[Study on the Therapeutic Effect of Lenalidomide on Hemophilic Arthropathy].

OBJECTIVE: To explore the effect of lenalidomide on human fibroblast-like synovial cells (HFLS) and the therapeutic efficacy on hemophilic arthropathy in hemophilia A mice model. METHODS: In vitro, to remodel the inflammatory environment of synovial tissue after hemorrhage, ferric citrate and recombinant TNF-α were added into the cell culture medium of HFLS. Cell Counting Kit-8 (CCK-8), Enzyme-linked immunosorbent assay (ELISA), Quantitative Real-time PCR (RT-qPCR) and flow cytometry were employed for detection of the effects of lenalidomide on the proliferation ability, pro-inflammatory cytokines release and apoptosis of HFLS cells. In vivo, hemophilia arthropathy was remodeled in hemophilia A mice by induction of hemarthrosis. A series of doses of lenalidomide (0.1, 0.3 and 1.0 g/kg) was administrated intra-articularly. Tissues of knee joints were collected on the 14th day after administration, and the protective effect of lenalidomide on arthritis in hemophilia A mice were evaluated by RT-qPCR and histological grading. RESULTS: In vitro, compared with the untreated control group, lenalidomide could significantly inhibit the proliferation of HFLS cells (P<0.05), and the effect was the most significant when the concentration was 0.01 µmol/L (P<0.001). Compared with the control group, lenalidomide could significantly inhibit the expression levels of TNF-α, IL-1ß, IL-6 and IFN-γ in HFLS cells (P<0.05). The flow cytometry results showed that lenalidomide could enhance the apoptotis of HFLS cells (P<0.05). The results of RT-qPCR showed that lenalidomide could significantly reduce the mRNA expression levels of TNF-α, IL-1ß, IL-6,MCP-1 and VEGF in the joint tissues (P<0.05). Histological results showed that compared with the injured group, lenalidomide could significantly reduce the pathological sequela after hemarthrosis induction, e.g. synovial thickening and neo-angiogenesis in the synovium. The protection displayed a dose-response pattern roughly. CONCLUSION: In vitro, lenalidomide can inhibit the proliferation of HFLS cells, promote their apoptosis, and inhibit the expression of pro-inflammatory cytokines. In vivo, lenalidomide can significantly decrease the expression of pro-inflammatory cytokines in the joints of mice, and prevent the development of inflammation and neo-angiogenesis. The results provide a theoretical and experimental basis for the clinical application of lenalidomide in the treatment of hemophilic arthropathy.

A detrimental mutation on USP40 unlocks the tumorigenesis in a rare case of lung cancer.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Previous research has shown heterogeneity in lung cancer, with the parallel existence of multiple subclones characterized by their own specific mutational landscape. The aim of our study was to gain insight into the evolutionary pattern of lung cancer by investigating the genomic heterogeneity between a nodule and its distant tumor. Luckily, we obtained nodule and tumor samples derived from surgery and a blood sample from a single patient. The samples are very unique, for tissues with the same genetic background from nodules to malignant tumors are rarely available and require precise micro-cutting. In this study, we performed whole-genome sequencing of these two samples, to identify novel candidate driver genes associated with LUAD. The nodule and tumor were found to have common significant ubiquitin-specific protease 40 (USP40) mutations, indicating an important driver role for the gene. Moreover, we also observed the two novel candidate driver genes ASCL5 and CAPNS1 in the LUAD sample. In summary, we pinpoint the predominant mutations in LUAD by WES, highlighting the substantial genetic alterations contributing to LUAD tumorigenesis. This may provide a better understanding of the clonal evolution during tumor development.