The T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer.

Comparatively less toxic and more tolerated, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommendable for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. Some EGFR wild-type patients with specific biomarkers also show a response to the drug. TAZ is an oncogene closely associated with the therapeutic effect of EGFR-TKIs. However, this association remains to be clarified. This study aimed to clarify the mechanism through which TAZ sensitizes EGFR wild-type NSCLC to gefitinib. We used CCK-8 assays and in vivo experiments to investigate the influence of TAZ on gefitinib in EGFR wild-type NSCLC. To further validate the tumorigenic role of TAZ, we performed Human umbilical vein endothelial cell (HUVEC) tube formation and migration assays. Luciferase reporter assays, quantitative real-time PCR (qPCR), immunoblotting and Chromatin immunoprecipitation collaborated with qPCR illuminated the mechanism through which TAZ caused those phenotypes. The results showed TAZ promoted the angiogenesis of NSCLC cell lines and improved gefitinib sensitivity in EGFR wild-type NSCLC in vitro and in vivo. Luciferase reporter assays and ChIP-qPCR experiments showed TAZ upregulated AREG by promoting its transcription. EGFR signaling pathway was activated as TAZ was highly expressed. Rescue experiments were conducted to confirm the indispensable role of AREG in tumorigenesis and gefitinib sensitivity regulated by TAZ. Our study concluded that TAZ sensitized EGFR wild-type NSCLC to gefitinib through promoting amphiregulin transcription.

Background. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia disease with no cure. Communication between injured cells is triggered and maintained by a complicated network of cytokines and their receptors. IL-19 is supported by increasing evidences for a deleterious role in respiratory diseases. However, its potential role in lung fibrosis has never been explored. Methods. Bioinformatic, immunohistochemistry and western blot analysis were used to assess the expression of IL-19 in human and mouse fibrosis lung tissues. CCK-8, transwell and flow cytometry assay were utilized to analyze the effect of IL-19 on biological behaviors of lung fibroblasts. Histopathology was used to elucidate profibrotic effect of IL-19 in vivo. Results. IL-19 was upregulated in fibrosis lung tissues. IL-19 promoted lung fibroblasts proliferation and invasion, inhibited cell apoptosis, and induced differentiation of fibroblasts to the myofibroblast phenotype, which could be revised by LY2109761, a TGF-β/Smad signaling pathway inhibitor. Furthermore, we found that IL-19 aggravated lung fibrosis in murine bleomycin-induced lung fibrosis. Conclusions. Our results imply the profibrotic role for IL-19 through direct effects on lung fibroblasts and the potential of targeting IL-19 for therapeutic intervention in pulmonary fibrosis.

Purpose: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers. Experimental Design: We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression. Results: Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition–induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells’ sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition–induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells. Conclusions: Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.

Objectives Due to the increased morbidity, mortality, and cost of community-acquired pneumonia (CAP) in older people, strategies directed at improving disease evaluation and prevention are imperative. We independently compared the 30-day in-hospital mortality prediction ability of a frailty index based on laboratory data (FI-Lab) with that of the CURB-65 and the Pneumonia Severity Index (PSI) and then proposed combining them to further improve prediction efficiency. Design Retrospective cohort study. Setting and Participants Patients aged ≥ 65 years (n = 2039) with CAP who were admitted to Jiangsu Provincial People’s Hospital of Nanjing Medical University and Jiangsu Provincial Hospital of Chinese Medicine from January 2019 to June 2022. Measures The 29-item FI-Lab, PSI and, CURB-65 were administered at admission. We defined frailty by the cut-off value of the FI-Lab score (> 0.43). Multivariable logistic regression analysis, together with the calculation of the area under the receiver operating characteristic curve (ROC-AUC), was conducted to identify stratified risks and relationships between the three indices and 30-day mortality. Participants were divided into the following three groups based on age: 65–74 years, 75–84 years, and ≥ 85 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality due to frailty were calculated. Results A total of 495 participants ranging from 65 to 100 years of age were ultimately included and divided into age groups (65–74 years, n = 190, 38.4%; 75–84 years, n = 183, 37.0%; ≥ 85 years, n = 122, 24.6%). A total of 142 (28.7%) of the 495 patients were defined as having frailty. All three scores tested in this study were significantly associated with 30-day mortality in the total sample. The ORs were as follows: 1.06 (95% CI: 1.03–1.09, P < 0.001) and 2.33 (95% CI: 1.26–4.31, P = 0.007) for the FI-Lab when the score was treated as a continuous and categorical variable, respectively; 1.04 (95% CI: 1.02–1.05, P < 0.001) for the PSI; and 3.70 (95% CI: 2.48–5.50, P < 0.001) for the CURB-65. In the total sample, the ROC-AUCs were 0.783 (95% CI: 0.744–0.819) for the FI-Lab, 0.812 (95% CI: 0.775–0.845) for the PSI, and 0.799 (95% CI: 0.761–0.834) for the CURB-65 (P < 0.001). The ROC-AUC slightly improved when the FI-Lab was added to the PSI (AUC 0.850, 95% CI: 0.809–0.892, P = 0.031) and to the CURB-65 (AUC 0.839, 95% CI: 0.794–0.885, P = 0.002). Older patients with frailty showed a higher risk of in-hospital mortality, with an HR of 2.25 (95% CI: 1.14–3.58, P < 0.001). Conclusion and Implications The FI-Lab seems to generate simple and readily available data, suggesting that it could be a useful complement to the CURB-65 and the PSI as effective predictors of 30-day mortality due to CAP in older populations.