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Background DARS2 was overexpressed in multiple tumor types, but the biological role of DARS2 in lung adenocarcinoma (LUAD) have not been elucidated. Methods Firstly, the DARS2 expression in LUAD was explored using The Cancer Genome Atlas (TCGA). Then, qRT‐PCR and Western blot were performed to confirm DARS2 expression in LUAD. Next, Cox regression and Kaplan–Meier methods were utilized to evaluate whether DARS2 expression can affect the overall survival. The relationships between DARS2 expression and clinicopathological characteristics were investigated by TCGA database. Moreover, we utilized Gene Set Enrichment Analysis (GSEA) to detect DARS2‐related signaling pathways in LUAD. Finally, the special function of DARS2 in cell proliferation, invasion and apoptosis was assessed in vitro. Results The higher expression of DARS2 was found in LUAD compared to para‐carcinoma tissues and significantly related to tumor stage, T stage, and M stage. The survival analysis indicated that DARS2 overexpression was related to poor prognosis in LUAD. Multivariate analysis suggested that DARS2 expression was a prognostic indicator. GSEA revealed that DARS2 was primarily involved in cell cycle‐related pathways. In addition, upregulation of DARS2 facilitated LUAD cell proliferation, migration, invasion and inhabited apoptosis, DARS2 knockdown showed an opposite result. Conclusion DARS2 modulates the proliferation, invasion and apoptosis of LUAD cells, and sever as a promising therapeutic target for LUAD.

Objective This study aimed to evaluate the in vitro and in vivo effects of different combinations of antimicrobial agents against carbapenemase-producing and non-producing Klebsiella pneumoniae from China. Methods A checkerboard assay of meropenem (MEM), amikacin (AK), tigecycline (TGC), colistin (COL) and their combinations was carried out against 58 clinical carbapenem-resistant K. pneumoniae (CRKp) isolates, including 11 carbapenemase-non-producing K. pneumoniae isolates and 21 isolates producing KPC-2 enzyme, 11 NDM-1, 13 IMP, one VIM-1 and one OXA-48. The checkerboard assay was analyzed by the fractional inhibitory concentration index (FICI). A time–kill assay and Galleria mellonella infection model were conducted to evaluate the in vitro and in vivo effects of the four drugs alone and in combination. Results In the checkerboard assay, TGC+AK and MEM+AK combinations showed the highest synergistic effect against KPC-2 and NDM-1 carbapenemase-producing isolates, with synergy+partial synergy (defined as FICI <1) rates of 76.2% and 71.4% against KPC-2 producers, and 54.5% and 81.8% against NDM-1 producers. TGC+AK and MEM+COL combinations showed the highest rate of synergistic effect against IMP-producing isolates. Against carbapenemase-non-producing isolates, TGC+COL and TGC+AK combinations showed the highest rate of synergy effect (63.6% and 54.5%). MEM+AK showed a synergistic effect against one VIM-1 producer (FICI=0.31) and an additivite effect (FICI=1) against one OXA-48 producer. In the time–kill assay, COL+AK, COL+TGC, COL+MEM and AK+TGC showed good synergistic effects against the KPC-2-producing isolate D16. COL+MEM and COL+TGC combinations showed good effects against the NDM-1-producing isolate L13 and IMP-4-producing isolate L34. Against the carbapenemase-non-producing isolate Y105, MEM+TGC and COL+AK showed high synergistic effects, with log 10 CFU/mL decreases of 6.2 and 5.5 compared to the most active single drug. In the G. mellonella survival assay, MEM-based combinations had relatively high survival rates, especially when combined with colistin, against KPC-2 producers (90% survival rate) and with amikacin against metallo-beta-lactamase producers (95–100% survival rate). Conclusion Our study suggests that different antimicrobial agent combinations should be considered against CRKp infections with different resistance mechanisms.