No abstract

There is a major limitation in the immunotherapy for solid cancer is that it only benefited a minority of cancer patients. This study aims to investigate whether the differential composition of the lung microbiome could affect the sustained clinical responses in lung cancers treated with immunotherapy. Methods: Twenty-seven non-responders and 19 responders treated with anti-PD-1 therapy were included in the discovery set. Bacterial load in bronchoalveolar lavage from lung cancer patients was examined by quantitative PCR of 16S rRNA copies. Bacterial 16S rDNA was sequenced using the Illumina HiSeq on the 16S rDNA V3-V4 variable region. Operational taxonomic unit (OTU) analysis was performed using VSEARCH v2. The α-diversity and β-diversity were calculated using QIIME software. Results:The mean copy number of bacterial 16S DNA levels significantly decreased after anti-PD-1 treatment (after: 1.8 ± 0.6×10 4 copies per milliliter vs prior to treatment: 3.3 ± 1.1x10 4 , p = 0.0036). In addition, longitudinal analysis revealed that microbial diversity was reduced taxonomically after treatment compared to those prior to the treatment (Shannon values: before: 3.291 ± 0.067 vs after: 2.668 ± 0.168, p < 0.01). Further, we observed a reduction of Fusobacterium nucleatum, including phylum Fusobacteria (p < 0.01), class Fusobacteria (p < 0.01), order Fusobacteria (p < 0.01), family Fusobacteria (p < 0.01), genus Fusobacteria (p = 0.025) in the responders post anti-PD-1 treatment. However, there was no significant difference of Fusobacterium in non-responders. An independent cohort was used to validate the levels of Fusobacterium, demonstrating that patients with higher abundance of Fusobacterium prior to treatment were significantly more likely to have poor response to anti-PD-1 therapy (p < 0.001). Conclusion: Airway enriched Fusobacterium prior to anti-PD-1 therapy is associated with poor response in lung cancer, which indicated that potential resistance to immunotherapy can be attributed to lung microbiome.

Background The causal relationship between insomnia and migraine is contradictory and no study has been carried out among the Chinese population to date. Methods In this case, we conducted a case–control study and a bidirectional mendelian randomization (MR) analysis to determine whether insomnia is causally related to the development of migraine. The instrumental variables for insomnia were derived from the largest genome-wide association study of 1,331,010 participants, while the genetic instruments for migraine were available from the largest meta-analysis of migraine with 59,674 cases and 316,078 controls. Results In case–control study, subjects with insomnia have significantly higher risk of migraine (OR=4.29, 95% CI: 3.21–5.74, P<0.001), compared with those without insomnia. The bidirectional two-sample MR analysis revealed that insomnia was significantly associated with higher risk of migraine (OR=1.24, 95% CI: 1.11–1.38, P=1.01×10-4), and the results were validated in the UK Biobank data. The results showed no indication for directional pleiotropy effects as assessed by the MR-Egger intercept (P>0.05). Conclusion Conclusively, our study highlighted that increased migraine risk was confined to subjects with a genetic pre-disposition to insomnia, and these findings had potential implications for improving the sleep quality to reduce the burden of migraine.

Background Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated. Methods The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4−/− mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines. Results TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. Conclusion In summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.