MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers.

BACKGROUND: The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib. METHODS: Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo. RESULTS: Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo. CONCLUSIONS: These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC.

Downregulation of circEPSTI1 represses the proliferation and invasion of non-small cell lung cancer by inhibiting TRIM24 via miR-1248 upregulation.

The circular RNA (circRNA) circEPSTI1 has been recently identified as a new cancer-associated circRNA in multiple types of cancer. However, the involvement of circEPSTI1 in non-small cell lung cancer (NSCLC) remains unexplored. The purpose of this study was to explore the expression pattern and function of circEPSTI1 in NSCLC. We found that circEPSTI1 expression was significantly elevated in NSCLC. In vitro experiments elucidated that knockdown of circEPSTI1 caused a significant reduction in NSCLC cell proliferation and invasion. Moreover, circEPSTI1 was identified as an miRNA sponge of miRNA-1248. Knockdown of circEPSTI1 markedly increased the expression of miR-1248 in NSCLC cells. Upregulation of miR-1248 significantly restricted the proliferation and invasion of NSCLC cells. Inhibition of miR-1248 promoted the proliferation and invasion of NSCLC cells and blocked the circEPSTI1 knockdown-mediated inhibitory effect on NSCLC cell proliferation and invasion. Subsequent data revealed that the tumor-promoting gene tripartite motif-containing protein 24 (TRIM24) is a target gene of miR-1248. The upregulation of TRIM24 partially reversed circEPSTI1 knockdown- or miR-1248 overexpression-induced tumor suppressive effect in NSCLC cells. In summary, our data demonstrate that downregulation of circEPSTI1 represses the proliferation and invasion of NSCLC by inhibiting TRIM24 via miR-1248 upregulation.

Clinical characteristics of imported and second-generation coronavirus disease 2019 (COVID-19) cases in Shaanxi outside Wuhan, China: a multicentre retrospective study.

The mortality of coronavirus disease 2019 (COVID-19) differs between countries and regions. This study aimed to clarify the clinical characteristics of imported and second-generation cases in Shaanxi. This study included 134 COVID-19 cases in Shaanxi outside Wuhan. Clinical data were compared between severe and non-severe cases. We further profiled the dynamic laboratory findings of some patients. In total, 34.3% of the 134 patients were severe cases, 11.2% had complications. As of 7 March 2020, 91.8% patients were discharged and one patient (0.7%) died. Age, lymphocyte count, C-reactive protein, erythrocyte sedimentation rate, direct bilirubin, lactate dehydrogenase and hydroxybutyrate dehydrogenase showed difference between severe and no-severe cases (all P < 0.05). Baseline lymphocyte count was higher in survived patients than in non-survivor case, and it increased as the condition improved, but declined sharply when death occurred. The interleukin-6 (IL-6) level displayed a downtrend in survivors, but rose very high in the death case. Pulmonary fibrosis was found on later chest computed tomography images in 51.5% of the pneumonia cases. Imported and second-generation cases outside Wuhan had a better prognosis than initial cases in Wuhan. Lymphocyte count and IL-6 level could be used for evaluating prognosis. Pulmonary fibrosis as the sequelae of COVID-19 should be taken into account.

Stage-associated differences in the serum N- and O-glycan profiles of patients with non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death in China and around the world. Early detection is key to improving the survival rate of non-small cell lung cancer (NSCLC). Alteration in glycosylation has been observed in cancers, and glycans can be a source for the development of new biomarkers for NSCLC. METHODS: In this glycan biomarker discovery study, we measured serum N- and O-glycan profiles in NSCLC patients with different stages and healthy controls by performing lectin microarray analysis. The alterations of serum glycopatterns were compared between NSCLC patients and controls, and the stage-related changes in serum glycosylation were evaluated. RESULTS: There were 18 lectins (e.g., AAL, Jacalin, GSL-I and DBA) to give significantly alterations of serum glycopatterns in lung adenocarcinoma compared with control group. Meanwhile, 16 lectins (e.g., Jacalin, HHL, and PHA-E+L) exhibited significantly alterations of serum glycopatterns in squamous cell carcinoma (SCC) compared with control group. Importantly, most of the lectins showing altered signals exhibited significantly increased or decreased NFIs in patients with early stage adenocarcinoma and SCC. CONCLUSIONS: The serum glycan profiles were significantly different between NSCLC and healthy control, and most of the glycosylation changes had occurred at early stage. Further evaluation is needed to examine the diagnostic value of the glycan markers identified in this study.

Effects of pH and substrate concentrations on dark fermentative biohydrogen production from xylose by extreme thermophilic mixed culture.

Biohydrogen is considered as one of the most promising energy alternatives considering the climate and energy crisis. The dark fermentative hydrogen production from xylose at extreme thermophilic condition (70 °C) using mixed culture was conducted in this study. The effects of initial pH values (ranged from 5.0 to 10.0) and substrate concentrations (ranged from 2.5 to 15.0 g/L) on the hydrogen production, substrate degradation and metabolite distributions were investigated using batch-mode operations. Results showed that initial substrate pH values in the neutral region (6.0-7.0) were beneficial for hydrogen production. The fermentation at initial pH 7.0 and 7.5 g/L xylose reached an optimal hydrogen yield of 1.29 mol-H2/mol-xyloseconsumed. Ethanol, butyrate, and propionate were the major liquid metabolites. The xylose biodegradation efficiency of the mixed culture decreased sharply at high initial culture pH values. The increase of xylose concentration resulted in the accumulation of propionate and an obvious decrease in the final pH value, as well as a low hydrogen yield. Polymerase chain reaction-denaturing gradient gel electrophoresis analysis indicated that hydrogen producing bacteria were enriched by repeated culture under extreme thermophilic conditions. Also, the mixed culture was dominated with bacterial species related to Clostridium and Thermoanaerobacterium.

miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2.

MicroRNAs (miRNAs) play a critical role in cancer development and progression. Deregulated expression of miR-204 has been reported in several cancers, but the mechanism through which miR-204 modulates human non-small cell lung cancer (NSCLC) is largely unknown. In this study, we investigate the expression and functional role of miR-204 in human NSCLC tissues and cell lines. RNA isolation, qRT-PCR, MTT, colony formation assay, cell cycle assay, cell apoptosis assay, cell migration assay, and Western blot were performed. Statistical analysis was performed using SPSS 18.0 software and statistical significance was accepted at p value <0.05. miR-204 level was significantly reduced in NSCLC tissues as compared to that of non-neoplastic tissues. Transient over-expression of miR-204 by transfecting with miR-204 mimics suppressed NSCLC cell proliferation, migration, and induced apoptosis and G1 arrest, whereas inhibition of miR-204 showed the converse effects. Additionally, activating transcription factor 2 (ATF2), an important transcription factor, was demonstrated as a potential target gene of miR-204. Subsequent investigations found a negative correlation between miR-204 level and ATF2 expression in NSCLC tissue samples. Moreover, we observed that miR-204 expression inversely affected endogenous ATF2 expression at both mRNA and protein levels in vitro. Taken together, miR-204 may act as a tumor suppressor by directly targeting ATF2 in NSCLC.

Differentially expressed glycosylated patterns of α-1-antitrypsin as serum biomarkers for the diagnosis of lung cancer.

Lung cancer is the most common malignancy worldwide. Thus, there is a critical need for diagnostic biomarkers with adequate sensitivity and specificity for lung cancer detection. Glycans in glycoproteins are significantly altered in cancer, and may serve as a tool for identifying potential diagnostic biomarkers. Recent studies have reported changes in α-1-antitrypsin (A1AT) glycosylation in lung cancer serum, tissue and cell lines. In this study, a lectin microarray was used to detect glycosylation changes in serum A1AT from patients with lung adenocarcinoma (ADC), squamous cell lung cancer, small-cell lung cancer (SCLC) and benign pulmonary diseases. Differentially expressed glycosylated patterns of A1AT were identified by lectin arrays and were confirmed by lectin-based enzyme-linked immunosorbent assay (ELISA). We found that galactosylated A1AT could distinguish non-small-cell lung cancer (NSCLC) from benign pulmonary diseases (AUC = 0.834); fucosylated A1AT showed exceptional capability in distinguishing ADC from benign diseases (AUC = 0.919) or other lung cancer subtypes (AUC = 0.844), and A1AT containing poly-LacNAc could detect SCLC from benign diseases (AUC = 0.905) or NSCLC (AUC = 0.707). The present study indicates that glycosylated patterns of A1AT may serve as potential biomarkers for detection of lung cancer. Further studies in larger sample sizes are necessary to validate the clinical utility of these markers.

Attention modulates facial expression processing in subsyndromal depression: A behavioral and ERP study.

Impaired facial expression perception is a core element in depression, but the underlying mechanism remains controversial. This event-related potential study investigated how attention modulates facial expression perception in depression using a nonclinical sample. A group of healthy controls (HC, N = 39) and a group of individuals with subsyndromal depression (SD, N = 39) categorized faces based on either facial expression (happy vs. sad) or gender (male vs. female). Behaviorally, the SD group was less sensitive to the emotional valence of facial expression than the HC group when their attention was directed to facial expression, as revealed by comparable subjective ratings and accuracy rates in response to facial expressions. When attention was directed towards facial gender, the SD group versus the HC group showed a negative bias, as revealed by a faster N170 for sad faces than happy faces. Together, our findings suggest that attention plays a role in understanding the relationship between depression and facial expression perception.

Distinct neural dynamics underlying risk and ambiguity during valued-based decision making.

Uncertainty can be fractioned into risk and ambiguity psychologically and neurobiologically. However, whether and how risk and ambiguity are dissociated in terms of neural dynamics during value-based decision making remain elusive. The present event-related potential (ERP) study addressed these issues by asking participants to perform a wheel-of-fortune task either during a risky context (Experiment 1; N = 30) where outcome probability was known or during an ambiguous context (Experiment 2; N = 30) where outcome probability was unknown. Results revealed that the cue-P3 was more enhanced for risk versus ambiguity during the anticipatory phase, whereas the RewP was more increased for ambiguity than risk during the consummatory phase. Moreover, the SPN and the fb-P3 components were further modulated by the levels of risk and ambiguity, respectively. These findings demonstrate a neural dissociation between risk and ambiguity, which unfolds from the anticipatory phase to the consummatory phase.

Contextual valence influences the neural dynamics of time and magnitude representation during feedback evaluation.

Contextual valence is an important dimension during value-based decision-making. Previous research has revealed behavioral and neural asymmetries between the gain context and the loss context. The present event-related potential study investigated the effects of contextual valence on neural dynamics underlying magnitude and time, two important reward dimensions, during feedback evaluation. Forty-two participants performed a simple guessing task in which they experienced both a gain context wherein high or low rewards were delivered immediately or six months later, and a loss context wherein high or low losses were delivered in the same way. Results showed that in the gain context, time and magnitude information were processed in a parallel way during the time windows of the reward positivity (RewP) and the P3. In the loss context, however, time and magnitude information were processed in a serial way such that time information was encoded during the RewP and P3 periods, whereas magnitude information was not tracked until the time window of the late positive potential. Our findings suggest that the neural dynamics underlying time and magnitude information are distinct between the gain and loss contexts, thus providing a novel perspective for the well-known gain-loss asymmetry.

The Use of Cytotoxic Drugs as First Line Chemotherapy for EGFR (+) Nonsquamous NSCLC: A Network Meta-Analysis.

Objective: To assess the use of cytotoxic drugs as first-line chemotherapy for nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutation. Method: This study uses the network meta-analysis (NMA) method, with the inclusion of prospective randomized control studies related to the treatment of EGFR-positive nonsquamous NSCLC, to compare the efficacy of various EGFR-TKIs. As of September 4, 2022, 16 studies on a total of 4180 patients were included. The retrieved literature was comprehensively evaluated as per the established inclusion and exclusion criteria, and valid data were extracted and included for analysis. Results: The 6 treatment regimens included cetuximab, CTX (cyclophosphamide), icotinib, gefitinib, afatinib, and erlotinib. All of the 16 studies reported their findings about overall survival (OS), and 15 of them also reported findings about progression-free survival (PFS). The NMA results showed that there was no significant difference in OS among the 6 treatment regimens. It was observed that erlotinib had the highest likelihood of obtaining the best OS, followed by afatinib, gefitinib, icotinib, CTX, and cetuximab, in descending order. This indicates that the highest possibility of achieving the best OS was with erlotinib, while the lowest was with cetuximab. The NMA results also showed that the PFS achieved with treatment using afatinib, erlotinib, and gefitinib were all higher than that with treatment using CTX, with statistically significant differences. The results showed that there was no significant difference in PFS among erlotinib, gefitinib, afatinib, cetuximab, and icotinib. CTX, cetuximab, icotinib, gefitinib, afatinib, and erlotinib were ranked in descending order based on the PFS indicator SUCRA values, which implied that erlotinib had the highest possibility in achieving the best PFS, while CTX had the lowest. Discussion. EGFR-TKIs must be carefully selected for the treatment of different histologic subtypes of NSCLC. For EGFR mutation (+) nonsquamous NSCLC, erlotinib is most likely to achieve the best OS and PFS, which makes it the first choice in the formulation of a treatment plan.

Fucosyltransferase 8 is Overexpressed and Influences Clinical Outcomes in Lung Adenocarcinoma Patients.

Background: Lung adenocarcinoma (LUAD), the most prevalent type of lung cancer, is often metastatic and has a poor prognosis. Recent studies have demonstrated an important role for fucosyltransferase 8 (FUT8) in carcinogenesis and cancer progression. Methods: A meta-analysis with 15 eligible datasets from Gene Expression Omnibus (GEO) was performed to explore the expression of FUT8 in LUAD. The results were further verified in The Cancer Genome Atlas (TCGA) database, followed by survival analysis using Kaplan-Meier plotter. We also validated the protein expression of FUT8 by immunohistochemistry (IHC). In vitro experiments were conducted to determine the biological effects of FUT8 in LUAD cells. Results: The meta-analysis showed the FUT8 expression in LUAD tissues was significantly higher than those in normal lung tissues [standard mean difference (SMD): 1.40; 95% confidence interval (CI): .95-1.85]. The results of TCGA database verified the expression of FUT8 increased in LUAD tissues versus normal tissues. IHC analyses indicated that the protein levels of FUT8 were up-regulated in LUAD, and elevated FUT8 expression was significantly correlated with poor prognosis in LUAD patients. Multivariable Cox regression analysis revealed that FUT8 expression was an independent prognostic factor. Besides, in vitro experiments showed that knockdown of FUT8 in LUAD cells markedly restrained cell proliferation, and stimulated cell apoptosis. Conclusion: This study indicates that increased FUT8 expression is correlated with shortened survival of LUAD patients and might favor the progression of the disease.

MECOM/PRDM3 and PRDM16 Serve as Prognostic-Related Biomarkers and Are Correlated With Immune Cell Infiltration in Lung Adenocarcinoma.

BACKGROUND: The MDS1 and EVI1 complex locus (MECOM, also called PRDM3) and PR domain containing 16 (PRDM16) are two highly related zinc finger transcription factors associated with many malignancies. However, the mechanisms of MECOM and PRDM16 in prognosis and tumor immune infiltration in lung adenocarcinoma (LUAD) remain uncertain. METHODS: The Cancer Genome Atlas (TCGA), Oncomine, UALCAN, GEPIA, and TIMER databases were searched to determine the relationship between the expression of MECOM and PRDM16, clinicopathological features, immune infiltration, and prognosis in LUAD. Coexpressed genes of the two genes were investigated by CBioPortal, and the potential mechanism of MECOM- and PRDM16-related genes was elucidated by GO and KEGG analyses. STRING database was utilized to further construct the protein-protein interaction network of the coexpressed genes, and the hub genes were identified by Cytoscape. Finally, qRT-PCR was performed to identify the mRNA levels of the target genes in LUAD. RESULTS: mRNA levels of MECOM and PRDM16 were downregulated in LUAD (p < 0.05), and the low expression of the two genes was associated with the age, gender, smoking duration, tissue subtype, poor stage, nodal metastasis status, TP53 mutation, and prognosis in LUAD (p < 0.05). MECOM and PRDM16 were also found to be correlated with the expression of a variety of immune cell subsets and their markers. KEGG analysis showed that both of them were mainly enriched in the cell cycle, cellular senescence, DNA replication, and p53 signaling pathway. Importantly, the mRNA levels of the two genes were also found to be decreased in the clinical samples of LUAD by qRT-PCR. CONCLUSION: MECOM and PRDM16 may serve as potential prognostic biomarkers which govern immune cell recruitment to LUAD.

MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription.

Death receptor 4 (DR4) is a cell surface protein that is generally thought to mediate apoptosis upon binding to its ligand named TRAIL. However, its contribution to apoptosis resistance has also been reported. MET (or c-MET) gene amplification represents an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutant non-small cell lung cancer (NSCLC). This study focuses on demonstrating the impact of MET inhibition on DR4 modulation in MET-amplified EGFR mutant NSCLC cell lines and the underlying mechanisms. Several MET inhibitors decreased DR4 levels in MET-amplified HCC827 cell lines resistant to EGFR-TKIs with no or limited effects on modulating DR5 levels, while increasing DR4 levels in HCC827 parental cells and other NSCLC cell lines. MET inhibitors did not affect DR4 stability, but decreased DR4 mRNA levels with suppression of AP-1-dependent DR4 promoter transactivation. Moreover, these inhibitors suppressed ERK and c-Jun phosphorylation accompanied with decreasing c-Jun levels. Hence, it is likely that MET inhibition downregulates DR4 expression in MET-amplified EGFR mutant NSCLC cells through suppressing AP-1-mediated DR4 transcription. Osimertinib combined with MET inhibition synergistically induces apoptosis in the MET-amplified EGFR mutant NSCLC cells accompanied with augmented DR4 reduction both in vitro and in vivo. Furthermore, MET inhibition combined with TRAIL enhanced killing of MET-amplified EGFR mutant HCC827/AR cells, but not HCC827 parental cells. These data collectively suggest that DR4 may possess an unrecognized anti-apoptotic function, contributing to apoptosis resistance under given conditions.

Identification of the ferroptosis-related long non-coding RNAs signature to improve the prognosis prediction and immunotherapy response in patients with NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most prevalent type of lung carcinoma with an unfavorable prognosis. Ferroptosis is involved in the development of multiple cancers. Whereas, the prognostic value of ferroptosis-related lncRNAs in NSCLC remains uncertain. METHODS: Gene expression profiles and clinical information of NSCLC were retrieved from the TCGA database. Ferroptosis-related genes (FRGs) were explored in the FerrDb database and previous studies, ferroptosis-related lncRNAs (FRGs-lncRNAs) were identified by the correlation analysis and the LncTarD database. The differentially expressed FRGs-lncRNAs were screened and FRGs-lncRNAs associated with the prognosis were explored by univariate Cox regression analysis and Kaplan-Meier survival analysis. Then, an FRGs-lncRNAs signature was constructed and verified by the Lasso-penalized Cox analysis. Finally, the potential correlation between risk score, immune checkpoint genes, and chemotherapeutic sensitivity was further investigated. RESULTS: 129 lncRNAs with a potential regulatory relationship with 59 differentially expressed FRGs were found in NSCLC, of which 10 were related to the prognosis of NSCLC (P < 0.05). 9 prognostic-related FRGs-lncRNAs were used to construct the prognostic model and stratify NSCLC patients into high- and low-risk groups. A worse outcome was found in patients with high risk (P < 0.05). Moreover, a good predictive capacity of this signature in predicting NSCLC prognosis was confirmed. Additionally, 45 immune checkpoint genes and 4 chemotherapeutics drugs for NSCLC were identified to be correlated with the risk score. CONCLUSION: A novel FRGs-lncRNAs signature was successfully constructed, which may contribute to improving the management strategies of NSCLC.

EHF enhances malignancy by modulating AKT and MAPK/ERK signaling in non­small cell lung cancer cells.

Overexpression of ETS­homologous factor (EHF) in non­small cell lung cancer (NSCLC) is associated with poor patient prognosis. To explore the mechanism of the effect of EHF in NSCLC, EHF expression was examined in NSCLC and its role in cell proliferation, invasion, cell cycle, and apoptosis of NSCLC cells was evaluated by overexpressing EHF and/or knocking down EHF expression in NSCLC cells in vitro and in cancer cell grafted mice in vivo. The results revealed that the knockdown of EHF expression in NSCLC with siRNA significantly inhibited cell proliferation and invasion, arrested the cell cycle at the G0/G1 phase, and induced apoptosis, whereas overexpression of EHF in NSCLC promoted cell proliferation, tumor growth, and cancer cell migration in vitro. The in vivo experiments demonstrated that siRNA­mediated downregulation of EHF expression in NSCLC cells significantly suppressed tumor growth in xenografted nude mice as compared to cancer progression in the mice grafted with NSCLC cells transfected with non­specific control siRNA. The biochemical analyses revealed that EHF promoted NSCLC growth by regulating the transcription of Erb­B2 receptor tyrosine kinase 2/3 (ERBB2, ERBB3) and mesenchymal­epithelial transition (MET) factor tyrosine kinase receptors and modulating the AKT and ERK signaling pathways in the NSCLC cells. The present findings indicated that EHF could be used as a prognostic marker for NSCLC, and tyrosine kinase receptors of ERBB2, ERBB3 and MET could be drug targets for NSCLC treatment.

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated. Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored. Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways. Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.

Downregulation of death receptor 4 is tightly associated with positive response of EGFR mutant lung cancer to EGFR-targeted therapy and improved prognosis.

Death receptor 4 (DR4), a cell surface receptor, mediates apoptosis or induces inflammatory cytokine secretion upon binding to its ligand depending on cell contexts. Its prognostic impact in lung cancer and connection between EGFR-targeted therapy and DR4 modulation has not been reported and thus was the focus of this study. Methods: Intracellular protein alterations were measured by Western blotting. Cell surface protein was detected with antibody staining and flow cytometry. mRNA expression was monitored with qRT-PCR. Gene transactivation was analyzed with promoter reporter assay. Drug dynamic effects in vivo were evaluated using xenografts. Gene modulations were achieved with gene overexpression and knockdown. Proteins in human archived tissues were stained with immunohistochemistry. Results: EGFR inhibitors (e.g., osimertinib) decreased DR4 levels only in EGFR mutant NSCLC cells and tumors, being tightly associated with induction of apoptosis. This modulation was lost once cells became resistant to these inhibitors. Increased levels of DR4 were detected in cell lines with acquired osimertinib resistance and in NSCLC tissues relapsed from EGFR-targeted therapy. DR4 knockdown induced apoptosis and augmented apoptosis when combined with osimertinib in both sensitive and resistant cell lines, whereas enforced DR4 expression significantly attenuated osimertinib-induced apoptosis. Mechanistically, osimertinib induced MARCH8-mediated DR4 proteasomal degradation and suppressed MEK/ERK/AP-1-dependent DR4 transcription, resulting in DR4 downregulation. Moreover, we found that DR4 positive expression in human lung adenocarcinoma was significantly associated with poor patient survival. Conclusions: Collectively, we suggest that DR4 downregulation is coupled to therapeutic efficacy of EGFR-targeted therapy and predicts improved prognosis, revealing a previously undiscovered connection between EGFR-targeted therapy and DR4 modulation.

LncRNA MALAT1 Depressed Chemo-Sensitivity of NSCLC Cells through Directly Functioning on miR-197-3p/p120 Catenin Axis.

This study was aimed to explore if lncRNA MALAT1 would modify chemo-resistance of non-small cell lung cancer (NSCLC) cells by regulating miR-197-3p and p120 catenin (p120-ctn). Within this investigation, we totally recruited 326 lung cancer patients, and purchased 4 NSCLC cell lines of A549, H1299, SPC-A-1 and H460. Moreover, cisplatin, adriamycin, gefitinib and paclitaxel were arranged as chemotherapies, and half maximal inhibitory concentration (IC50) values were calculated to evaluate the chemo-resistance of the cells. Furthermore, mice models of NSCLC were also established to assess the impacts of MALAT1, miR-197-3p and p120-ctn on tumor growth. Our results indicated that MALAT1 and miR-197-3p were both over-expressed within NSCLC tissues and cells, when compared with normal tissues and cells (P < 0.05). The A549, H460, SPC-A-1 and SPC-A-1 displayed maximum resistances to cisplatin (IC50 = 15.70 µg/ml), adriamycin (IC50 = 5.58 µg/ml), gefitinib (96.82 µmol/L) and paclitaxel (141.97 nmol/L). Over-expression of MALAT1 and miR-197-3p, or under-expression of p120-ctn were associated with promoted viability and growth of the cancer cells (P < 0.05), and they could significantly strengthen the chemo-resistance of cancer cells (P < 0.05). MALAT1 Wt or p120-ctn Wt co-transfected with miR-197-3p mimic was observed with significantly reduced luciferase activity within NSCLC cells (P < 0.05). Finally, the NSCLC mice models were observed with larger tumor size and weight under circumstances of over-expressed MALAT1 and miR-197-3p, or under-expressed p120-ctn (P < 0.05). In conclusion, MALAT1 could alter chemo-resistance of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.

Association between Polymorphisms of Vitamin D Receptor and Lung Cancer Susceptibility: Evidence from an Updated Meta-analysis.

Purpose: The aim of this meta-analysis was to investigate polymorphism of Bsm1, Apal, Taq1 and Cdx-2 in vitamin D receptor (VDR) associations in relation to lung cancer (LC) susceptibility. Methods: 9 literatures were recruited into this meta-analysis from PubMed, PMC, Embase, Web of Science, Cochrane library and CNKI. STATA version 15.1 was used for statistical tests. The heterogeneity was tested using I2 statistics. According to the value of I2 , the random-effect model (REM) or fixed-effect model (FEM) was selected to combine data from studies, respectively. Potential publication bias was evaluated by Egger's test. Sensitivity analysis was also performed to evaluate the stability and reliability in results. Results: Decreased susceptibility of LC was found in all genetic models contrast in Bsm1 gene of VDR (a vs. A: OR = 0.62, 95 % CI = 0.44-0.87; aa vs. AA: OR = 0.76, 95 % CI = 0.60-0.96; Aa vs. AA: OR = 0.59, 95 % CI = 0.39-0.88; aa vs. AA+Aa: OR = 0.80, 95 % CI = 0.64-0.99; Aa+aa vs. AA: OR = 0.57, 95 % CI = 0.37-0.86). The similar results were also found in partial genetic models of Taq1 (a vs. A: OR = 0.88, 95 % CI = 0.79-0.98; aa vs. AA+Aa: OR = 0.84, 95 % CI = 0.73-0.98) and Cdx-2 (Aa vs. AA: OR = 0.80, 95 % CI = 0.66-0.98; Aa+aa vs. AA: OR = 0.79, 95 % CI = 0.65-0.96). Likewise, significant correlation between Bsm1, Taq1 polymorphism and LC risk was detected among Asians. Cdx-2 polymorphism was considered as a protective factor in Caucasians, whereas no association of Apal polymorphism with LC risk was observed in Asians and Caucasians for all genetic models. Conclusion: The results of this meta-analysis suggested that Bsm1, Taq1 and Cdx-2 polymorphism may contribute to lung cancer susceptibility, more studies need be conducted to confirm in the future.