VEGFR2 phosphorylation at Y1175 (Y1173 in mice), thereby fine-tuning VEGF signaling in ECs.—Kim, D. Y., Park, J. A., Kim, Y., Noh, M., Park, S., Lie, E., Kim, E., Kim, Y.-M., Kwon, Y.-G. SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175.

ObjectiveWe developed a new chest compression depth (CCD) measuring technology using radar and impulse-radio ultra-wideband (IR-UWB) sensor. This study was performed to determine its accuracy on a soft surface.MethodsFour trials, trial 1: chest compressions on the floor using an accelerometer device; trial 2: chest compressions on the floor using an IR-UWB sensor; trial 3: chest compressions on a foam mattress using an accelerometer device; trial 4: chest compressions on a foam mattress using an IR-UWB sensor, were performed in a random order. In all the trials, a cardiopulmonary resuscitation provider delivered 50 uninterrupted chest compressions to a manikin.ResultsThe CCD measured by the manikin and the device were as follows: 57.42 ± 2.23 and 53.92 ± 2.92 mm, respectively in trial 1 (p < 0.001); 56.29 ± 1.96 and 54.16 ± 3.90 mm, respectively in trial 2 (p < 0.001); 55.61 ± 1.57 and 103.48 ± 10.48 mm, respectively in trial 3 (p < 0.001); 57.14 ± 3.99 and 55.51 ± 3.39 mm, respectively in trial 4 (p = 0.012). The gaps between the CCD measured by the manikin and the devices (accelerometer device vs. IR-UWB sensor) on the floor were not different (3.50 ± 2.08 mm vs. 3.15 ± 2.27 mm, respectively, p = 0.136). However, the gaps were significantly different on the foam mattress (48.53 ± 5.65 mm vs. 4.10 ± 2.47 mm, p < 0.001).ConclusionThe IR-UWB sensor could measure the CCD accurately both on the floor and on the foam mattress.

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