The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non-small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXRhighPD-L1low patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXRhighPD-L1low NSCLC cell lines, effector function and proliferation of CD8+ T cell in vitro are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXRhighPD-L1low subtype in which FXR suppresses tumor-infiltrating immune cells. Anti-PD-1 therapy was effective against FXRhighPD-L1low mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXRhighPD-L1low NSCLC subtype and provide translational insights into therapeutic response in PD-L1low NSCLC patients treated with anti-PD-1. We recommend FXRhighPD-L1low as a biomarker to predict responsiveness to anti-PD-1 immunotherapy.
Interstitial lung abnormalities (ILAs), which refer to mild or subtle nongravity-dependent interstitial changes, may be neglected by some clinicians due to many reasons, such as lack of diagnostic criteria for ILAs and absence of available treatments and surveillance strategies. However, without intervention, some ILAs may progress to interstitial lung disease (ILD). This review summarizes our current knowledge of this condition and ways of diagnosing it together with current management. We hope that this will lead to better recognition of ILAs.We reviewed the literature on PubMed between 2008 and 2020 focusing on prevalence, etiology, symptoms, diagnostic biomarkers, clinical associations, and management of ILAs.Timely diagnosis with close monitoring of ILAs and appropriate intervention should be recognized as the management approach to ILAs. Research into ILAs should continue to improve its management.
Abstract Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20–25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
<div>Abstract<p>The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non–small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXR<sup>high</sup>PD-L1<sup>low</sup> patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC cell lines, effector function and proliferation of CD8<sup>+</sup> T cell <i>in vitro</i> are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXR<sup>high</sup>PD-L1<sup>low</sup> subtype in which FXR suppresses tumor-infiltrating immune cells. Anti–PD-1 therapy was effective against FXR<sup>high</sup>PD-L1<sup>low</sup> mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC subtype and provide translational insights into therapeutic response in PD-L1<sup>low</sup> NSCLC patients treated with anti–PD-1. We recommend FXR<sup>high</sup>PD-L1<sup>low</sup> as a biomarker to predict responsiveness to anti–PD-1 immunotherapy.</p></div>
To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A (TSA)on bleomycin-induced pulmonary fibrosis. To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A ( TSA ) on HDAC2, p-SMAD2, HDAC2 mRNA, SMAD2mRNA in pulmonary fibrosis rats and investigate impossible mechanism.46 SPF level male SD rats were randomly divided into four groups: ten for normal control group, fourteen for model control group I, twelve for model control group II and ten for treatment group. Rat pulmonary fibrosis was induced by bleomycin(5mg/kg) via single intratracheal perfusion in the two model control groups and treatment group. Normal control mice were instilled with a corresponding volume of 0.9% saline intratracheally. Treatment group was treated by the dilution of TSA 2mg/kg DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day ,once a day for three days. Model control group II was treated by the dilution of DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. Model control group I and normal control group were treated by 0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. All the animals were sacrificed on the 21 day after modeling. The pathological changes were observed by hematoxylin and eosin(HE)stain and masson trichrome stain. The expression of HDAC2 mRNA,SMAD2 mRNA were measured by real-time PCR. The protein level of HDAC2 and p-SMAD2 in serum was measured by Western blot.The pulmonary fibrosis in treatment group were significantly alleviated compared to the two model control groups (P<0.05). Real-time PCR showed that the treatment group had lower expression of lung tissue HDAC2 mRNA than the two model control groups and normal control group (P<0.05). The expression of lung tissue SMAD2 mRNA increased in the two model control groups and treatment group (P<0.05),but there were no significant differences among the three groups(P>0.05). Western blot indicated that the protein level of HDAC2 and p-SMAD2 in serum increased in the two model control groups compared with normal control group(P<0.05).But treatment group had lower protein level of HDAC2 (P<0.05) and no significant difference in the protein level of p-SMAD2 compared to the two model control groups (P>0.05).Non selective histone deacetylase inhibitors of Trichostatin A (TSA) can reduce the bleomycin induced pulmonary fibrosis in rats. TSA attenuates pulmonary fibrosis and it can inhibit HDAC2 expression at the gene and protein level. Bleomycin induced fibrosis has the relationship with p-SMAD2 in gene and protein levels, but TSA inhibit bleomycin-induced lung fibrosis effect with no relation with SMAD2 phosphorylation pathways.
Interstitial lung disease (ILD), consisting of more than 200 subtypes of diseases, is a large group of heterogeneous diseases characterized by varying degrees of alveolitis and pulmonary parenchymal fibrosis. There are many challenges in its diagnosis and treatment. In recent years, new understanding of the clinical classification, disease behavior, early diagnosis, and treatment of ILD has been obtained. The anti-fibrotic drugs have been expanded successfully from treatment of idiopathic pulmonary fibrosis (IPF) to progressive-fibrosing interstitial lung diseases (PF-ILD). A new international clinical practice guideline categorized hypersensitivity pneumonitis (HP) into two clinical phenotypes, namely nonfibrotic and fibrotic HP. The clinical classification of ILD according to disease behavior and a progressing fibrotic phenotype is of important value for the establishment of treatment strategies for patients with ILD. Interstitial pulmonary abnormalities (ILA) may represent the subclinical stages of different types of ILD, and long-term follow-up of ILA is key to improving the early diagnosis of ILD. Interstitial pneumonia with autoimmune features (IPAF) may represent an early phase or prodromal state of a connective tissue disease (CTD), and patients with IPAF need to be under longitudinal surveillance for evolution to CTD.
<div>Abstract<p>The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non–small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXR<sup>high</sup>PD-L1<sup>low</sup> patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC cell lines, effector function and proliferation of CD8<sup>+</sup> T cell <i>in vitro</i> are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXR<sup>high</sup>PD-L1<sup>low</sup> subtype in which FXR suppresses tumor-infiltrating immune cells. Anti–PD-1 therapy was effective against FXR<sup>high</sup>PD-L1<sup>low</sup> mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC subtype and provide translational insights into therapeutic response in PD-L1<sup>low</sup> NSCLC patients treated with anti–PD-1. We recommend FXR<sup>high</sup>PD-L1<sup>low</sup> as a biomarker to predict responsiveness to anti–PD-1 immunotherapy.</p></div>
Abstract Dual-energy spectral computed tomography (DESCT) is based on fast switching between high and low voltages from view to view to obtain dual-energy imaging data, and it can generate monochromatic image sets, iodine-based material decomposition images and spectral CT curves. Quantitative spectral CT parameters may be valuable for reflecting Ki-67 expression and EGFR mutation status in non-small-cell lung cancer (NSCLC). We investigated the associations among the quantitative parameters generated in DESCT and Ki-67 expression and EGFR mutation in NSCLC. We studied sixty-five NSCLC patients with preoperative DESCT scans, and their specimens underwent Ki-67 and EGFR evaluations. Statistical analyses were performed to identify the spectral CT parameters for the diagnosis of Ki-67 expression and EGFR mutation status. We found that tumour grade and the slope of the spectral CT curve in the venous phase were the independent factors influencing the Ki-67 expression level, and the area under the curve (AUC) of the slope of the spectral CT curve in the venous phase in the receiver operating characteristic analysis for distinguishing different Ki-67 expression levels was 0.901. Smoking status and the normalized iodine concentration in the venous phase were independent factors influencing EGFR mutation, and the AUC of the two-factor combination for predicting the presence of EGFR mutation was 0.807. These results show that spectral CT parameters may be useful for predicting Ki-67 expression and the presence of EGFR mutation in NSCLC.
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