We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

BTK kinase is a member of the TEC kinase family and is a key regulator of the B-cell Receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as MCL, CLL and AML. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has shown moderate efficacy for AML cell lines proliferation. Through a structure-based drug design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and non-covalent binding to MNK. Compared to the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 displays a stronger anti-proliferative effect against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0–G1 stage and can induce strong apoptotic cell death. These results demonstrated that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.

The methylated status of ASC/TMS1 promoter had the potential applicability for clinical evaluation the prognosis of GC.

No abstract

Dear Editor, Early diagnosis is critical for successful treatment of gastric adenocarcinoma (GA). However, the sensitivities of tumor markers carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and CA72-4 for GA detection are approximately 20% [1], and the sensitivities of all markers combined for early gastric cancer detection is still very low [2]. DNA methylation plays a major role in tumorigenesis and therefore has obvious potential as a non-invasive biomarker for cancer detection [3]. Through genome-wide methylation analysis and histological verification, we previously identified ring finger protein 180 (RNF180) as a novel preferentially methylated gene in GA [4,5].To increase the sensitivity for detecting GA, we combined mRNF180 and other methylated DNA markers. According to previous studies, the sensitivity and specificity of circulating methylated SEPTIN9 (mSEPT9) are estimated to be 50%-70% and ≥ 90%, respectively, to detect colorectal cancer (CRC) [6,7]. GA and CRC share similar biological features. Notably, GA and CRC share many similar aberrant promoter DNA methylations, resulting in sharing many consistent gene methylation biomarkers [8]. Therefore, we attempted to establish a panel of mRNF180 and mSEPT9 (RS9 panel) for the early detection of GA. The study protocols are included in the Supplementary Materials.To assess the diagnostic potential of the RS9 panel, we prospectively examined 324 plasma specimens from 195 GA patients and 129 controls in the training cohort