New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1), because PD-L1 expression on tumor cells has limited power for selecting patients who may benefit from such therapy. Here we investigated the significance of PD-L1 and PD-L2 gene copy number gains using fluorescence in situ hybridization as well as PD-L1 and PD-L2 expression in 654 patients with resected non-small-cell lung cancer. The prevalence of PD-L1 amplification and polysomy was 3.1% and 13.2%, respectively. The PD-L1 gene copy number status was in agreement with both the PD-L2 and Janus kinase 2 gene copy number statuses. PD-L1 and PD-L2 expression was observed in 30.7% and 13.1%, respectively. Both PD-L1 copy number gains and expression were associated with smoking-related tumors. Tumor cells with PD-L1 genomic gains exhibited significantly higher levels of PD-L1 expression than those without, but PD-L2 copy number gains were not related to PD-L2 augmentation. PD-L1 gene amplification and polysomy were independently associated with PD-L1 expression, with high immune infiltrates and EGFR expression in a multivariate logistic regression model. Comparative analysis between primary tumors and synchronous regional lymph node metastases revealed that the PD-L1 gene copy number alterations were highly consistent and reproducible compared with the PD-L1 expression. Both PD-L1 amplification and level of protein expression were predictors of poor survival using Cox univariate analyses. Therefore, we conclude that an increase in PD-L1 gene copy number can be a feasible alternative biomarker for predicting response to anti-PD-1/PD-L1 therapy.

This new method of FOT is useful in the differential diagnosis of COPD and asthma.

A comprehensive study of ice-crystal fabrics and textures was conducted on the Dome F (Antarctica) ice core. Crystal ,-axis orientations, crystal sizes and crystal shape were measured on thin sections with an automatic ice-fabric analyzer. The general feature of textural and fabric development through a 2500 m long core was obtained by a 20 m interval study. Crystal size steadily increases with depth except for depths of about 500,1800, 2000, 2200 and 2300 m, at which depths crystal size decreases suddenly. There is a clear correlation between crystal-size and ´18O values. Crystals tend to elongate horizontally with depth, and the aspect ratio (long axis vs short axis of a grain) increases twofold at 1600 m depth and fluctuates below that depth. The .-axis orientation fabrics gradually change with depth from a random orientation pattern near the surface to a strong vertical single maximum at 2500 m. These are very similar to those from the GRIP (Greenland) core The observations of crystal shape and the fabric measurements indicate that nucleation-recrystallization does not take place at Dome F.

IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL-17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic-polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll-IL-1 receptor domain-containing adaptor-inducing INF-β (TRIF)-NF-κB pathway, Pepinh-TRIF, BAY11, NF-κB inhibitor III, and NF-κB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3-TRIF-NF-κB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human β-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL-17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell-derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium.