Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer. STEM CELLS

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. .

Abstract. Increased reactive nitrogen (Nr, NO3− + NH4++ + dissolved organic nitrogen) emission from the Asian continent poses profound threats to ecosystem safety from terrestrial throughout the ocean proper. To quantify atmospheric Nr input, diagnose its sources, and evaluate influence on marine nitrogen cycle of the South China Sea (SCS), an oligotrophic marginal sea adjacent to the emission hot spot China, we conducted measurements of concentrations of nitrate and ammonium as well as other major ions and dual isotopes of nitrate (δ15NNO3 and δ18ONO3) in atmospheric deposition collected from Dongsha Island off southern China. The δ15NNO3 and δ18ONO3 for dry deposition averaged at −2.8‰ and +58.8‰, ranging from −7.5 to +3.7‰ and from ∼ +17 to +88‰, respectively. Wet deposition, although with limited samples, showed a similar flux-weighted mean in δ15NNO3 (−2.6‰) yet a significantly higher mean in δ18ONO3 (+78.8‰). The dual isotope ratios showed an anti-correlation and an inverse seasonality; the δ15NNO3 values were higher in summer compared to those in winter, while the δ18ONO3 values were higher in winter than those in summer. In winter, not only dual isotopic compositions of nitrate but also the ammonium and nitrate dry deposition fluxes were relatively uniform, demonstrating a persistent influence of fossil fuel combustion sourced from Asian continental outflows via the northeasterly monsoon winds. More variable isotopic values in summer likely suggest varying sources and dynamical formation processes of dry deposition nitrate. Biomass burning and lightning are suggested to be responsible for the observed higher δ15NNO3 values in summer. Atmospheric nitrate and ammonium deposition together was estimated to be ∼50 mmol N m−2 year−1, with the dominance of nitrate in dry deposition but ammonium slightly higher in wet deposition. If not including this additional fertilization of atmospheric inorganic nitrogen deposition to enhance the carbon sequestration, CO2 release out of the SCS would be double than that of the present amount, 460 ± 430 mmol C m−2 year−1. Our study demonstrates that atmospheric deposition may serve as an important external Nr supplier to the SCS; however it is difficult to separate the isotopic signal from N2 fixation (−2–0‰) due to their similarity in δ15NNO3. More studies related to isotopic composition of nitrogen speciation in atmospheric Nr deposition, their relative contributions and source identification, and the role of typhoons in the SCS are required.

Bacteria commonly form aggregates in a range of coral species [termed coral-associated microbial aggregates (CAMAs)], although these structures remain poorly characterized despite extensive efforts studying the coral microbiome. Here, we comprehensively characterize CAMAs associated with Stylophora pistillata and quantify their cell abundance. Our analysis reveals that multiple Endozoicomonas phylotypes coexist inside a single CAMA. Nanoscale secondary ion mass spectrometry imaging revealed that the Endozoicomonas cells were enriched with phosphorus, with the elemental compositions of CAMAs different from coral tissues and endosymbiotic Symbiodiniaceae, highlighting a role in sequestering and cycling phosphate between coral holobiont partners. Consensus metagenome-assembled genomes of the two dominant Endozoicomonas phylotypes confirmed their metabolic potential for polyphosphate accumulation along with genomic signatures including type VI secretion systems allowing host association. Our findings provide unprecedented insights into Endozoicomonas -dominated CAMAs and the first direct physiological and genomic linked evidence of their biological role in the coral holobiont.