Background The current prognosis of thymic epithelial tumors (TETs) is according to the World Health Organization (WHO) histologic classification and the Masaoka staging system. These methods of prognosis have certain limitations in clinical application and there is a need to seek new method for determining the prognosis of patients with TETs. To date, there have been no studies done on the use of DNA methylation biomarkers for prognosis of TETs. The present study was therefore carried out to identify DNA methylation biomarkers that can determine the overall survival in patients with TETs. Methods Bioinformatic analysis of TCGA 450 K methylation array data, transcriptome sequencing data, WHO histologic classification and Masaoka staging system was performed to identify differentially expressed methylation sites between thymoma and thymic carcinoma as well as the different DNA methylation sites associated with the overall survival in patients with TETs. Using pyrosequencing, 4 different methylation sites (cg05784862, cg07154254, cg02543462, and cg06288355) were sequenced from tumor tissues of 100 Chinese patients with TETs. A prognostic model for TETs was constructed using these four methylation sites. Results The TCGA dataset showed 5155 and 6967 hyper- and hypomethylated CpG sites in type A–B3 group and type C group, respectively, of which 3600 were located within the gene promoter regions. One hundred thirty-four genes were silenced by promoter hypermethylation and 174 mRNAs were upregulated. Analysis of univariate and multivariate Cox regression showed significant association between the methylation levels of 187 sites and the overall survival in patients with TETs. cg05784862( KSR1 ), cg07154254( ELF3 ), cg02543462( ILRN ), and cg06288355( RAG1 ) were identified as independent prognostic factors for overall survival in patients with TETs after adjusting for Masaoka staging in 100 Chinese patients. The prognostic model which consists of the four abovementioned genes had higher accuracy for predicting the 5-year overall survival in patients with TETs as compared to the Masaoka clinical staging. (Time-dependent ROC analysis AUC 1.000 vs 0.742, P = 2.7 × 10 −6 ). Conclusions The methylation levels of cg05784862( KSR1 ), cg07154254( ELF3 ), cg02543462( ILRN ), and cg06288355( RAG1 ) sites are associated with the progression of TETs and may serve as new biomarkers for predicting the overall survival in patients with TETs. Electronic supplementary material The online version of this article (10.1186/s13148-019-0619-z

LSD1 is identified as an essential drug target, which is closely correlated to the development of several tumor types. In this work, on the basis of comprehensive analysis of the binding site of LSD1 and other FAD-dependent enzymes, a novel series of potent and selective LSD1 inhibitors were designed by incorporation of privileged indoline scaffold strategies. Representative compound 7e (LSD1; IC50 = 24.43 nM, selectivity over LSD2 and MAOs of >200- and 4000-fold) possessed selective antiproliferative activities against MV-4-11 cell lines. Further study indicates that 7e could activate CD86 expression (EC50 = 470 nM) and induce differentiation of AML cell lines. More importantly, compound 7e demonstrated an acceptable oral PK profile and good in vivo antitumor efficacy with a T/C value of 30.89% in an MV-4-11 xenograft mouse model. Collectively, this work provides a promising lead compound for the development of novel LSD1 inhibitors for the treatment of AML.

Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK‑8 assay, flow cytometry and western blotting assays. Twenty‑six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p‑FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p‑FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9±2.1 and 4.13±0.12 µM in TE10 cells, and 9.85±5.5 and 3.21±0.76 µM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p‑FGFR1 and p‑AKT than that in EC9706 cells. AZD4547 and gefitinib co‑treatment resulted in a significant decrease in the level of p‑AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib.

Purpose This study aimed to develop and validate a prognostic model for metastasis-free survival (MFS) based on genes that may functionally interact with cytotoxic T lymphocytes (CTLs) and M2 macrophages in patients with triple-negative breast cancer (TNBC) who underwent adjuvant radiotherapy.Methods The transcriptional pro les and phenotypical les of TNBC and other subtypes of breast cancer were downloaded from the Gene Expression Omnibus (GEO). The abundance of in ltrated immune cells was evaluated through CIBERSORTx or MCP-counter. A weighted linear model, the score for MFS (SMFS), was developed by using least absolute shrinkage and selection operator (LASSO) in GSE58812 and validated in GSE2034 and GSE12276. The biological implication of SMFS was explored by evaluating its associations with TNBC molecular subtypes and other radiosensitivity-or immune-related signatures.Results A model consisting of the gene expression ratios of PCDH12/ELP3, PCDH12/MSRA and FAM160B2/MSRA with nonzero coe cients nally selected by LASSO was developed in GSE58812. In GSE2034 (treatment with adjuvant radiotherapy), SMFS was signi cantly associated with MFS in TNBC patients (HR=8.767, 95% CI: 1.856-41.408, P=0.006) and, to a lesser extent, in non-TNBC patients (HR=2.888, 95% CI: 1.076-7.750, P=0.035). However, the interaction of subtype (TNBC vs non-TNBC) and SMFS tended to be signi cant (P interaction =0.081). In contrast, SMFS was not signi cantly associated with MFS in either TNBC patients (P=0.499) or non-TNBC patients (P=0.536) in GSE12276 (treatment without radiotherapy). Among the four TNBC molecular subtypes, the c1 and c4 subtypes exhibited higher CTL in ltration and lower SMFS values than the c2 and c3 subtypes. In addition, SMFS was positively correlated with the abundance of endothelial cells (r=0.413, P<0.001). ConclusionsThe proposed model has the potential to predict MFS in TNBC patients after adjuvant radiotherapy. SMFS may represent a measurement of tumor immune suppression.

Radiotherapy has an important role in the comprehensive treatment of breast cancer. However, the clinical outcome of adjuvant radiotherapy may be limited due to intrinsic radioresistance, it is necessary to explore efficient radiosensitization methods that improve the clinical outcome of patients undergoing radiotherapy. The present study aimed to investigate whether the novel mechanistic target of rapamycin (mTOR) inhibitor Torin2 enhances the radiosensitivity of MCF‑7 breast cancer cells. A Cell Counting Kit‑8 (CCK‑8) assay was performed to measure the effect of Torin2 on cell proliferation, while clonogenic assays were employed to determine the effect of Torin2 in combination with radiation on the proliferation of MCF‑7 cells. The effect of Torin2 and/or radiation on the cell cycle was analyzed using flow cytometry. Furthermore, the protein expression of components of the phosphatidylinositol 3‑kinase/Akt/mTOR pathway, and the expression of proteins involved in DNA damage repair, was measured by western blot analysis. The results demonstrated that Torin2 exhibited a higher potency in MCF‑7 cells, while MDA‑MB‑231 cells were less sensitive to Torin2. Compared with irradiation alone, pretreatment with 20 nM Torin2 followed by irradiation resulted in an increased level of γ‑H2A histone family member X. Radiation induced the activation of the Akt/mTOR signaling pathway and upregulated the expression of phosphorylated (p)‑Akt473 and p‑eukaryotic translation initiation factor 4E binding protein 1 (4EBP1)37/46. Notably, pretreatment with Torin2 attenuated the radiation‑induced activation of the Akt/mTOR signaling pathway. In addition, Torin2 partially blocked the repair of double‑strand breaks induced by radiation by reducing the activation of ataxia telangiectasia‑mutated, and sensitized MCF‑7 cells to radiation. In conclusion, administration of Torin2 prior to irradiation enhanced the radiotherapeutic effect on breast cancer cells in vitro, and these results may provide a foundation for the rational use of combined therapy with irradiation and Torin2 for breast cancer in clinical practice.