Introduction: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade. Methods: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.

Acute lung injury (ALI) is a syndrome associated with a high mortality rate. Nrf2 is a key regulator of intracellular oxidation homeostasis that plays a pivotal role in controlling lipid peroxidation, which is closely related to the process of ferroptosis. However, the intrinsic effect of Nrf2 on ferroptosis remains to be investigated in ALI. We found that MDA expression increased while GSH and GPX4 decreased in ALI models. Furthermore, the characteristic mitochondrial morphological changes of ferroptosis appear in type II alveolar epithelial cells in IIR models. Additional pre-treatment of Fe and Ferrostatin-1 in ALI significantly aggravated or ameliorated the pathological injuries of lung tissue, pulmonary edema, lipid peroxidation, as well as promoted or prevented cell death, respectively. Knocking down Nrf2 notably decreased the expression of SLC7A11 and HO-1. Interference with SLC7A11 markedly increased Nrf2-HO-1 and dramatically attenuated cell death in OGD/R models. These findings indicate that ferroptosis can be inhibited by Nrf2 through regulating SLC7A11 and HO-1, which may provide a potential therapeutic strategy for IIR-ALI.

More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.