For never-smokers (smoked <100 lifetime cigarettes), lung cancer (LC) has emerged as an important issue. We aimed to investigate the effects of prevalence changes in tobacco smoking and particulate ...matter (PM) 2.5 (PM2.5) levels on LC in Taiwan, in relation to contrasting PM2.5 levels, between Northern Taiwan (NT) and Southern Taiwan (ST).
We reviewed 371,084 patients with LC to assess smoking prevalence and correlations between the incidence of adenocarcinoma lung cancer (AdLC) and non-AdLC. Two subsets were selected to assess different AdLC stage trends and the effect of PM2.5 on survival of patients with AdLC.
From 1995 to 2015, the proportion of male adult ever-smokers decreased from 59.4% to 29.9% whereas the female smoking rate remained low (3.2% to 5.3%). AdLC incidence in males and females increased from 9.06 to 23.25 and 7.05 to 24.22 per 100,000 population, respectively. Since 1993, atmospheric visibility in NT improved (from 7.6 to 11.5 km), but deteriorated in ST (from 16.3 to 4.2 km). The annual percent change in AdLC stages IB to IV was 0.3% since 2009 (95% confidence interval CI: -1.9%–2.6%) in NT, and 4.6% since 2007 (95% CI: 3.3%–5.8%) in ST; 53% patients with LC had never smoked. Five-year survival rates for never-smokers, those with EGFR wild-type genes, and female patients with AdLC were 12.6% in NT and 4.5% in ST (hazard ratio: 0.79, 95% CI: 0.70–0.90).
In Taiwan, greater than 50% of patients with LC had never smoked. PM2.5 level changes can affect AdLC incidence and patient survival.
RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal ...lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21
expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21
up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.
The impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) ...patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR-mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR-mutant NSCLC patients with acquired T790M mutation.
Pleural effusion is a rare immune-related adverse event for lung cancer patients receiving immune checkpoint inhibitors (ICIs). We enrolled 281 lung cancer patients treated with ICIs and 17 were ...analyzed. We categorized the formation of pleural effusion into 3 patterns: type 1, rapid and massive; type 2, slow and indolent; and type 3, with disease progression. CD4/CD8 ratio of 1.93 was selected as the cutoff threshold to predict survival. Most patients of types 1 and 2 effusions possessed pleural effusion with CD4/CD8 ratios ≥ 1.93. The median OS time in type 1, 2, and 3 patients were not reached, 24.8, and 2.6 months, respectively. The median PFS time in type 1, 2, and 3 patients were 35.5, 30.2, and 1.4 months, respectively. The median OS for the group with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were not reached and 2.6 months. The median PFS of those with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were 18.4 and 1.2 months. In conclusion, patients with type 1 and 2 effusion patterns had better survival than those with type 3. Type 1 might be interpreted as pseudoprogression of malignant pleural effusion. CD4/CD8 ratio ≥ 1.93 in pleural effusion is a good predicting factor for PFS.
It remains unclear how programmed death-ligand 1 (PD-L1) expression interacts with anaplastic lymphoma kinase (ALK) mutation, its variants, and the outcome of treatment. One hundred and twenty four ...out of 1255 patients (9.9%) were deemed ALK-positive by the Ventana IHC assay. PD-L1 status and ALK variants were available in 100 and 59 patients, respectively. PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rate was 50% and 16%, respectively. A total of 64 variant types were detected in 59 patients. V1 (32.8%) and V3a/b (28.1%) were the most common variants. There was no significant association between ALK variants and the PD-L1 expression. The presence of V3a/b subtype independently predicted a worse overall survival in patients receiving ALK inhibitor(s) (aHR 5.10 95% CI 1.22-21.25, P = 0.025) and platinum plus pemetrexed (aHR 9.62 95% CI 1.90-48.80, P = 0.006). While incorporating ALK variants and PD-L1 expression together, patients with non-V3a/b/positive PD-L1 showed a trend towards longer OS. In conclusion, ALK-positive NSCLC patients possess a high PD-L1 expression rate. Although there was no significant association between PD-L1 expression and ALK variants, the outcome of ALK-positive patients could be sorted by these two biomarkers.
The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell ...Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.
In this study, we firstly showed that p53 transcriptionally represses Aurora‐A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin ...immunoprecipitation assay indicated that p53 physically bound to the Aurora‐A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora‐A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides −360 to −354 (CCTGCCC), upstream of the Aurora‐A transcriptional start site, was responsible for the p53‐mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora‐A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53‐HDAC1‐mSin3a complex with the nucleotides −365∼‐345 region, and enhanced the Aurora‐A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53‐HDAC1‐mSin3a repressive complex onto this promoter region and elevated the Aurora‐A promoter activity and gene expression. Moreover, the p53‐HDAC1‐mSin3a repressive complex also involved in the inhibition of Aurora‐A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora‐A and p53 exhibited an inverse correlation in both the expression level and prognostic status, and the low p53/high Aurora‐A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora‐A gene expression in NSCLC cells.
What's new?
Many types of cancer feature a boost in production of the kinase Aurora‐A, and several studies have implicated the protein in transformation and tumorigenesis. Some evidence suggests that p53 affects Aurora‐A expression, and in this study, the authors set out to describe that relationship. They found that p53 binds directly to the Aurora‐A promoter, repressing transcription. Next, they showed that treatment with trichostatin A thwarts this repression, allowing Aurora‐A transcription to proceed. Clinical investigation revealed that lung cancer patients with low p53 and high Aurora‐A expression had the worst prognosis.
The current study investigated the effect of chlorogenic acid, a polyphenolic compound found in numerous plant products, on a kainic acid-induced seizure rat model and its potential mechanism. Rats ...were administered chlorogenic acid (10 and 50 mg/kg) intraperitoneally for 30 min before kainic acid (15 mg/kg) intraperitoneal administration. Pretreatment with chlorogenic acid decreased the seizure score, increased the latency to onset of the first seizure, and decreased the mortality rate. Chlorogenic acid pretreatment also resulted in a significant reduction in glutamate elevation and neuronal death in the hippocampus of kainic acid-treated rats. In addition, electron microscopy revealed that kainic acid-induced changes in hippocampal mitochondrial structure were prevented by chlorogenic acid pretreatment. Additionally, the levels of mitochondrial function-related proteins, including sirtuin 3, Complex I, glutamate dehydrogenase 1 and ATP synthase, were increased, and the level of the mitochondrial damage marker cytochrome C was decreased in the hippocampus of chlorogenic acid/kainic acid rats. Furthermore, the expression of mitochondrial biogenesis-related proteins AMP-activated protein kinase (AMPK), sirtuin1, and peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) and mitophagy-related proteins phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), Parkin, and microtubule-associated protein 1 light chain 3 (LC3) was decreased in the hippocampus of kainic acid-treated rats, which was reversed by chlorogenic acid pretreatment. These observations reveal the marked neuroprotective potential of chlorogenic acid against kainic acid-induced neurotoxicity and seizures through prevention of glutamate increase and preservation of AMPK/sirtuin 1/PGC-1α-mediated mitochondrial biogenesis and PINK1/Parkin-induced mitophagy to maintain adequate mitochondrial homeostasis and function.
We aimed to evaluate whether different driver mutations have varying impacts on the programmed cell death-ligand 1 (PD-L1) expression of non-small cell lung cancer (NSCLC), and whether the prognostic ...roles of PD-L1 amongst our patients were divergent. This was a single-institute study that included patients with NSCLC. Six driver mutations, PD-L1 status, and the outcomes of treatment were assessed. A total of 1,001 NSCLC patients were included for analysis. Overall, the PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rates were 52.2% and 17.3%, respectively. As compared with wild type lung adenocarcinoma, EGFR-mutant and HER2-mutant patients had similarly low PD-L1 and strong PD-L1 positive rates. BRAF-mutant patients had numerically higher PD-L1 and strong PD-L1 positive rates. Patients with fusion mutation (ALK and ROS1) (aOR 2.32 95% CI 1.10-4.88, P = 0.027 and 2.33 95% CI 1.11-4.89, P = 0.026), KRAS mutation (aOR 2.58 95% CI 1.16-5.75, P = 0.020 and 2.44 95% CI 1.11-5.35, P = 0.026), and non-adenocarcinoma histology (aOR 2.73 95% CI 1.72-4.34, P < 0.001 and 1.93 95% CI 1.13-3.30, P = 0.016) all had significantly higher PD-L1 and strong PD-L1 positive rates. A trend towards longer survival was noted in ROS-1 rearranged and KRAS-mutant patients with strong PD-L1 expression who had received crizotinib and chemotherapy, respectively. In conclusion, individual driver mutations had various impacts on the PD-L1 expression of NSCLC patients. The prognostic role of PD-L1 may also be divergent amongst patients harboring different driver mutations.
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