Objective To profile gut microbiome-associated metabolites in serum and investigate whether these metabolites could distinguish individuals with colorectal cancer (CRC) or adenoma from normal healthy individuals. Design Integrated analysis of untargeted serum metabolomics by liquid chromatography-mass spectrometry and metagenome sequencing of paired faecal samples was applied to identify gut microbiome-associated metabolites with significantly altered abundance in patients with CRC and adenoma. The ability of these metabolites to discriminate between CRC and colorectal adenoma was tested by targeted metabolomic analysis. A model based on gut microbiome-associated metabolites was established and evaluated in an independent validation cohort. Results In total, 885 serum metabolites were significantly altered in both CRC and adenoma, including eight gut microbiome-associated serum metabolites (GMSM panel) that were reproducibly detected by both targeted and untargeted metabolomics analysis and accurately discriminated CRC and adenoma from normal samples. A GMSM panel-based model to predict CRC and colorectal adenoma yielded an area under the curve (AUC) of 0.98 (95% CI 0.94 to 1.00) in the modelling cohort and an AUC of 0.92 (83.5% sensitivity, 84.9% specificity) in the validation cohort. The GMSM model was significantly superior to the clinical marker carcinoembryonic antigen among samples within the validation cohort (AUC 0.92 vs 0.72) and also showed promising diagnostic accuracy for adenomas (AUC=0.84) and early-stage CRC (AUC=0.93). Conclusion Gut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.

Modification of the novel N⁶-methyladenine (m6A) DNA implicates this epigenetic mark in human malignant disease, but its role in atherosclerosis (AS) is largely unknown. Here, we found that the leukocyte level of m6A but not 5mC DNA modification was decreased with increasing of carotid plaque size and thickness in 207 AS patients as compared with 142 sex- and age-matched controls. Serum low-density lipoprotein (LDL) and leukocyte m6A levels were associated with the progression of carotid plaque size and thickness. Both LDL level and plaque thickness were also independently and negatively related to m6A level. Reduced m6A level was further confirmed in leukocytes and endothelium in western diet-induced AS mice and in oxidized-LDL (ox-LDL)-treated human endothelium and monocyte cells. Decreased m6A level was closely related to the upregulation of AlkB homolog 1 (ALKBH1), the demethylase of m6A. Silencing of ALKBH1 or hypoxia-inducible factor 1α (HIF1α) could rescue the ox-LDL–increased level of MIAT, a hypoxia-response gene. Mechanically, ox-LDL induced HIF1α for transfer into the nucleus. Nuclear HIF1α bound to the ALKBH1-demethylated MIAT promoter and transcriptionally upregulated its expression. Therefore, elevated ALKBH1 level in endothelium and leukocytes reduced m6A level, which is a novel and sensitive biomarker for AS progression.

Purpose: With the advancement of minimally invasive surgery and catheters for hepatocellular carcinoma (HCC), it is becoming more and more inconvenient to get tissues or the tissues gained are insufficient for testing. Screening of blood-derived markers is of great significance for prognosis assessment. Patients and Methods: Data-independent acquisition (DIA) and parallel reaction monitoring (PRM) were implemented to identify valuable prognostic HCC biomarkers in 48 patients with different prognosis. The potential candidate biomarkers were examined in 205 HCC patients using enzyme-linked immunosorbent assay (ELISA) and then validated in The Cancer Genome Atlas (TCGA) HCC cohort. Results: DIA screened 86 significantly differentially regulated proteins between patients with poor prognosis and those with good prognosis. Eight proteins from the DIA proteomic analyses were quantified by PRM, and six of them (KLKB1, IGFBP3, SHBG, SAA1, C7, and CD44) presented consistent expression trends between DIA and PRM. Then, the results of ELISA indicated that KLKB1 was abnormally expressed in HCC patients, and the serum level of KLKB1 also exhibited significant changes before and after treatment (P = 0.016). Patients with higher KLKB1 serum levels had significantly superior overall survival (P = 0.035) and progression-free survival (P = 0.027) than those with lower KLKB1 expression. In the TCGA-HCC cohort, Cox regression analysis suggested that KLKB1 was an independent prognostic factor for overall survival (P = 0.032) of HCC patients. Conclusion: Aberrant expression of KLKB1 was strongly associated with the prognosis of HCC patients. KLKB1 may be used to evaluate the prognosis and guide the treatment for HCC.

Cancer patients with Tissue Factor (TF)-bearing MPs have been presented association with increased risk of venous thromboembolism (VTE), but results of these studies have not been consistent. We aimed to conduct a meta-analysis to assess the relationship between TF-bearing MPs and risk of VTE in patients with cancer. PubMed, Web of Science and EMBASE Databases were systematically retrieved up to1^th June 2017. Two case-control studies and four cohort studies met the entry requirements in this analysis. The summary odd ratio (OR) were estimated by a random effect model. The overall OR was 1.76 (95% CI: 1.21–2.56, I² = 62.0%). The OR of case-control studies was 3.41 (95% CI: 1.45–8.02, I² = 0.0%) and that of cohort studies was1.53 (95% CI: 1.05–2.24, I² = 66.1%). The association between TF-bearing MPs and the risk of VTE in cancer patients was found in this meta-analysis. Publication bias testing and sensitivity subgroup analysis suggested that results of this meta-analysis were robustness. In conclusion, TF-bearing MPs were associated with increased risk of VTE in patients with cancer. Whereas, more well-designed studies and more comprehensive adjustments for confounders in further studies are warranted to affirm the association.

Viral mimicry refers to an active antiviral response triggered by the activation of endogenous retroviruses (ERVs), usually manifested by the formation of double-stranded RNA (dsRNA) and activation of the cellular interferon response, which activates the immune system and produces anti-tumor effects. Epigenetic studies have shown that epigenetic modifications (e.g. DNA methylation, histone modifications, etc.) play a crucial role in tumorigenesis, progression, and treatment resistance. Particularly, alterations in DNA methylation may be closely associated with the suppression of ERVs expression, and treatment by demethylation may restore ERVs activity and thus strengthen the tumor immune response. Therefore, we propose that viral mimicry can induce immune responses in the tumor microenvironment by activating the expression of ERVs, and that epigenetic alterations may play a key regulatory role in this process. In this paper, we review the intersection of viral mimicry, epigenetics and tumor immunotherapy, and explore the possible interactions and synergistic effects among the three, aiming to provide a new theoretical basis and potential strategies for cancer immunotherapy.