Long noncoding RNAs (lncRNAs) play important roles in human diseases including vascular disease. Given the large number of lncRNAs, however, whether the majority of them are associated with vascular disease remains unknown. For this purpose, here we present a genomic location based bioinformatics method to predict the lncRNAs associated with vascular disease. We applied the presented method to globally screen the human lncRNAs potentially involved in vascular disease. As a result, we predicted 3043 putative vascular disease associated lncRNAs. To test the accuracy of the method, we selected 10 lncRNAs predicted to be implicated in proliferation and migration of vascular smooth muscle cells (VSMCs) for further experimental validation. The results confirmed that eight of the 10 lncRNAs (80%) are validated. This result suggests that the presented method has a reliable prediction performance. Finally, the presented bioinformatics method and the predicted vascular disease associated lncRNAs together may provide helps for not only better understanding of the roles of lncRNAs in vascular disease but also the identification of novel molecules for the diagnosis and therapy of vascular disease.

Historically, owing to not changing amino acid composition of protein sequences, synonymous mutations are commonly assumed to be neutral during evolution and therefore have no effect on the phenotype and disease. Here, based on observations from large-scale analysis of genomic data, we predicted the putative synonymous SNPs that could result in functional consequences and disease risk through changing the microRNA-mediated gene regulation. We found that nearly half of the synonymous SNPs could affect protein expression by changing microRNA regulation in human genome and these SNPs significantly prefer to be associated with human diseases and traits. The synonymous SNPs changing microRNA-mediated gene regulation tend to be more under recent positive selection, prefer to affect gene expression, and implicate in human disease. We conclude that the miRNA-mediated regulation changes could be a potential mechanism for the contributions of synonymous SNPs to protein functions and disease risks.

IMMH-010 is an ester prodrug of YPD-29B, a potent programmed cell death ligand 1 (PD-L1) inhibitor. The metabolism of IMMH-010 was investigated and compared in various species. Four metabolites of IMMH-010 were identified, and the major metabolite was the parent compound, YPD-29B, which was mainly catalyzed by carboxylesterase 1 (CES1). We observed IMMH-010 metabolism in the plasma of various species. IMMH-010 was rapidly metabolized to YPD-29B in rat and mouse plasma, whereas it remained stable in human and monkey plasma. In the liver S9 fractions of human, monkey, dog, and rat, IMMH-010 was quickly transformed to YPD-29B with no obvious differences among species. In addition, the transformation ratio of IMMH-010 to YPD-29B was low in rat and human intestines, which indicated that the intestine was not an important site for IMMH-010 hydrolysis. Moreover, we demonstrated the remarkable antitumor efficacy of IMMH-010 in B16F10 melanoma and MC38 colon carcinoma xenograft mouse models. We also compared the pharmacokinetic profiles of IMMH-010 in rodents and primates. After oral administration of IMMH-010, the general exposure of active metabolite YPD-29B was slightly lower in primates than in rodents, suggesting that data should be extrapolated cautiously from rodents to humans.

Deciphering molecular mechanisms underlying the division of hematopoietic stem cells (HSCs) and malignant precursors would improve our understanding of the basis of stem cell-fate decisions and oncogenic transformation. Using a novel reporter of hematopoietic precursor, Evi1-GFP, we tracked the division of hematopoietic precursors in culture in real time. First, we confirmed that Evi1-GFP is a faithful reporter of HSC activity and identified three dividing patterns of HSCs: symmetric renewal, symmetric differentiation, and asymmetric division. Moreover, we found that the cytokine and growth factor combination (STIF) promotes symmetric renewal, whereas OP9 stromal cells balance symmetric renewal and differentiation of HSCs ex vivo. Interestingly, we found that Tet2 knockout HSCs underwent more symmetric differentiation in culture compared with the wild-type control. Intriguingly, OP9 stromal cells reverse the phenotype of Tet2 knockout HSCs ex vivo. Furthermore, we demonstrated that Tet2 –/– ;Flt3ITD acute myeloid leukemia (AML) precursors primarily underwent symmetric renewal divisions in culture. Mechanistically, we demonstrated that inhibiting DNA methylation can reverse the aberrant division phenotypes of Tet2 –/– and Tet2 –/– ;FLT3ITD precursors, suggesting that abnormal DNA methylation plays an important role in controlling (pre-)leukemic precursor fate decision ex vivo. Our study exploited a new system to explore the molecular mechanisms of the regulation of benign and malignant hematopoietic precursor division ex vivo. The knowledge learned from these studies will provide new insights into the molecular mechanisms of HSC fate decision and leukemogenesis.

Programmed cell death protein 1 (PD‐1) /programmed cell death ligand 1 (PD‐L1) blockade is an important therapeutic strategy for melanoma, despite its low clinical response. It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients. We analyzed clinical dataset GSE96619, which contains clinical information from five melanoma patients before and after anti‐PD‐1 therapy (five pairs of data). We identified 704 DEGs using these five pairs of data, and then the number of DEGs was narrowed down to 286 in patients who responded to treatment. Next, we performed KEGG pathway enrichment and constructed a DEG‐associated protein‐protein interaction network. Smooth muscle actin 2 (ACTA2) and tyrosine kinase growth factor receptor (KDR) were identified as the hub genes, which were significantly downregulated in the tumor tissue of the two patients who responded to treatment. To confirm our analysis, we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xenograft model. This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD‐1/PD‐L1 blockade therapy.