Viruses evolve multiple ways to interfere with NF-κB signaling, a key regulator of innate and adaptive immunity. Enterovirus 71 (EV71) is one of primary pathogens that cause hand-foot-mouth disease. Here, we identify RelA(p65) as a novel binding partner for EV71 2C protein from yeast two-hybrid screen. By interaction with IPT domain of p65, 2C reduces the formation of heterodimer p65/p50, the predominant form of NF-κB. We also show that picornavirus 2C family proteins inhibit NF-κB activation and associate with p65 and IKKβ. Our findings provide a novel mechanism how EV71 antagonizes innate immunity.

Background: Left ventricular noncompaction cardiomyopathy (LVNC) is a hereditary heart disease characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. The guidelines for management of LVNC patients aim to improve quality of life by preventing cardiac heart failure. However, the mechanism underlying LVNC-associated heart failure remains poorly understood. Methods: Using protein mass spectrometry analysis, we established that Sorbin And SH3 Domain Containing 2 (SORBS2) is up-regulated in LVNC hearts without changes to structure proteins. We conducted in vivo experiments wherein the heart tissues of wild-type mice were injected with an AAV9 vector to overexpress SORBS2, followed by analysis using echocardiography, T-tubule analysis and Ca 2+ imaging to identify functional and morphological changes. In addition, we analyzed the function and structure of SORBS2 overexpressing human embryonic stem cell (hESC) derived cardiomyocytes (hESC-CM) via immunoblotting, immunohistochemistry, immunofluorescence, and confocal Ca 2+ imaging. Findings: LVNC myocardial tissues feature strongly elevated expression of SORBS2, microtubule densification and redistribution of Junctophilin 2 (JP2). SORBS2 interacts with b-tubulin, promoting its polymerization in 293T cells and hESC-derived CMs. In vivo, cardiac dysfunction, b-tubulin densification, JP2 translocation, Ttubule disorganization and Ca 2+ handling dysfunction were observed in mice overexpressing SORBS2.Interpretation: We identified a novel mechanism through which SORBS2 interacts with b-tubulin and promotes microtubule densification, eventually effecting JP2 distribution and T-tubule, potentially contributing to heart failure in LVNC disease.

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Background: Biliary tract cancers (BTCs) are rare and highly heterogenous malignant neoplasms. Because obtaining BTC tissues is challenging, the purpose of this study was to explore the potential roles of bile as a liquid biopsy medium in patients with BTC. Patients and methods: Sixty-nine consecutive patients with suspected BTC were prospectively enrolled in this study. Capture-based targeted sequencing was performed on tumor tissues, whole blood cells, plasma, and bile samples using a large panel consisting of 520 cancer-related genes. Results: Of the 28 patients enrolled in this cohort, tumor tissues were available in eight patients, and plasma and bile were available in 28 patients. Somatic mutations were detected in 100% (8/8), 71.4% (20/28), and 53.6% (15/28) of samples comprising tumor tissue DNA, bile cell-free DNA (cfDNA), and plasma cfDNA, respectively. Bile cfDNA showed a significantly higher maximum allele frequency than plasma cfDNA (P ¼ 0.0032). There were 56.2% of somatic single-nucleotide variant (SNVs)/insertions and deletions (indels) shared between bile and plasma cfDNA. When considering the genetic profiles of tumor tissues as the gold standard, the by-variant sensitivity and positive predictive value for SNVs/indels in bile cfDNA positive for somatic mutations were both 95.5%. The overall concordance for SNVs/indels in bile was significantly higher than that in plasma (99.1% versus 78.3%, P < 0.0001). Moreover, the sensitivity of CA 19-9 combined with bile cfDNA achieved 96.4% in BTC diagnosis. Conclusion: We demonstrated that bile cfDNA was superior to plasma cfDNA in the detection of tumor-related genomic alterations. Bile cfDNA as a minimally invasive liquid biopsy medium might be a supplemental approach to confirm BTC diagnosis.

Aims: This study aimed to identify potential, non-invasive biomarkers for diagnosis and monitoring of the progress in multiple myeloma (MM) patients.Methods: MM patients and age-matched healthy controls (HC) were recruited in Discovery phase and Validation phase, respectively. MM patients were segregated into active group (AG) and responding group (RG). Serum samples were collected were conducted to non-targeted metabolomics analyses. Metabolites which were significantly changed (SCMs) among groups were identified in Discovery phase and was validated in Validation phase. The signaling pathways of these SCMs were enriched. The ability of SCMs to discriminate among groups in Validation phase was analyzed through receiver operating characteristic curve. The correlations between SCMs and clinical features, between SCMs and survival period of MM patients were analyzed.Results: Total of 23 SCMs were identified in AG compared with HC both in Discovery phase and Validation phase. Those SCMs were significantly enriched in arginine and proline metabolism and glycerophospholipid metabolism. 4 SCMs had the discriminatory ability between MM patients and healthy controls in Validation phase. Moreover, 12 SCMs had the ability to discriminate between the AG patients and RG patients in Validation phase. 10 out of 12 SCMs correlated with advanced features of MM. Moreover, 8 out of 12 SCMs had the negative impact on the survival of MM. 5′-Methylthioadenosine may be the only independent prognostic factor in survival period of MM.Conclusion: 10 SCMs identified in our study, which correlated with advanced features of MM, could be potential, novel, non-invasive biomarkers for active disease in MM.