POLRMT over-expression is linked to WNT/beta-catenin signaling, immune infiltration, and unfavorable outcomes in lung adenocarcinoma patients.

BACKGROUND: Mitochondrial RNA polymerase (POLRMT) is essential for the expression of mitochondrial genes. In recent studies, POLRMT expression promoted non-small cell cancer cell proliferation in cell lines and xenografts. The present study investigated the impact of POLRMT expression and function on lung adenocarcinoma (LUAD) patients. METHOD: Multi-omics data (genomics, transcriptomics, and proteomics) from publicly available databases were used to assess the role of POLRMT expression and function in LUAD. These findings were further verified using cancer tissues from clinical samples. RESULTS: POLRMT was over-expressed in LUADs, with mutation frequencies ranging from 1.30% to 5.71%. Over-expression of POLRMT was associated with an abnormal clinicopathological condition resulting in a decreased lifespan. Furthermore, gene sets enrich analysis revealed that POLRMT expression was linked to WNT/beta-catenin signaling; the expression of downstream target genes was positively correlated with POLRMT expression. Also, POLRMT expression was positively correlated with immunosuppressive genes, thereby affecting immune infiltration. CONCLUSION: POLRMT is over-expressed in LUAD, thereby impacting patient survival. It is also involved in WNT/beta-catenin signaling and may affect tumor infiltration.

TPD52L2 Is a Prognostic Biomarker and Correlated With Immune Infiltration in Lung Adenocarcinoma.

Tumor protein D52-like 2 (TPD52L2) belongs to the members of the TPD52 family. TPD52L2 was reported to regulate proliferation and apoptosis in cancer cells. However, its role in lung adenocarcinoma (LUAD) was uncertain. We evaluated the expression, methylation, copy number alteration, and prognostic significance of TPD52L2 using RNA-seq data from The Cancer Genome Atlas (TCGA). Enrichment analysis of TPD52L2 was conducted using the R package "clusterProfiler." We further assessed the association between TPD52L2 and immune cell infiltration level, immunosuppressive genes, and tumor mutational burden (TMB). The difference of gene mutant frequency in high- and low-TPD52L2 groups was also analyzed. The results showed that TPD52L2 was over-expressed and predicted worse survival status in LUAD. We also found that TPD52L2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and negatively correlated with immune killer cells, such as CD8+ T and NK cells in pan-cancer, including LUAD. In addition, TPD52L2 expression was associated with immunosuppressive genes and TMB. High expression of TPD52L2 was with more mutant frequency of TP53. In summary, our results show that TPD52L2 is an oncogene and a potential prognostic biomarker in LUAD. High TPD52L2 expression is a possible indicator of immune infiltration and associated with tumor immunosuppressive status in LUAD.

FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer.

Background: The expression of Fucosidase, alpha-L-2 (FUCA2) varies across tumors. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) is poorly defined. Methods: We analyzed profiles of FUCA2 expression using datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Next, gene alteration, clinical characteristics and prognostic values of FUCA2 were elucidated based on TCGA pan-cancer data. This was followed by gene set enrichment analysis by R software. Relationships between FUCA2 expression and immune infiltration and immune-related genes were also evaluated. Moreover, the association of immune cell infiltration with FUCA2 expression was evaluated across three different sources of immune cell infiltration data, namely the TIMER online, ImmuCellAI databases, as well as a published study. In addition, MTT assays was also conducted to validate the oncogene role of FUCA2 in lung cancer cells. Results: FUCA2 was upregulated in most tumors, and this was significantly associated with poor survival rates. Gene set enrichment analysis uncovered that FUCA2 correlated with immune pathways in different tumor types. FUCA2 expression was positively related to tumor associated macrophages (TAMs), especially M2-like TAMs. Moreover, FUCA2 level showed a positive relationship with most immunosuppression genes, including programmed death-ligand 1 (PD-L1), transforming growth factor beta 1 (TGFB1), and interleukin-10 (IL10) in most cancer types. FUCA2 knockdown inhibited the cell viability in lung cancer cells. Conclusions: Our study reveals that FUCA2 is a potential oncogene and is indicative biomarker of a worse prognosis in pan-cancer. High FUCA2 expression may contribute to increased infiltration of TAMs and associates with an immunosuppressive microenvironment, providing a potential target for tumor therapy.

A novel GHR-ALK fusion gene in a patient with metastatic lung adenocarcinoma and its response to crizotinib: a case report.

Anaplastic lymphoma kinase (ALK) rearrangement occurs in approximately 5% of non-small cell lung cancers (NSCLCS), and EML4-ALK is the most commonly observed ALK fusion variant in NSCLC. However, growth hormone receptor (GHR) as the fusion partner for ALK and the clinical response to ALK tyrosine kinase inhibitors in patients with metastatic lung adenocarcinoma (LUAD) who carry the GHR-ALK variant have not been documented. This case describes a 63-year-old woman diagnosed with metastatic LUAD. Immunohistochemistry revealed positive ALK expression, and the patient was treated with crizotinib. After 3 weeks of treatment, the patient had a partial response. Because of treatment-related adverse events, the dose of crizotinib was reduced. After 3.7 months, computed tomography uncovered disease progression. Next-generation sequencing identified a novel GHR-ALK fusion in the plasma of the patient. The patient was treated again with crizotinib, but the disease progressed again 2 months later. Then, the patient received chemotherapy. She succumbed to her disease 11 months after the initial diagnosis. Our work provides evidence supporting the use of crizotinib in patients with metastatic LUAD harboring GHR-ALK.

Metabolomics Analysis on Obesity-Related Obstructive Sleep Apnea After Weight Loss Management: A Preliminary Study.

Objective: Roux-en-Y gastric bypass (RYGB) surgery is an effective type of weight loss management and may improve obesity-related obstructive sleep apnea (OSA). Obese subjects who meet the criteria for surgery with OSA were enrolled. We investigated the metabolomic effects of RYGB on OSA. Methods: Clinical data, serum measurements including indices of glycolipid metabolism, and polysomnography (PSG) measurements were collected at baseline and 6 months after RYGB surgery. Metabolomic analysis was performed using ultra-performance liquid chromatography-mass spectrometry. Results: A group of 37 patients with obesity, type 2 diabetes (T2DM) and suspected OSA were enrolled of which 27 were OSA subjects. After RYGB surgery, metabolic outcomes and sleep parameters were all significantly improved. The OSA remission group had lower valine, isoleucine, and C24:1(cis-15) levels, and higher trimethylamine N-oxide, hippurate, and indole-3-propionic acid levels after RYGB surgery. A combination of preoperative indices (age, apnea-hypopnea index (AHI), fasting C-peptide level, and hippurate level) predicted the RYGB effect size in obese patients with T2DM and OSA, with an area under receiver operating characteristic curve of 0.947, specificity of 82.4%, and sensitivity of 100%. Conclusions: RYGB surgery may significantly improve the metabolic status of patients with obesity, T2DM and OSA. A combination of preoperative indices (age, AHI, fasting C peptide level, and hippurate level) may be useful for predicting the effect size of RYGB in obese patients with T2DM and OSA. The mechanisms underlying OSA remission need to be explored.

The tumor suppressor p53 regulates autophagosomal and lysosomal biogenesis in lung cancer cells by targeting transcription factor EB.

The cellular protein degradation system, such as proteasomal or autophagy-lysosomal system plays an important role in the pathogenesis of a variety of human diseases including cancer. Transcription factor EB (TFEB) is a master transcriptional factor in the regulation of autophagy-lysosome pathway (ALP), and it has multiple biological functions including protein degradation, cell homeostasis and cell survival. In the present study we show that the tumor suppressor p53 can regulate TFEB nuclear translocation and activity in lung cancer cells. We found p53 deletion or chemical inhibition of p53 using pifithrin-α could promote the translocation of TFEB from cytoplasm to the nucleus, thus increased the TFEB-mediated lysosomal and autophagosomal biogenesis in lung cancer cells. Moreover, re-expression of p53 could decrease the expression levels of TFEB-targeting genes involved in ALP, and knockdown of TFEB could abolish the effect of p53 on the regulation of ALP gene expression. Taken together, our data indicate that p53 affects ALP through regulating TFEB nuclear translocation in lung cancer cells. Importantly, our study reveals a critical link between two keys factors in tumourigenesis and autophagy, and suggests a potential important role of p53-TFEB signaling axis in lung cancer.

Increased soluble and membrane-bound PD-L1 contributes to immune regulation and disease progression in patients with tuberculous pleural effusion.

Soluble and membrane-bound programmed death ligand-1 (sPD-L1 and mPD-L1, respectively) have been demonstrated to participate in the immune suppression of non-small cell lung cancer. However, the contribution of sPD-L1 and mPD-L1 to immune regulation and disease progression in patients with pleural effusions remains unknown. The present study evaluated the levels of sPD-L1 and membrane-bound PD-1/PD-L1 in the peripheral blood and pleural effusions of patients with tuberculous pleural effusion (TPE), malignant pleural effusion (MPE) and non-tuberculous non-malignant pleural effusion (n-TB n-M). Furthermore, selected T lymphocytes and cluster of differentiation (CD)14+ monocytes were co-cultured to investigate the potential effect of the PD-1/PD-L1 pathway in TPE. Levels of sPD-L1 and PD-L1 on CD14+ monocytes were increased in the TPE group, as compared with the MPE and n-TB n-M groups. Furthermore, sPD-L1 levels and the expression levels of PD-L1 on CD14+ monocytes were demonstrated to be positively correlated with interferon (IFN)-γ concentration in pleural effusions. Therefore, IFN-γ may increase the expression of PD-L1 on CD14+ monocytes in vitro. Cell counting kit-8 analysis demonstrated that anti-PD-L1 antibody was able to partially reverse the proliferation of T lymphocytes in the co-culture system. The results of the present study indicated that sPD-L1 or mPD-L1 are associated with the immune regulation and disease progression of TPE, and may serve as possible biomarkers of TPE. Furthermore, sPD-L1 and the PD-1/PD-L1 pathway of TPE may be associated with the Th1 immune response; therefore, an anti-PD-1/PD-L1 pathway suggests a potential immune therapy strategy for the treatment of TPE.

Roles of interleukin (IL)-6 gene polymorphisms, serum IL-6 levels, and treatment in obstructive sleep apnea: a meta-analysis.

BACKGROUND: Inconsistent results regarding the relationship between interleukin (IL)-6 gene polymorphisms, serum IL-6 levels, and the treatment in obstructive sleep apnea (OSA) have been reported. This meta-analysis assessed the associations between IL-6 gene polymorphisms and OSA susceptibility, IL-6 levels in OSA, and CPAP (continuous positive airway pressure) and T&A (tonsillectomy and adenoidectomy) therapy for IL-6 in OSA. METHODS: Studies regarding IL-6 polymorphisms, serum IL-6 levels, and OSA treatment were identified using PubMed and Embase. The associations between IL-6 gene polymorphisms and OSA risk (estimated by pooling odds ratios (ORs) with 95 % confidence intervals (CIs)) were assessed using an allele model. The pooled standardized mean differences (SMDs) with 95 % CI of IL-6 were estimated using a random-effects model. Meta-regression, sensitivity analysis, and publication bias were also evaluated. RESULTS: In total, 53 studies were included. In adults, a significant association between -174 G/C and OSA susceptibility was observed (OR = 1.46, 95 % CI = 1.14-1.87) and IL-6 levels were higher in OSA compared to controls (SMD = 1.56, 95 % CI = 1.18-1.95); however, no association was observed for the -572 G/C allele (OR = 1.13, 95 % CI = 0.87-1.47) and OSA susceptibility and there was no significant change in IL-6 in pre- and post-CPAP therapy (SMD = -0.24, 95 % CI = -0.73 to 0.26). In children, IL-6 levels were also higher in OSA (SMD = 1.27, 95 % CI = 0.29-2.26) and T&A treatment significantly decreased them (SMD = -0.97, 95 % CI = -1.72 to -0.22). CONCLUSIONS: This meta-analysis indicates that the IL-6 gene polymorphism -174 G/C, and not -572 G/C, is associated with adult OSA risk. Although IL-6 levels increased in OSA, CPAP did not significantly suppress them in adults with OSA. In children with OSA, IL-6 levels also increased and T&A therapy significantly decreased them.

Prognostic value of programmed cell death-ligand 1 expression in patients with non-small-cell lung cancer: evidence from an updated meta-analysis.

BACKGROUND: The association between the expression of programmed cell death-ligand 1 (PD-L1) and survival in patients with non-small-cell lung cancer (NSCLC) is controversial. Thus, we conducted a meta-analysis of all available studies to evaluate the prognostic role of PD-L1 expression in NSCLC. MATERIALS AND METHODS: PubMed, Embase, and Chinese (China National Knowledge Infrastructure and Wanfang) databases were searched to identify all eligible studies evaluating PD-L1 expression and the survival of NSCLC patients. Hazard ratios (HRs) and 95% confidence interval (CI) used to assess overall survival were extracted and pooled. Subgroup, sensitivity, and publication-bias analyses were also performed. RESULTS: Eleven articles reporting 12 studies that included a total of 1,653 patients met the inclusion criteria and were included in the meta-analysis. Higher PD-L1 expression did not correlate with prognosis in terms of overall survival in patients with NSCLC (HR =1.21, 95% CI: 0.85-1.71, P=0.29). However, a subgroup analysis showed a significant association between PD-L1 expression and poor prognosis in Chinese patients with NSCLC (HR =1.55, 95% CI: 1.04-2.29, P=0.03). The sensitivity analysis showed that the pooled results were not affected by the removal of any single study. There was also no significant publication bias. CONCLUSION: Our meta-analysis indicated no statistically significant difference between PD-L1 expression and prognosis for patients with NSCLC. Additional, high-quality studies with larger sample sizes are needed to determine the prognostic value of PD-L1 expression in NSCLC.

-148 C/T polymorphism of Axin2 contributes to a decreased risk of cancer: evidence from a meta-analysis.

Several studies have reported an association between -148 C/T polymorphism of Axis inhibition protein 2 (Axin2) and cancer risk; however, the results are inconsistent. In this study, a meta-analysis was performed to assess the association between -148 C/T polymorphism of Axin2 and susceptibility to cancer. Published case-control and cohort-based studies from PubMed, Embase, Wanfang, and CNKI were retrieved, and data were manually extracted. The odds ratios (ORs) and 95% confidence intervals (CIs) of the included studies were pooled. Begg's and Egger's tests were used to evaluate publication bias. Cumulative and recursive cumulative meta-analyses (CMA) were performed as evidence accumulated to investigate the trends and stability of the effect size. Nine articles with 1,664 cases and 1,796 controls were included. The pooled effect size showed an association between -148 C/T polymorphism and the risk of cancer (dominant model, OR: 0.72, 95% CI: 0.63-0.83; allele model, OR: 0.81, 95% CI: 0.73-0.90). CMA showed an association trend, and the recursive CMA indicated that more evidence is needed to make conclusions about significance. In a subgroup analysis, a significant association between -148 C/T polymorphism and low cancer susceptibility was detected for lung cancer (dominant model, 0.69, 95% CI: 0.56-0.85; recessive model, OR: 0.75, 95% CI: 0.56-0.99; allele model, 0.76, 95% CI: 0.66-0.86). The -148 C/T polymorphism was also associated with low cancer susceptibility among Asians (dominant model, OR: 0.68, 95% CI: 0.57-0.81; recessive model, OR: 0.75, 95% CI: 0.56-0.99; allele model, OR: 0.76, 95% CI: 0.66-0.86). The Axin2 -148 C/T polymorphism was found to be significantly associated with a decreased risk of cancer, particularly lung cancer, in Asians and population-based controls. Thus, Axin2 should be considered as a potential therapeutic target for preventing tumor growth.

The efficacy and safety of pemetrexed-based doublet therapy compared to pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer: an updated meta-analysis.

BACKGROUND: Pemetrexed is currently recommended as the second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether pemetrexed-based doublet therapy improves treatment efficacy and safety. Thus, this meta-analysis was performed to resolve this controversial question. METHODS: Electronic databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles before April 2015. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) were used to analyze the overall response rate (ORR) and grade ≥3 toxicities. Subgroup analysis, sensitivity analysis, and publication bias were also evaluated. RESULTS: A total of 2,519 patients from ten randomized controlled trials were included. Compared to pemetrexed alone, PFS and ORR significantly improved in the pemetrexed-based doublet group (HR, 0.86; 95% CI [confidence interval], 0.75-0.99; P=0.038; and OR, 1.98; 95% CI, 1.25-3.12; P=0.003, respectively). However, no statistically significant differences in OS were observed between groups (HR, 0.92; 95% CI, 0.83-1.02; P=0.132). In addition, subgroup analyses indicated that improved OS was only observed in nonsquamous NSCLC patients who received the combination of pemetrexed and erlotinib. An increasing incidence of grade ≥3 neutropenia and thrombocytopenia was observed in the pemetrexed-based doublet group. CONCLUSION: Among patients with advanced NSCLC, pemetrexed-based doublet treatment tended to be associated with improved PFS, ORR, and increased toxicity, but not OS.

An updated meta-analysis of the association between tumor necrosis factor-α -308G/A polymorphism and obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Several studies have reported that the tumor necrosis factor-α (TNF-α) -308G/A polymorphism is associated with susceptibility to obstructive sleep apnea-hypopnea syndrome (OSAHS). However, these results are controversial and conflicting. OBJECTIVE: To evaluate the association between TNF-α-308G/A and OSAHS risk by meta-analysis. METHODS: Electronic databases, including PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu, were searched to identify relevant studies. Data were extracted from the included studies. A model-free approach using odds ratio (OR), generalized odds ratio (ORG) and 95% confidence interval (CI) of the allele contrast to assess the association between the -308G/A polymorphism and OSAHS risk. Cumulative and recursive cumulative meta-analyses (CMA) were also carried out to investigate the trend and stability of effect sizes as evidence accumulated. RESULTS: Seven studies including 1369 OSAHS patients and 1064 controls were identified in this meta-analysis. Significant associations were derived from the variants of the allele contrast [(OR, 1.78; 95% CI, 1.45-2.18) or (ORG, 2.01; 95% CI, 1.27-3.19). CMA showed a trend of an association. Recursive CMA indicated that more evidence is needed to conclude on the status of significance. No significant publication bias was found. CONCLUSIONS: Our meta-analysis suggested that the TNF-α-308G/A polymorphism contribute to the risk of OSAHS. Further studies with larger sample should be performed to confirm our findings.