No abstract

ObjectiveTo 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.DesignIntegrated 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.ResultsIn 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).ConclusionGut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.

Hyperhomocysteinemia (HHcy) has been shown to promote vascular inflammation and atherosclerosis, but the underlying mechanisms remain largely unknown. The NLRP3 inflammasome has been identified as the cellular machinery responsible for activation of inflammatory processes. In this study, we hypothesized that the activation of NLRP3 inflammasomes contributes to HHcy-induced inflammation and atherosclerosis. ApoE−/− mice were fed regular chow, high-fat (HF) diet, or HF plus high methionine diet to induce HHcy. To assess the role of NLRP3 inflammasomes in HHcy-aggravated atherosclerosis, NLRP3 shRNA viral suspension was injected via tail vein to knock down the NLRP3 gene. Increased plasma levels of IL-1β and IL-18, aggravated macrophage infiltration into atherosclerotic lesions, and accelerated development of atherosclerosis were detected in HHcy mice as compared with control mice, and were associated with the activation of NLRP3 inflammasomes. Silencing the NLRP3 gene significantly suppressed NLRP3 inflammasome activation, reduced plasma levels of proinflammatory cytokines, attenuated macrophage infiltration and improved HHcy-induced atherosclerosis. We also examined the effect of homocysteine (Hcy) on NLRP3 inflammasome activation in THP-1-differentiated macrophages in the presence or absence of NLRP3 siRNA or the caspase-1 inhibitor Z-WEHD-FMK. We found that Hcy activated NLRP3 inflammasomes and promoted subsequent production of IL-1β and IL-18 in macrophages, which were blocked by NLRP3 gene silencing or Z-WEHD-FMK. As reactive oxygen species (ROS) may have a central role in NLRP3 inflammasome activation, we next investigated whether antioxidant N-acetyl-l-cysteine (NAC) prevented Hcy-induced NLRP3 inflammasome activation in macrophages. We found Hcy-induced NLRP3 inflammasome activation was abolished by NAC. Treatment with NAC in HHcy mice also suppressed NLRP3 inflammasome activation and improved HHcy-induced atherosclerosis. These data suggest that the activation of NLRP3 inflammasomes contributes to HHcy-aggravated inflammation and atherosclerosis in apoE−/− mice. Hcy activates NLRP3 inflammasomes in ROS-dependent pathway in macrophages. These results may have implication for the treatment of HHcy-associated cardiovascular diseases.

No abstract

N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes. Accumulating evidence suggests that dysregulation of m6A modification significantly correlates with tumorigenesis and progression. In this study, we observed an increased expression and positive correlations of all 25 m6A regulators in esophageal cancer (ESCA) data obtained from the TCGA database. Through expression profiling of these regulators, a prognostic score model containing HNRNPA2B1, ALKBH5, and HNRNPG was established, and the high-risk subgroup exhibited strong positive correlations with ESCA progression and outcome. The risk score obtained from this model may represent an independent predictor of ESCA prognosis. Notably, the gene most frequently associated with increased risk was HNRNPA2B1; in ESCA, the increased expression of this gene alone predicted poor prognosis by affecting tumor-promoting signaling pathways through miR-17-92 cluster. An experimental study demonstrated that elevated HNRNPA2B1 expression was positively associated with distant metastasis and lymph node stage, and predicted the poor outcomes of ESCA patients. Knockdown of HNRNPA2B1 significantly decreased the expression of miR-17, miR-18a, miR-20a, miR-93, and miR-106b and inhibited the proliferation of ESCA cells. Therefore, our study indicated that the dynamic changes in 25 m6A regulators were associated with the clinical features and prognosis of patients with ESCA. Importantly, HNRNPA2B1 alone may affect the prognosis of patients with ESCA by regulating the miR-17-92 cluster.

No abstract

Accurate identification of in vivo nonlinear, anisotropic mechanical properties of the aortic wall of individual patients remains to be one of the critical challenges in the field of cardiovascular biomechanics. Since only the physiologically loaded states of the aorta are given from in vivo clinical images, inverse approaches, which take into account of the unloaded configuration, are needed for in vivo material parameter identification. Existing inverse methods are computationally expensive, which take days to weeks to complete for a single patient, inhibiting fast feedback for clinicians. Moreover, the current inverse methods have only been evaluated using synthetic data. In this study, we improved our recently developed multi-resolution direct search (MRDS) approach and the computation time cost was reduced to 1~2 hours. Using the improved MRDS approach, we estimated in vivo aortic tissue elastic properties of two ascending thoracic aortic aneurysm (ATAA) patients from pre-operative gated CT scans. For comparison, corresponding surgically-resected aortic wall tissue samples were obtained and subjected to planar biaxial tests. Relatively close matches were achieved for the in vivo-identified and ex vivo-fitted stress-stretch responses. It is hoped that further development of this inverse approach can enable an accurate identification of the in vivo material parameters from in vivo image data.

Recent studies have revealed the oncogenic role of notch reporter 3 (NOTCH3) in ovarian cancer (OC). However, the possible regulators and mechanisms underlying notch receptor 3 (NOTCH3)-mediated behaviors in OC remain to be completely investigated. In the present study, we aimed to identify regulators of NOTCH3 and their interactions underlying the pathogenesis of OC. Bioinformatics analysis and luciferase reporter assay were used to identify potential regulatory miRNAs and lncRNAs of NOTCH3 in OC. Several in vivo and in vitro assays were performed to evaluate their effects on the proliferative ability mediated by NOTCH3. We identified microRNA-1299 (miR-1299) as a novel negative regulator of NOTCH3. miR-1299 was downregulated in OC and was found to be considerably correlated with tumor differentiation. Upregulation of miR-1299 inhibited cell proliferation, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation, as well as induced cell cycle arrest in the G0G1 phase in OC cells. Overexpression of miR-1299 in xenograft mouse models suppressed tumor growth in vivo. The lncRNA taurine upregulated gene 1 (TUG1), acting as a sponge of miR-1299, was found to upregulate NOTCH3 expression and promote cell proliferation in OC through the competing endogenous RNA mechanism. In addition, TUG1 was found to be a potential downstream target of NOTCH3, forming a miR-1299/NOTCH3/TUG1 feedback loop in the development of OC. Collectively, our findings improve the understanding of NOTCH3-mediated regulation in OC pathogenesis and facilitate the development of miRNA-and lncRNA-directed diagnostics and therapeutics against this disease.