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High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination.Significance:These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.

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Strontium surface segregation is the main issue that causes long-term performance degradation in strontium-containing electrodes for solid oxide electrolysis cells. In this research, we effectively suppress strontium segregation by applying an anodic current that drives the segregated strontium back to the perovskite lattice and mitigate electrode performance degradation. By monitoring the impedance of Sr2Fe1.5Mo0.5O6-δ (SFM) air electrode under open circuit voltage at high temperature with changing current densities over time, the degradation caused by strontium segregation is verified. The applied current successfully prevent the polarization resistance from increasing is observed. The cell with 0.8 A/cm2 of the applied current increase only 3% of polarization resistance as compared to the cell without applied current after testing at 800 ℃ for 24 h. The atomic ratio of strontium on the SFM electrode surface shows lower strontium content after undergoing applied current, which means that the strontium is indeed migrated back to perovskite lattice under the applied current and result in slower degradation of the SFM electrode. Ministry of Education (MOE) The authors thank the funding support of AcRF Tier 1 project RG181/18 (S) from Ministry of Education, Singapore.

Additional file 1: Supplementary Table 1. The incident cases and ASIR of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019. Supplementary Table 2. The death cases and ASDR of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019. Supplementary Table 3. The DALYs and Age-standardized DALY rate of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019. Supplementary Figure 1. The change trends ofdeath cases, ASDR and EAPC among different SDI quintiles. SupplementaryFigure 2. The change trendsof DALYs, age−standardized DALY rate and EAPC among different SDI quintiles. SupplementaryFigure 3. The correlationbetween ASIR, ASDR, age−standardized DALY in 2019 and SDI, and the correlationbetween EAPCs and ASIR, ASDR, DALY in 1990.