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.

Inflammatory bowel disease is an autoimmune disease that causes chronic inflammation of the gastrointestinal tract. Endothelial dysfunction, defined by a reduced endothelial barrier and an increase in the expression of adhesion molecules, is part of the pathology of inflammatory bowel disease. In this study, we assessed the therapeutic effect of CU06-1004, an endothelial dysfunction blocker that reduces vascular hyperpermeability and inflammation in a mouse model of colitis. Acute colitis was induced in mice using 3% (w/v) dextran sodium sulfate added to their drinking water for 7 days. Twenty-four hours after the addition of dextran sodium sulfate, either mesalazine or CU06-1004 was administered orally each day. Administration of CU06-1004 significantly reduced the clinical manifestations (weight loss, diarrhea, and bloody stool) and histological changes (epithelium loss, inflammatory cell infiltration, and crypt destruction) induced by dextran sodium sulfate. Proinflammatory cytokines were also reduced, indicating that inflammation was ameliorated. From a vascular perspective, CU06-1004 reduced interrupted and tortuous vessels, enhanced junction protein expression, and reduced inflammatory adhesion molecules, indicating a broad improvement of endothelial dysfunction. Endothelial protection induced epithelial barrier restoration and decreased epithelial inflammation. Blocking endothelial dysfunction with CU06-1004 significantly ameliorated the progression of inflammatory bowel disease. Therefore, CU06-1004 may represent a potential therapeutic agent for the treatment of inflammatory bowel disease as well as other inflammatory diseases.

BackgroundWe examined the relationship between vitamin D status and health-related quality of life, and explored other related factors in the general Korean population.MethodsWe used data from the 2007–2012 Korea National Health and Nutrition Examination Survey on 14,104 adults, aged 20–49 years, who had consented to serum vitamin D measurement and answered health-related quality of life questions. EuroQol-5 was used for measurement. Serum vitamin D levels were measured at intervals of 0–9.99, 10–19.99, 20–29.99, and ≥30 ng/mL.ResultsParticipants with higher serum vitamin D (serum 25-hydroxyvitamin D) levels were significantly less likely to report problems with depression and anxiety. After adjustment for age, gender, income level, education level, marital status, alcohol consumption, smoking status, and the existence of depressive disorders, the odds ratio for reporting a problem with depression and anxiety was 0.60 (95% confidence interval [CI], 0.39–0.91). The odds ratio for the prevalence of any problem was 0.69 (95% CI, 0.53–0.89) before adjustment, but was not statistically significant after adjustment. No significant associations were observed for problems with mobility, self-care, usual activity, or pain and discomfort.ConclusionThis is the first study to examine the associations between vitamin D and health-related quality of life for the general Korean population. Vitamin D status was not significantly associated with the dimensions of EuroQol-5 except for depression and anxiety problems.