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In recent years, protein homeostasis imbalance caused by endoplasmic reticulum stress has become a major hallmark of cancer. Studies have shown that endoplasmic reticulum stress is closely related to the occurrence, development, and drug resistance of non-small cell lung cancer, however, the role of various endoplasmic reticulum stress-related genes in non-small cell lung cancer is still unclear. In this study, we established an endoplasmic reticulum stress scores based on the Cancer Genome Atlas for non-small cell lung cancer to reflect patient features and predict prognosis. Survival analysis showed significant differences in overall survival among non-small cell lung cancer patients with different endoplasmic reticulum stress scores. In addition, endoplasmic reticulum stress scores was significantly correlated with the clinical features of non-small cell lung cancer patients, and can be served as an independent prognostic indicator. A nomogram based on endoplasmic reticulum stress scores indicated a certain clinical net benefit, while ssGSEA analysis demonstrated that there was a certain immunosuppressive microenvironment in high endoplasmic reticulum stress scores. Gene Set Enrichment Analysis showed that scores was associated with cancer pathways and metabolism. Finally, weighted gene co-expression network analysis displayed that CAV1 was closely related to the occurrence of non-small cell lung cancer. Therefore, in order to further analyze the role of this gene, Chinese non-smoking females were selected as the research subjects to investigate the relationship between CAV1 rs3779514 and susceptibility and prognosis of non-small cell lung cancer. The results showed that the mutation of rs3779514 significantly reduced the risk of non-small cell lung cancer in Chinese non-smoking females, but no prognostic effect was found. In summary, we proposed an endoplasmic reticulum stress scores, which was an independent prognostic factor and indicated immune characteristics in the microenvironment of non-small cell lung cancer. We also validated the relationship between single nucleotide polymorphism locus of core genes and susceptibility to non-small cell lung cancer.

Hypoxia exerts a profound influence on the tumor microenvironment and immune response, shaping treatment outcomes and prognosis. Utilizing consistency clustering, we discerned two hypoxia subtypes in OPSCC bulk sequencing data from GEO. Key modules within OPSCC were identified through weighted gene correlation network analysis (WGCNA). Core modules underwent CIBERSORT immune infiltration analysis and GSEA functional enrichment. Univariate Cox and LASSO analyses were employed to construct prognostic models for seven hypoxia-related genes. Further investigation into clinical characteristics, the immune microenvironment, and TIDE algorithm prediction for immunotherapy response was conducted in high- and low-risk groups. scRNA-seq data were visually represented through TSNE clustering, employing the scissors algorithm to map hypoxia phenotypes. Interactions among cellular subpopulations were explored using the Cellchat package, with additional assessments of metabolic and transcriptional activities. Integration with clinical data unveiled a prevalence of HPV-positive patients in the low hypoxia and low-risk groups. Immunohistochemical validation demonstrated low TDO2 expression in HPV-positive (P16-positive) patients. Our prediction suggested that HPV16 E7 promotes HIF-1α inhibition, leading to reduced glycolytic activity, ultimately contributing to better prognosis and treatment sensitivity. The scissors algorithm effectively segregated epithelial cells and fibroblasts into distinct clusters based on hypoxia characteristics. Cellular communication analysis illuminated significant crosstalk among hypoxia-associated epithelial, fibroblast, and endothelial cells, potentially fostering tumor proliferation and metastasis.

Abstract Introduction Evidence on the willingness of men who have sex with men (MSM) with oral pre-exposure prophylaxis (PrEP) experience, especially those with suboptimal adherence, to take long-acting injectable PrEP (LAI-PrEP) is critical to guide future LAI-PrEP implementation. Objective The objective was to assess the willingness of MSM with oral PrEP experience to take LAI-PrEP. Methods MSM who participated in the China Real-world Study of Oral PrEP (CROPrEP) were enrolled in this study. Information on the willingness of MSM to take LAI-PrEP and potential correlates was collected using a structured online questionnaire. The main outcomes were the willingness of MSM to take LAI-PrEP and its association with HIV-related behaviours, sexually transmitted infections, and oral PrEP history. Logistic regression was used to identify correlates of the willingness of MSM to take LAI-PrEP. Results A total of 612 former CROPrEP participants (FCPs) were included in this study. There were 315 (51.5%) daily oral PrEP (D-PrEP) users and 297 (48.5%) event-driven oral PrEP (ED-PrEP) users at the last follow-up. Most FCPs (77.8%) were willing to take free LAI-PrEP. FCPs with no less than two sexual male partners (aOR = 1.54, [95% CI: 1.04, 2.29], P = 0.031), those with male partners with unknown HIV statuses (aOR = 2.04, [95% CI: 1.31, 3.18], P = 0.002), those with recreational drug use (aOR = 1.58, [95% CI: 1.05, 2.40], P = 0.030), and those with HSV-2 positivity (aOR = 2.15, [95% CI: 1.30, 3.57], P = 0.003) were more willing to take LAI-PrEP, while ED-PrEP users (aOR = 0.66, [95% CI: 0.45, 0.98], P = 0.037) and FCPs with suboptimal oral PrEP adherence (aOR = 0.58, [95% CI: 0.36, 0.94], P = 0.026) were less willing to take LAI-PrEP. Conclusion LAI-PrEP has good prospects for expanding PrEP coverage. However, FCPs with suboptimal oral PrEP adherence are less likely to take LAI-PrEP. Further intervention and implementation efforts are needed to improve the willingness of MSM to use LAI-PrEP, and sexual health should be considered during the discussion about PrEP initiation.

Current evidence suggests that DEP domain containing 1 (DEPDC1) has an important effect on non-small-cell lung cancer (NSCLC). However, the diagnostic value and the regulatory function within NSCLC are largely unclear. This work utilized publicly available databases and in vitro experiments for exploring, DEPDC1 expression, clinical features, diagnostic significance and latent molecular mechanism within NSCLC. According to our results, DEPDC1 was remarkably upregulated in the tissues of NSCLC patients compared with non-carcinoma tissues, linked with gender, stage, T classification and N classification based on TCGA data and associated with smoking status and stage according to GEO datasets. Meanwhile, the summary receiver operating characteristic (sROC) curve analysis result showed that DEPDC1 had a high diagnostic value in NSCLC (AUC = 0.96, 95% CI: 0.94-0.98; diagnostic odds ratio = 99.08, 95%CI: 31.91-307.65; sensitivity = 0.89, 95%CI: 0.81-0.94; specificity = 0.92, 95%CI: 0.86-0.96; positive predictive value = 0.94, 95%CI: 0.89-0.98; negative predictive value = 0.78, 95%CI: 0.67-0.90; positive likelihood ratio = 11.77, 95%CI: 6.11-22.68; and negative likelihood ratio = 0.12, 95%CI: 0.06-0.22). Subsequently, quantitative real-time PCR (qRT-PCR) and western blotting indicated that DEPDC1 was high expressed in NSCLC cells. According to the in vitro MTS and apoptotic assays, downregulated DEPDC1 expression targeting P53 signaling pathway inhibited the proliferation of NSCLC cells while promoting apoptosis of NSCLC cells. Moreover, DEPDC1 was significantly correlated with immune cell infiltrating levels in NSCLC based on TCGA data, which were primarily associated with T cells CD4 memory activated, macrophages M1, B cells memory, mast cells resting, T cells regulatory, monocytes, and T cells CD4 memory resting. Compared with the group with high expression of DEPDC1, the group with low expression level had higher scores for immune checkpoint inhibitors (ICIs) treatment. GSEA confirmed that DEPDC1 was involved in gene expression and tumor-related signaling pathways. Finally, DEPDC1 and its associated immune-related genes were shown to be enriched in 'receptor ligand activity', 'external side of plasma membrane', 'regulation of innate immune response', and 'Epstein-Barr virus infection' pathways. The present study demonstrates that DEPDC1 may contribute to NSCLC tumorigenesis and can be applied as the biomarker for diagnosis and immunology.

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Background With the changes in social and medical environments and people’s health needs, the nursing core competency should be updated and developed promptly. This study aimed to explore the core competencies of nurses in Chinese tertiary hospitals under the new health development strategy. Methods Descriptive qualitative research was conducted using qualitative content analysis. 20 clinical nurses and nursing managers from 11 different provinces and cities were interviewed via purposive sampling. Results Data analysis revealed 27 competencies, which were grouped into three major categories according to the onion model. These categories were motivation and traits (responsibility, enterprise, etc.), professional philosophy and values (professionalism, career perception, etc.), and knowledge and skills (clinical nursing competency, leadership and management competency, etc.). Conclusion Based on the onion model, core competencies for nurses in Chinese tertiary hospitals were established, revealing three layers of core competencies and giving a theoretical reference for nursing managers to conduct competency training courses based on the competency levels.

Abstract The application of radiogenomics in oncology has great prospects in precision medicine. Radiogenomics combines large volumes of radiomic features from medical digital images, genetic data from high-throughput sequencing, and clinical-epidemiological data into mathematical modelling. The amalgamation of radiomics and genomics provides an approach to better study the molecular mechanism of tumour pathogenesis, as well as new evidence-supporting strategies to identify the characteristics of cancer patients, make clinical decisions by predicting prognosis, and improve the development of individualized treatment guidance. In this review, we summarized recent research on radiogenomics applications in solid cancers and presented the challenges impeding the adoption of radiomics in clinical practice. More standard guidelines are required to normalize radiomics into reproducible and convincible analyses and develop it as a mature field.

Targeting the tumor microenvironment is increasingly recognized as an effective treatment of advanced lung adenocarcinoma (LUAD). However, few studies have addressed the efficacy of immunotherapy for LUAD. Here, a novel method for predicting immunotherapy efficacy has been proposed, which combines single-cell and bulk sequencing to characterize the immune microenvironment and metabolic profile of LUAD. TCGA bulk dataset was used to cluster two immune subtypes: C1 with “cold” tumor characteristics and C2 with “hot” tumor characteristics, with different prognosis. The Scissor algorithm, which is based on these two immune subtypes, identified GSE131907 single cell dataset into two groups of epithelial cells, labeled as Scissor_C1 and Scissor_C2. The enrichment revealed that Scissor_C1 was characterized by hypoxia, and a hypoxic microenvironment is a potential inducing factor for tumor invasion, metastasis, and immune therapy non-response. Furthermore, single cell analysis was performed to investigate the molecular mechanism of hypoxic microenvironment-induced invasion, metastasis, and immune therapy non-response in LUAD. Notably, Scissor_C1 cells significantly interacted with T cells and cancer-associated fibroblasts (CAF), and exhibited epithelial–mesenchymal transition and immunosuppressive features. CellChat analysis revealed that a hypoxic microenvironment in Scissor_C1elevated TGFβ signaling and induced ANGPTL4 and SEMA3C secretion. Interaction with endothelial cells with ANGPTL4, which increases vascular permeability and achieves distant metastasis across the vascular endothelium. Additionally, interaction of tumor-associated macrophages (TAM) and Scissor_C1 via the EREG/EFGR pathway induces tyrosine kinase inhibitor drug-resistance in patients with LAUD. Thereafter, a subgroup of CAF cells that exhibited same features as those of Scissor_C1 that exert immunosuppressive functions in the tumor microenvironment were identified. Moreover, the key genes (EPHB2 and COL1A1) in the Scissor_C1 gene network were explored and their expressions were verified using immunohistochemistry. Finally, the metabolism dysfunction in cells crosstalk was determined, which is characterized by glutamine secretion by TAM and uptake by Scissor_C1 via SLC38A2 transporter, which may induce glutamine addiction in LUAD cells. Overall, single-cell sequencing clarifies how the tumor microenvironment affects immunotherapy efficacy via molecular mechanisms and biological processes, whereas bulk sequencing explains immunotherapy efficacy based on clinical information.

Abstract Globally, lung cancer remains one of the most prevalent malignant cancers. However, molecular mechanisms and functions involved in its pathogenesis have not been clearly elucidated. This study aimed to evaluate the specific regulatory mechanisms of exosomal miR-338-3p/CHL1/MAPK signaling pathway axis in non-small-cell lung cancer. Western blotting and qRT-PCR (reverse transcription-polymerase chain reaction) were used to determine the expression levels of CHL1 and exosomal miR-338-3p in NSCLC (non-small-cell lung cancer). The CHL1 gene was upregulated and downregulated to evaluate its functions in NSCLC progression. In vitro MTS and apoptotic assays were used to investigate the functions of CHL1 and exosomal miR-338-3p in NSCLC progression. The high-throughput sequencing was used to explore differently expressed exosomal miRNAs. The biological relationships between MAPK signaling pathway and CHL1 and exosomal miR-338-3p in NSCLC were predicted through bioinformatics analyses and verified by western blotting. Elevated CHL1 levels were observed in NSCLC tissues and cells. Upregulated CHL1 expression enhanced NSCLC cells’ progression by promoting tumor cells proliferation while suppressing their apoptosis. Conversely, the downregulation of the CHL1 gene inhibited NSCLC cells’ growth and promoted tumor cells’ apoptotic rate. Additionally, CHL1 activated the MAPK signaling pathway. Besides, we confirmed that miR-338-3p directly sponged with CHL1 to mediate tumor cells progression. Moreover, exosomal miR-338-3p serum levels in NSCLC patients were found to be low. BEAS-2B cells can transfer exosomal miR-338-3p to A549 cells and SK-MES-1 cells. In addition, elevated exosomal miR-338-3p levels significantly inhibited tumor cells proliferation and promoted their apoptosis by suppressing activation of the MAPK signaling pathway. Exosomal miR-338-3p suppresses tumor cells' metastasis by downregulating the expression of CHL1 through MAPK signaling pathway inactivation.

Abstract Objective PM2.5, which is a major contributor to air pollution, has large effects on lung cancer mortality. We want to analyse the long-term trends in lung cancer burden attributable to PM2.5 exposure and provide evidence that can be used for preventive measures and health resource planning. Methods Mortality data related to lung cancer were obtained from the Global Burden of Disease (GBD) 2019 project. A joinpoint regression analysis was used to assess the magnitude and direction of the trends in mortality from 1990 to 2019, and the age-period-cohort method was used to analyse the temporal trends in the mortality rate of lung cancer attributable to PM2.5 exposure by age, period, and cohort. Results From 1990 to 2019, the age-standardized mortality rate (ASMR) attributable to PM2.5 exposure trended slowly upwards, and the ASMR due to ambient PM2.5 exposure (APE) increased significantly, that due to household PM2.5 exposure (HPE) decreased. The longitudinal age curves show that the mortality rates due to PM2.5 exposure among younger individuals were low, and they significantly increased from their levels among those in the 45–49 age group to their levels among those in the over-85 age group. From 1990 to 2019, the period RRs due to APE increased, but those due to HPE decreased. Similar trends were observed in the cohort RRs. The overall net drift per year attributable to PM2.5 exposure was below 0. The local drift values increased with age and were above 0 for the over-80 age groups. The overall net drifts per year were above zero for APE and below zero for HPE. The corresponding results among males were higher than those among females. Conclusions In China, the type of air pollution responsible for lung cancer has changed from household air pollution to ambient air pollution. PM2.5 exposure is more harmful among males and older people. Ambient air pollution should be emphasized, and China should strengthen its implementation of effective public policies and other interventions.

Abstract Background The mechanism of rapidly increased non‐small cell lung cancer (NSCLC) among never‐smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone‐binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never‐smoking female NSCLC. Methods Candidate genes were selected by a genome‐wide association (GWAS) meta‐analysis and gene expression profiles of never‐smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two‐stage case‐control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never‐smoking Chinese women. Chi‐square test and multivariate logistic regression were applied. Results Beginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never‐smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two‐stage case‐control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15–2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02–2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients’ tumor tissues and was associated with a poor prognosis in NSCLC. Conclusion Our findings indicated that a sex hormones regulation‐related SNP rs12233719 was associated with never‐smoking female lung cancer risk, which might partially explain NSCLC‐susceptibility in Chinese women.

Candida auris is an emerging pathogenic fungal species found worldwide. Since April 2016, C. auris colonization/infection cases have been found in a general hospital in Shenyang, China. The genome-based phylogenetic studies of these isolates remain undefined. In the current study, the microbiological characteristics and antifungal susceptibility of these C. auris isolates, which were collected in Shenyang during the three-year period (2016–2018), were investigated. Whole-genome sequencing was applied to investigate the genetic variation and molecular epidemiological characteristics. A total of 93 C. auris isolates, including 92 clinical isolates and 1 environmental screening isolate were identified. Among the investigated wards, the C. auris cases were the most prevalent (97.4%, 37/38) in four intensive care units (ICUs). The Shenyang isolates carrying the VF125AL mutation in the key drug-resistance gene ERG11 were mainly fluconazole resistant and formed a distinct subclade under the South African clade according to the phylogenetic and population structural analyses. In addition, the Shenyang subclade was found to be closely related to the British subclade in the aspect of genetic distance. As a conclusion, this study provides an important clue for revealing the origin of C. auris found in Shenyang and could also contribute to improve the understanding of the epidemiological characteristics of C. auris worldwide.

Abstract Background Candida auris is a new pathogen called “superbug fungus” which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic review and meta-analysis was undertaken to determine the epidemic situation, drug resistance patterns and mortality of C. auris. Methods We systematically searched studies on the clinical report of Candida auris in Pubmed, Embase and Cochrane databases until October 6, 2019. A standardized form was used for data collection, and then statics was performed with STATA11.0. Results It showed that more than 4733 cases of C. auris were reported in over 33 countries, with more cases in South Africa, United States of America, India, Spain, United Kingdom, South Korea, Colombia and Pakistan. C. auirs exhibited a decrease in case count after 2016. Clade I and III were the most prevalent clades with more cases reported and wider geographical distribution. Blood stream infection was observed in 32% of the cases, which varied depending on the clades. Resistance to fluconazole, amphotericin B, caspofungin, micafungin and anidulafungin in C. auris were 91, 12, 12.1, 0.8 and 1.1%. The overall mortality of C. auris infection was 39%. Furthermore, subgroup analyses showed that mortality was higher in bloodstream infections (45%), and lower in Europe (20%). Conclusions Over 4000 cases of C. auris were reported in at least 33 countries, which showed high resistance to fluconazole, moderate resistance to amphotericin B and caspofungin, high sensitivity to micafungin and anidulafungin. The crude mortality for BSI of C. auris was 45% which was similar to some drug-resistant bacteria previously reported. In conclusion, C. auris displayed similar characteristics to some drug resistance organisms. This study depicts several issues of C. auris that are most concerned, and is of great significance for the clinical management.

Abstract Background Many cancer-associated single nucleotide polymorphisms (SNPs) are located in the genomic regions of long non-coding RNAs (lncRNAs). Mechanisms of these SNPs in connection to cancer risk are not fully understood. Methods Association of SNP (rs140618127) in lncRNA LOC146880 with non-small cell lung cancer (NSCLC) was evaluated in a case-control study of 2707 individuals. The mechanism of the SNP’s biologic influence was explored with in vitro and in vivo experiments, including plasmid transfection, siRNA knockdown, flow cytometry assessment, and assays of cell proliferation, migration, invasion, and colony formation. Results Association analysis showed that A allele of SNP rs140618127 was associated with low risk of NSCLC in the Chinese population. Lab experiments indicated that SNP rs140618127 contained a binding site for miR-539-5p and the binding between miR-539-5p and LOC146880 resulted in declined phosphorylation of an oncogene, ENO1. The reduced phosphorylation of ENO1 led to decreased phosphorylation of PI3K and Akt, which is further linked to the decline in cell proliferation and tumor progression. Conclusion The study demonstrates that SNP rs140618127 in lncRNA loc146880 provides an alternate binding site for microRNA miR-539-5p which affects the phosphorylation of ENO1 and activation of the PI3K and Akt pathway.

Objective: The clinical use of intermittent infusion of vancomycin (IIV) and continuous infusion of vancomycin (CIV) is controversial. The aim of this study was to assess the effectiveness and safety of IIV and CIV by using a meta-analysis for cohort studies and randomized controlled trials. Methods: We compared the probabilities of target attainment (PTA) for the measured concentration (Cm) ≥the target concentration (Ct), the PTA for the area under the drug concentration curve/minimal inhibitory concentration (AUC/MIC) ≥400, the duration of treatment, nephrotoxicity, and overall mortality after vancomycin treatment as reported in PubMed, Embase, Cochrane, and Web of Science. Results: A total of 14 studies with 1640 patients were included in the meta-analysis. For IIV, the PTA of Cm ≥ Ct (RR = 0.72, 95% CI = 0.60–0.88), and nephrotoxicity (RR = 1.70, 95% CI = 1.34–2.14) were significantly different from those of CIV. The treatment duration (SMD = 0.08, 95% CI = −0.08–0.25), the PTA of AUC/MIC ≥ 400 (RR = 0.84, 95% CI = 0.70–1.00) and mortality (RR = 0.94, 95% CI = 0.72–1.25) were not significantly different from those of CIV. Conclusions: The results showed that CIV was easier to achieve Ct and safer than IIV. Additional randomized controlled trials focusing on the concentration of vancomycin are needed for further analysis. Keywords: Vancomycin, Intermittent, Continuous, Effectiveness, Safety

Background: Augmented renal clearance (ARC) refers to enhanced renal elimination of circulating solute has attracted attention widely and in recent years increasing attention has been paid to patients with ARC. A population pharmacokinetic (PPK) analysis was performed to provide a reference for clinical individual therapy of vancomycin in in ARC patients. Methods: Patients hospitalized in the First Affiliated Hospital of China Medical University from July 2013 to December 2015 and suspected or confirmed infection caused by gram-positive bacteria were enrolled in this study. The serum concentrations were determined by enzyme multiplied immunoassay technique. A nonlinear mixed effects model (NONMEM) was used to evaluate the influence of covariates on vancomycin pharmacokinetics and obtain the PPK model. Bootstrap, visual predictive checks and normalized prediction distribution errors were used to evaluate the estabolishe model. Results: A total of 186 vancomycin serum samples from 95 patients, including 24 females and 71 males were studied. The final model was as follows:Cli=8.515×1−0.01175×Age−45×eηi and Vi=155.4×eηi. The final PPK model in ARC patients was proved to be robust and reliable. Age was identified as the most significant covariate in the final model. Conclusions: In this study, a simple population pharmacokinetic (PPK) model of vancomycin in Chinese patients with ARC was established using a nonlinear mixed-effects model (NONMEM). The final PPK model could achieve a good predictive effect, which provides a reference for clinical individual therapy. Keywords: Vancomycin, Population pharmacokinetics, Augmented renal clearance, Chinese patients, NONMEM

Background. Biological agents used to treat moderate-to-severe plaque psoriasis have been associated with Candida infection and other serious infections. It is, however, necessary to verify whether biologic agents increase the risk of Candida infection and serious infections and whether these risks vary among biologics. Methods. PubMed, EMBASE, and Cochrane Library were searched for eligible randomized controlled trials (RCTs) from their inception to December 2021. Results from individual RCT were pooled using Peto’s method with a fixed-effects model, and I2 was calculated to assess the heterogeneity. A Cochrane collaboration tool was used to examine bias risk, and Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) were used to assess the quality of evidence. Results. This study included 48 published articles with data from 52 RCTs involving 27297 participants. The anti-interleukin (IL)-17 agents (95% confidence interval (CI) = 1.54–3.45, P

Background: Obstructive sleep apnoea (OSA) is highly prevalent in patients with Stanford type B aortic dissection (TBAD). Few studies have evaluated the effects of OSA on vascular changes in TBAD patients. This study aimed to explore the effect of OSA on aortic morphological changes in TBAD patients and its relation to late aortic events (LAEs).Methods: This case-control study included 143 TBAD patients. The diameters of different parts of the aorta were measured based on computed tomography angiography (CTA). According to the apnoea-hypopnoea index (AHI), OSA was classified as mild (5 ≤ AHI ≤ 15), moderate (15 < AHI ≤ 30), or severe (AHI > 30). The false lumen (FL) status was evaluated and classified as partially thrombosed, patent, or completely thrombosed.Results: The OSA prevalence in TBAD patients was 64.3%, and image differences related to LAEs between TBAD patients with and without OSA included the maximum aortic diameter at onset (37.3 ± 3.9 vs. 40.3 ± 4.5 mm, p < 0.001), the FL diameter of the proximal descending thoracic aorta (16.0 ± 6.8 vs. 20.3 ± 4.7 mm, p < 0.001), and the proportion of the FL that was partially thrombosed (39.2 vs. 64.1%, p = 0.004). Additionally, in the multivariable analysis of patients with OSA, the risks of an aortic diameter ≥40 mm, a proximal descending aorta FL ≥ 22 mm and a partially thrombosed FL were 4.611 (95% CI: 1.796–11.838, p = 0.001), 2.544 (95% CI: 1.050–6.165, p = 0.039), and 2.565 (95% CI: 1.167–5.637, p = 0.019), respectively, after adjustment for confounding factors. Trend tests showed that the risks of an aortic diameter ≥40 mm and a partially thrombosed FL increased with increasing OSA severity.Conclusions: TBAD patients with moderate to severe OSA have aortic dilatation in different parts of the aorta. OSA is an independent risk factor for multiple imaging signs related to LAEs, suggesting that OSA is an important factor affecting the prognosis of TBAD patients.

The aim is to comprehensively and accurately assess potential relationships between single nucleotide polymorphisms (SNP) and lung cancer (LC) risk by summarizing the evidence in systematic reviews and meta-analyses. This umbrella review was registered with the PROSPERO international prospective register of systematic reviews under registration number CRD42020204685. The PubMed, Web of Science, and Embase databases were searched to identify eligible systematic reviews and meta-analyses from inception to August 14, 2020. The evaluation of cumulative evidence was conducted for associations with nominally statistical significance based on the Venice criteria and false positive report probability (FPRP). This umbrella review finally included 120 articles of a total of 190 SNP. The median number of studies and sample size included in the meta-analyses were five (range, 3–52) and 4 389 (range, 354–256 490), respectively. A total of 85 SNP (in 218 genetic models) were nominally statistically associated with LC risk. Based on the Venice criteria and FPRP, 13 SNP (in 22 genetic models), 47 SNP (in 99 genetic models), and 55 SNP (in 94 genetic models) had strong, moderate, and weak cumulative evidence of associations with LC risk, respectively. In conclusion, this umbrella review indicated that only 13 SNP (of 11 genes and one miRNA) were strongly correlated to LC risk. These findings can serve as a general and helpful reference for further genetic studies.

Abstract Background Long non-coding RNAs became the hot spots in the carcinogenesis of various tumors. This case-control study evaluated the association between the rs2151280 in lncRNA CDKN2B-AS1 and lung cancer risk. Methods This study included 507 lung cancer patients and 542 healthy individuals. Odds ratios and their 95% confidence intervals were calculated by unconditional logistic regression analysis to evaluate the association between the rs2151280 and lung cancer risk. Results Compared with individuals carrying TT genotype, individuals carrying CC genotype of rs2151280 had a decreased risk of lung cancer (OR = 0.640, 95%CI = 0.421–0.972, P = 0.036). In the recessive model, rs2151280 CC genotype was observed to reduce the risk of lung cancer (OR = 0.684). C allele was associated with non-small cell lung cancer risk (OR = 0.674). The rs2151280 was significantly associated with lung adenocarcinoma risk (CCvsTT: OR = 0.567, 95%CI = 0.333–0.965, P = 0.037; CCvsTC+TT: OR = 0.543, 95%CI 0.330–0.893, P = 0.016, respectively). However, there was no significant association between rs2151280 and lung squamous cell carcinoma risk in five models. The quantitative analysis suggested that there were no significant interactions of rs2151280 with smoking exposure to lung cancer susceptibility. Conclusions This hospital-based case-control study suggested that CDKN2B-AS1 rs2151280 T>C was associated with the risk of lung cancer.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Lung cancer is a leading cause of cancer death all around the world. Long non-coding RNAs (lncRNAs) have been confirmed to be involved in carcinogenesis of malignancies. However, the molecular mechanism of most lncRNAs in various kinds of cancers remains unclear. LncRNA HOTAIR and HNRNPA1 are reported to play an oncogenic role in non-small cell lung cancer, and the overexpression of HNRNPA1 is shown to promote the proliferation of lung adenocarcinoma cells. In our study, we find that the overexpression of HOTAIR could promote the proliferation and overexpression of miR-149-5p could inhibit the proliferation of lung cancer cells. Flow cytometric analysis determines that overexpression of miR-149-5p induces cell cycle arrest in the G0/G1 phases, whereas overexpression of HOTAIR decreases the proportion of G0/G1phase cells. Also, overexpression of HOTAIR promotes the migration and invasion ability of lung cancer cells, confirmed by the wound-healing and transwell assays, which are suppressed by overexpression of miR-149-5p. Furthermore, the dual-luciferase reporter assay indicates that miR-149-5p could bind both HOTAIR and the 3′UTR of HNRNPA1. In summary, we find that HOTAIR can regulate HNRNPA1 expression through a ceRNA mechanism by sequester miR-149-5p, which post-transcriptionally targets HNRNPA1, thus promoting lung cancer progression.

The heterogeneity of lung adenocarcinoma is driven by key mutations in oncogenes. To determine the gene expression, single nucleotide polymorphisms, and co-mutations participating in the initiation and progression of lung adenocarcinoma, we comprehensively analyzed the data of 491 patients from The Cancer Genome Atlas. Using log-rank and Kruskal–Wallis analysis, Oncoprint, Kaplan–Meier survival plots, and a nomogram, we found that EGFRL858R with co-mutation TP53 was significant prognostic determinant versus that with co-wild TP53 (hazard ratio, 2.77, P = 0.012). Further gene co-expression network and functional enrichment analysis indicated that co-mutation of EGFRL858R/TP53 increases the expression of COMP and ITGB8, which are involved in extracellular matrix organization and cell surface receptor signaling pathways, thus contributing to poor prognosis in lung adenocarcinoma. Validation was performed using three GEO profiles along with colony formation and CCK-8 assays for proliferation, transwell and wound-healing for migration in transfected H1299 and A549 cell lines. To the best of our knowledge, these results are the first to indicate that patients harboring the co-mutation of EGFRL858R/TP53 show increased expression of COMP and ITGB8, which participate in extracellular matrix dysfunction and can be used as prognostic biomarkers in patients with lung adenocarcinoma.

Molecular dysregulation is believed to participate in the onset and progression of lung adenocarcinoma (LUAD). This study aimed to identify and evaluate the potential key long noncoding RNAs (lncRNAs) involved in the significant dysfunctional process of LUAD. We found that lncRNA retinoic acid early transcript 1K (RAET1K) was upregulated in tumor tissues and were correlated with a poor prognosis of patients with LUAD; further, for the first time, we detected the biological roles of RAET1K. Weighted gene correlation network and gene set enrichment analysis revealed that high RAET1K expression is related to cell cycle dysfunction through upregulated cyclin E1 (CCNE1) by targeting miR-135. The dual-luciferase reporter gene assay was performed to clarify the binding relationship between RAET1K and miR-135a-5p in transgenic A549 and H1299 cells. Real-time PCR and Western blot analyses showed that RAET1K overexpression and miR-135a-5p inhibition exerted a strong synergistic effect on CCNE1 expression, and cell cycle flow cytometry analysis was used to confirm the arrest of A549 and H1299 cells at the G1/S phase. The lncRNA RAET1K/miR-135a-5p axis might participate in the regulation of LUAD progression by influencing CCNE1 expression and the accumulation of cells arrested at the G1/S phase boundary.

Abstract Background Long non-coding RNA (lncRNA) H19 is a hot spot in tumor development, progression and metastasis. This study assessed the association between H19 genetic polymorphisms and the susceptibility of lung cancer. Methods The case-control study was conducted to evaluate the association between four selected single nucleotide polymorphisms (rs217727, rs2107425, rs2735469 and rs17658052) in H19 gene and the risk of lung cancer. There were 556 female never smoking lung cancer patients and 395 cancer-free controls. Unconditional logistic regression analysis was used to analyze the associations between four SNPs and lung cancer risks by calculating the odds ratios and their 95% confidence intervals. The gene-environment interactions were assessed on both additive and multiplicative scales. Results Compared with carriers carrying homozygous CC genotype, there was a statistically significant increased risk of lung cancer for carriers of the rs2107425 TT genotype (odds ratio = 1.599, 95%CI = 1.106–2.313, P = 0.013). In both dominant and recessive models, significant associations were found between rs2107425 and lung cancer risk, and the corresponding odds ratios were 1.346 (1.022–1.774) and 1.400 (1.011–1.937), with P values 0.035 and 0.043, respectively. There was no significant correlation between lung cancer risk and rs2735469, rs217727 and rs17658052. Interaction analysis showed that their combined effects had a greater impact on lung cancer than individual effects of polymorphism and cooking smoke exposure. However, further analysis showed that the both additive model and the multiplicative model were not statistically significant. Conclusion The polymorphism rs2107425 in H19 gene was associated with the risk of lung cancer among female who never smokes in Shenyang, China.

Abstract Background H19 was the first long non-coding RNA (lncRNA) to be confirmed. Recently, studies have suggested that H19 may participate in lung cancer (LC) development and progression. This study assessed whether single nucleotide polymorphisms (SNPs) in H19 are associated with the risk of LC in a Chinese population. Methods A case-control study was performed, and H19 SNP rs217727 was analyzed in 555 lung cancer patients from two hospitals and 618 healthy controls to test the association between this SNP and the susceptibility to LC. Results The A/A homozygous genotype of rs217727 was significantly associated with an increased LC risk (odds ratio (OR) = 1.661, 95% confidence interval (CI) = 1.155 to 2.388, P = 0.006). Significant associations remained after stratification by smoking status (P

Abstract Background The aberrant regulation of MALAT1 has been indicated to be involved in various carcinogenic pathways contributing to the tumourigenesis and progression of cancers. The current meta-analysis summarized the research advances of MALAT1 functions and analyzed its prognostic value among multiple types of cancers. Methods Eligible studies were identified through retrieving the PubMed, Web of Science, and CNKI databases, up to Mar 1, 2018. 28 studies of 5436 patients and 36 studies of 3325 patients were enrolled in the meta-analysis to evaluate the association of MALAT1 expression with survival outcomes and clinical parameters. Results The results demonstrated that over-expression of MALAT1 may predict lymph node metastasis (pooled OR = 2.335, 95% CI 1.606–3.395, P = 0.000) and distant metastasis (pooled OR = 2.456, 95% CI 1.407–4.286, P = 0.002). Moreover, MALAT1 was also related with tumour size (pooled OR = 1.875, 95% CI 1.257–2.795, P = 0.002) and TNM stage (pooled OR = 2.034, 95% CI 1.111–3.724, P = 0.021). Additionally, elevated MALAT1 expression could predict poor OS (pooled HR = 2.298, 95% CI 1.953–2.704, P = 0.000), DFS (pooled HR = 2.036, 95% CI 1.240–3.342, P = 0.005), RFS (pooled HR = 2.491, 95% CI 1.505–4.123, P = 0.000), DSS (pooled HR = 2.098, 95% CI 1.372–3.211, P = 0.001) and PFS (pooled HR = 1.842, 95% CI 1.138–2.983, P = 0.013) in multivariate model. Importantly, subgroup analyses disclosed that increased MALAT1 expression had a poor OS among different cancer types (Estrogen-dependent cancer: pooled HR = 2.656, 95% CI 1.560–4.523; urological cancer: pooled HR = 1.952, 95% CI 1.189–3.204; glioma: pooled HR = 2.315, 95% CI 1.643–3.263; digestive cancer: pooled HR = 2.451, 95% CI 1.862–3.227). Conclusions The present findings demonstrated that MALAT1 may be a novel biomarker for predicting survival outcome, lymph node metastasis and distant metastasis.

Abstract Background Long non-coding RNAs play pivotal roles in the carcinogenesis of multiple types of cancers. This study is firstly to evaluate influence of rs4848320 and rs1110839 polymorphisms in long non-coding RNA AC016683.6 on the susceptibility of lung cancer. Methods The present study was a hospital-based case–control study with 434 lung cancer patients and 593 cancer-free controls. Genotyping of the two SNPs detected by Taqman® allelic discrimination method. Results There were no statistically significant associations between rs4848320 and rs1110839 polymorphisms in AC016683.6 and risk of lung cancer in overall population. However, in the smoking population, rs4848320 and rs1110839 polymorphisms significantly increased the risk of lung cancer in dominant and homozygous models (Rs4848320: P = 0.029; Rs1110839: P = 0.034), respectively. In male population, rs1110839 genetic variant was related to the risk of lung cancer in all genetic models (GG vs. TT: P = 0.008; Dominant model: P = 0.029; Recessive model: P = 0.027) rather than heterozygous model. The crossover analyses provided rs4848320 and rs1110839 risk genotypes carriers combined with smoking exposure 2.218-fold, 1.755-fold increased risk of lung cancer (Rs4848320: P = 0.005; Rs1110839: P = 0.017). Additionally, there were significantly positive multiplicative interaction of rs4848320 polymorphism with smoking status, with adjusted OR of 2.244 (1.162–4.334), but rs1110839 polymorphism did not exist. Conclusions Rs4848320 and rs1110839 polymorphisms may be associated with lung cancer susceptibility. Interaction of rs4848320 risk genotypes with smoking exposure may strengthen the risk effect on lung cancer.

Abstract Background An increasing number of publications are drawing attention to the associations between six common polymorphisms in HOX transcript anti-sense RNA (HOTAIR) and the risk of cancers, while these results have been controversial and inconsistent. We conducted an up-to-date meta-analysis to pool eligible studies and to further explore the possible relationships between HOTAIR polymorphisms (rs920778, rs7958904, rs12826786, 4,759,314, rs874945, and rs1899663) and cancer risk. Methods A systematic retrieval was conducted up to 1 July 2017 in the PubMed, Web of Science, and CNKI databases. Eighteen eligible publications including 45 case-control studies with 58,601subjects were enrolled for assessing the associations between the 6 polymorphisms in HOTAIR and cancer risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed to reveal the polymorphisms and susceptibility to cancer. All the statistical analyses were performed using STATA 11.0 software. Results The pooled analyses detected significant associations between the rs920778 polymorphism and increased susceptibility to cancer in recessive, dominant, allelic, homozygous, and heterozygous models. For the rs7958904 polymorphism, we obtained the polymorphism significantly decreased susceptibility to overall cancer risk among five genetic models rather than recessive and homozygous models. For the rs12826786 polymorphism, we identified it significantly increased susceptibility to cancer risk in all genetic models rather than heterozygous models. However, no significant association was found between the rs1899663, rs874945, and rs4759314 polymorphisms and susceptibility of cancer. Conclusion These findings of the meta-analysis suggest that HOTAIR polymorphism may contribute to cancer susceptibility.

Purpose: This study tried to explore whether members of miR-92a family contribute to early diagnosis and prognosis for human cancers and how they work.Methods: Integrated meta-analysis retrieved from public repositories was employed to assess the clinical roles of the miR-92a family for cancer diagnosis and prognosis. Expression level of miR-92a was detected by the TCGA database and was confirmed by non-small-cell lung cancer (NSCLC) tissues. Targets of miR-92a were predicted using starbase, and validated by dual luciferase assay. Correlation between miR-92a and the target gene was assessed by linkedOmics while expression of the target gene and its role in cancer prognosis were analyzed with UALCAN and Gepia.Results: We recognized the miR-92a family could serve as a potential diagnostic biomarker with a pooled sensitivity of 0.85 [0.81–0.88] and specificity of 0.86 [0.83–0.90]. The overall hazard ratio (HR) was 2.26 [95% CI: 1.70–3.00] for high expression groups compared to low expression groups. Expression of miR-92a was identified to be upregulated in NSCLC, especially in lung squamous cell carcinoma (LUSC). Results from starbase and dual luciferase assay indicated the regulator of G-protein signaling 3 (RGS3) was a direct target of miR-92a. Statistical negative correlation was found for the expression of miR-92a and RGS3. In addition, expression of RGS3 was downregulated in NSCLC and patients with the high expression had a poor prognosis (HR = 1.3) for LUSC patients. However, results were to the contrary for lung adenocarcinoma (HR = 0.7).Conclusion: This study revealed that miR-92a family could be ideal biomarkers for cancer diagnosis and prognosis, which might function through targeting RGS3.

Abstract Background Recently, accumulating evidence have revealed that circular RNA (circRNA) was deregulated in multiple types of cancer, suggesting that circRNA might serve as a novel candidate biomarker of cancer diagnosis. However, inconsistent results have become an obstacle in applying circRNAs to clinical practice. The aim of this study is to evaluate diagnostic value of circRNAs among cancers. Methods A literature search was systematically performed among PubMed, Sciencedirect, Cochrane Library, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure databases up to February 15, 2019. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratios, negative likelihood ratios, diagnostic odds ratio, and area under the SROC curve (AUC) were applied to evaluate diagnostic performance of circRNAs. Results In total, the study included 64 studies with single circRNA and 13 studies with combined circRNAs. Overall, the study presented that a single circRNA had moderate diagnostic value, with a SEN of 0.75, a SPE of 0.76, and an AUC of 0.82. The plasma circRNAs had higher diagnostic accuracy than tissue (AUC: 0.87, 95% confidence interval [CI]: 0.83–0.89 for plasma/serum subgroup; AUC: 0.79, 95% CI: 0.75–0.82 for tissue subgroup). Furthermore, the combined circRNAs had good diagnostic efficacy for GC, with a SEN of 0.89, a SPE of 0.94, and an AUC of 0.97, respectively. Conclusion This study confirmed that circRNAs may be candidate biomarkers for cancer diagnosis. In particular, diagnosis of combined circRNAs will be a new alternative applied to clinical research and practice for cancer.

Background: Recent studies have investigated the relationships between PLCE1 polymorphisms and cancer susceptibility. However, some findings lack consistency.Objectives: In the current study, we conducted a meta-analysis to more accurately evaluate the relationships between PLCE1 (rs2274223, rs3765524, rs753724, rs11187842, and rs7922612) single nucleotide polymorphisms (SNPs) and risk for different types of cancer.Methods: We performed a comprehensive search strategy in PubMed, Web of Science, Medline, EMbase, and Scopus for articles available until 19 March 2018. A total of 54 case-control studies comprising 17,955 cases and 20,400 controls were included in the current meta-analysis, which together comprised a total of 32 publications. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationships between the PLCE1 polymorphisms and cancer susceptibility. All statistical analyses were performed using Stata 11 software.Results: Results of the meta-analysis demonstrated that the rs2274223 polymorphism showed a significant correlation with increased overall cancer susceptibility (AG vs. AA: OR 1.168, 95% CI 1.084–1.259; GG vs. AA: OR 1.351, 95% CI 1.163–1.570; AG+GG vs. AA: OR 1.193, 95% CI 1.103–1.290; GG vs. AA+AG: OR 1.262, 95% CI 1.102–1.446; G vs. A: OR 1.163, 95% CI 1.089–1.242). Results of subgroup analysis showed that the rs2274223 polymorphism was associated with higher risk for esophageal cancer and gastric cancer relative to colorectal cancer and head and neck cancer. In addition, the rs2274223 polymorphism was found to be associated with increased cancer risk, especially among the subgroups comprising Asians, studies with population-based controls, studies employing the TaqMan genotyping method, and studies consistent with Hardy-Weinberg equilibrium (HWE). The association between the rs3765524 polymorphism and reduced overall cancer risk was detected in one specific genetic model (CT vs. CC: OR 0.681, 95% CI 0.523–0.886). Results of subgroup analysis showed that the rs3765524 polymorphism was associated with cancer risk in a specific genetic model among the subgroups of colorectal cancer, esophageal cancer, Asians, studies with population-based controls, and studies consistent with HWE. However, relationships among the PLCE1 rs753724, rs11187842, and rs7922612 polymorphisms and tumor risk were not identified.Conclusions: Results of the current meta-analysis suggested that PLCE1 (rs2274223, rs3765524) polymorphisms are associated with cancer susceptibility.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

MicroRNAs (miRNAs) are a class of endogenous, short and non-coding RNAs that may play important roles in the pathogenesis of tumor. The associations between microRNA-499 rs3746444 polymorphism and cancer risk in different systems remain inconclusive. This article is aimed to obtain more exact estimation of these relationships through a meta-analysis based on 52,456 individuals. We retrieved relevant and eligible studies from Pubmed and Embase database up to January 10, 2018. ORs and 95% CIs were used to estimate the associations between miR-499 polymorphism and cancer susceptibility in different systems. All analyses were performed using the Stata 11.0 software. A total of 65 case-control studies were retrieved using explicit inclusion and exclusion criteria. The study included 23,762 cases and 28,694 controls. Overall cancer analysis showed the association between miR-499 polymorphism and susceptibility to cancer was significant. MicroRNA-499 rs3746444 was found to be significantly associated with increased risk of cancer of the respiratory system (CC vs. TT: OR = 1.575, 95% CI = 1.268–1.955, CC vs. TC+TT: OR = 1.527, 95% CI = 1.232–1.892), digestive system (CC vs. TT: OR = 1.153, 95% CI = 1.027–1.295; TC vs. TT: OR = 1.109, 95% CI = 1.046–1.176; CC+TC vs. TT: OR = 1.112, 95% CI = 1.018–1.216; CC vs. TC+TT: OR = 1.137, 95% CI = 1.016–1.272; C vs. T: OR = 1.112, 95% CI = 1.025–1.206), urinary system (TC vs. TT: OR = 1.307, 95% CI = 1.130–1.512; CC+TC vs. TT: OR = 1.259, 95% CI = 1.097–1.446; C vs. T: OR = 1.132, 95% CI = 1.014–1.264), and gynecological system (C vs. T: OR = 1.169, 95% CI = 1.002–1.364). In the subgroup analysis by ethnicity, the result showed that significant association with an increased cancer risk was found in Asian. Subgroup analysis based on type of tumor was also performed, miR-499 rs3746444 is associated with susceptibility of cervical squamous cell carcinoma, lung cancer, prostate cancer, and hepatocellular carcinoma.

Background and objective Interleukin-6 (IL-6) and interleukin-1β (IL-1β), known as multifunctional cytokines with high biological activity, play an important role in physiological and pathological responses such as inflammation, immune response and even tumors. There have been multiple polymorphism loci found in IL-6 gene and IL-1β gene. The aim of this study is to investigate the relationship between IL-6-643 (C/G) and IL-1β-31 (C/T) polymorphisms and lung cancer risk among female non-smokers and explore the interaction effects on lung cancer risk between this two polymorphisms and potential risk factors such as cooking oil fumes exposure and history of tuberculosis. Methods We performed a case-control study using 363 female lung cancer patients as cases and 370 healthy volunteers as controls. Genomic DNA was extracted from peripheral blood samples using classical phenol chloroform method. The genotyping of IL-6-634 or IL-1β-31 polymorphisms was performed using Taqman real time PCR technique by ABI7500. Two sided χ2 test was used to compare the distribution of the genotypes and risk factors between cases and controls. Unconditional Logistic regression analysis was performed to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for estimating the association between certain genotypes and lung cancer and exploring the interaction of risk factors and genetic polymorphisms. Results The risk of lung cancer was significantly higher in those with IL-6-634 CG genotype than those with CC genotype (OR=1.61, 95%CI: 1.19-2.19, P=0.002). The CG or GG genotype carriers had an elevated risk of lung cancer than CC genotype carriers (OR=1.48, 95%CI: 1.10-1.98, P=0.01). No significant association was observed between IL-1β-31 gene polymorphism and lung cancer risk. Compared with IL-6-634 CC genotype carriers with no cooking oil fumes exposure, a significant higher risk was found in individuals who were CG or GG genotype carriers with exposure to cooking oil fumes (OR=2.45, 95%CI: 1.54-3.90). Compared with IL-6-634 CC genotype carriers with no history of tuberculosis, a significant elevated risk was found in individuals who were CG or GG genotype carriers with history of tuberculosis (OR=2.44, 95%CI: 1.05-5.66). Conclusion Our results indicated that IL-6-634 polymorphism was associated with the risk of lung cancer risk in female non-smokers. Individuals with both IL-6-634 CG or GG genotype and exposure to cooking oil fumes had a higher risk of lung cancer. Also individuals with both IL-6-634 CG or GG genotype and history of tuberculosis had an elevated risk of lung cancer.

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.

Background and objective Epidemiological studies have suggested that menstrual and reproductive factors may influence lung cancer risk, but the results are controversial. We therefore carried out a meta-analysis aiming to examine the associations of lung cancer in women with menstrual and reproductive factors. Methods Relevant studies were searched from PubMed database, CNKI, WANFANG DATA and VIP INFORMATION up to January 2012, with no language restrictions. References listed from selected papers were also reviewed. We included studies that reported the estimates of relative risks (RRs) with 95% confidence intervals (CIs) for the association between menstrual and reproductive factors and lung cancer risk. The pooled RRs were calculated after the heterogeneity test with the software Stata 11, and publication bias and sensitivity were evaluated at the same time. Results Twenty-five articles, representing 24 independent studies, were included in this meta-analysis. Older age at menarche in North America women (RR=0.83; 95%CI: 0.73-0.94) was associated with a significant decreased risk of lung cancer. Longer length of menstrual cycle was also associated with decreased lung cancer risk (RR=0.72; 95%CI: 0.57-0.90). Other exposures were not significantly associated. Conclusions Our analysis provides evidence of the hypothesis that female sex hormones influence the risk of lung cancer in women, yet additional studies are warranted to extend this finding and to clarify the underlying mechanisms.

Rs2292832 is a single nucleotide polymorphism located in the precursor of mir-149 and was reported to be associated with varieties of malignancies. So far, the effect of miR-149 rs2292832 polymorphism on lung cancer risk was unclear. In addition, cooking oil fume exposure was demonstrated to be an important environmental risk factor in Chinese female. The aim of the present study was to evaluate the associations of rs2292832 polymorphism, cooking oil fume exposure and multiplicative interaction of cooking oil fume exposure and rs2292832 polymorphism with lung cancer risk in Chinese non-smoking female population.The present study was a hospital-based case-control study conducted in Chinese non-smoking females. 555 lung cancer patients and 395 cancer-free controls were interviewed to collect demographic data and exposure status of environmental risk factors, and then donate 10 ml venous blood which was used to be genotyped by Taqman allelic discrimination method. The statistical analyses were performed on SPSS 13.0 software.The association between miR-149 rs2292832 polymorphism and risk of lung cancer(TC vs. TT: OR = 1.006, 95%CI = 0.767-1.321, P = 0.963; CC vs. TT: OR = 0.41, 95%CI = 0.532-1.329, P = 0.458; Dominant model: OR = 0.965, 95%CI = 0.745-1.251, P = 0.788; Recessive model: OR = 0.816, 95%CI = 0.528-1.259, P = 0.357, adjusted for age), non-small cell lung cancer(TC vs. TT: OR = 1.006, 95%CI = 0.767-1.321, P = 0.963; CC vs. TT: OR = 0.841, 95%CI = 0.532-1.329, P = 0.458, adjusted for age), lung adenocarcinoma(TC vs. TT: OR = 0.944, 95%CI = 0.700-1.273, P = 0.707; CC vs. TT: OR = 0.801, 95%CI = 0.485-1.323, P = 0.386, adjusted for age) and squamous cell carcinoma(TC vs. TT: OR = 1.025, 95%CI = 0.641-1.638, P = 0.919; CC vs. TT: OR = 0.792, 95%CI = 0.346-1.813, P = 0.581, adjusted for age) were all not statistically significant. Result of Logistic regression showed that the multiplicative interaction of cooking oil fume exposure and rs2292832 polymorphism was not statistically significant (P = 0.063 for lung cancer and P = 0.064 for lung adenocarcinoma).MicroRNA-149 rs2292832 polymorphism may not be associated with lung cancer risk in Chinese non-smoking female.

Background and objective Cytochrome P450A1 (CYP1A1) gene and glutathione S-transferase M1 (GSTM1) gene both have single nucleotide polymorphisms and effects on lung cancer. Currently, however, the risk of lung cancer due to the CYP1A1 and GSTM1 genes has no clear evidence. In this present study, we propose to research the combined effects of CYP1A1 gene and GSTM1 gene polymorphism and their risks to lung cancer. Methods We conducted the study at different research areas and using various database, including PubMed, Embase, China Biology Medicine (CBM) and China National Knowledge Infrastructure (CNKI) last March 31, 2011. We calculated the adjusted odds ratio (OR) and 95% confidence interval (CI) for lung cancer in each study. Using STATA 10, a statistical program, we summarized the calculated estimates for the adjusted ORs and performed a meta-analysis.Results The meta-analysis includes 15 research studies. The CYP1A1 IIe/Val genotype which carries a homozygous mutant type has a higher chance of risk to lung cancer than that which carries a homozygous mutant type and a heterozygous type when the GSTM1 carries a null genotype. As a result, OR was 3.18 (95%CI: 1.27-7.98), 1.45 (95%CI: 1.08-1.94), respectively. Meanwhile, the same conclusion was obtained for the CYP1A1 MspI genotype. The overall OR was 1.90 (95%CI: 1.00-3.58), 1.57 (95%CI: 1.23-2.00), respectively. Conclusion We discovered through our meta-analysis that the combined effects of CYP1A1 gene and GSTM1 gene polymorphism are significantly associated with an increased risk to lung cancer. We also found that homozygous mutant genotype of CYP1A1 has a higher chance of risk to lung cancer than the homozygous or heterozygous genotype.

Background and objective Our previous studies revealed that hepatoma-derived growth factor (HDGF) is highly expressed in non-small cell lung cancer (NSCLC) cells, playing important roles in promoting NSCLC cells growth and invasion. The aim of this study is to detect the expression of HDGF in 158 cases of surgically resected NSCLC and evaluate its clinical significance. Methods Immunohistochemical SP method was used to detect the expression of HDGF in 158 NSCLC tissues and 12 normal control lung tissues. Survival analysis was further conducted. Results HDGF was found significantly highly expressed in 158 NSCLC tissues compared with normal control lung tissues (P < 0.001). The 5-year survival rate was 38.2% in HDGF high expression cases, compared with 63.1% in HDGF low expression cases, the difference was statistically significant (P=0.009). Linear correlation analysis discovered a significantly negative correlation between HDGF expression and the survival time (r=-0.183, P=0.022). COX proportion hazard model analysis revealed that pathological stages and HDGF expression were independent prognostic factors for this group of 158 resected NSCLC cases. Conclusion HDGF is highly expressed in human NSCLC tissues, predicting worse prognosis in resected NSCLCs. It might be useful molecular biomarker for predicting the prognosis of resected NSCLCs.

Lung cancer is the principal cause of cancer-associated deaths. HMGB1 has been reported to be associated with tumorigenesis. This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer. 850 cases and 733 controls were included. Logistic regression analysis and survival analysis were performed to investigate the association between SNPs and the risk and survival of lung cancer. Crossover analysis was used to analyze the interaction between SNPs and tobacco exposure. Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer. Carriers with CT and CC genotypes had a decreased risk of lung cancer (CT + CC vs.TT: adjusted OR = 0.736, p = 0.004). Similar results were obtained in the stratification analysis for non-smokers and female population. For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold. However, no significant interaction between polymorphisms and tobacco exposure or association between SNPs and the survival of lung cancer was observed. This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk.

Background and objective Many studies concluded that the polymorphisms of XPD were involved in the risk of lung cancer. However, several other studies suggested no association. To explore whether the polymorphisms of XPD contribute to the genetic susceptibility to lung cancer, we carried a meta-analysis based on the published works. Methods All works related to XPD and lung cancer risk were searched and carefully selected. The genotype frequencies of XPD and related variables were abstracted and the pooled ORs were calculated after the heterogeneity test with the software Stata 10. Publication bias and sensitivity were evaluated at the same time. Results Twenty-two studies were included according to the selection criteria, of which fifteen investigated the codon 312 of XPD and twenty studied the codon 751. The pooled OR of susceptibility to lung cancer with XPD312 Asn/Asn genotype compared to the wild Asp/Asp were 1.18 (95%CI: 1.03-1.34, P=0.018). And the polymorphisms of XPD codon 751 were also associated with increased lung cancer risk (Lys/Gln OR=1.09, 95%CI: 1.02-1.18; Gln/Gln OR=1.24, 95%CI: 1.10-1.41). However, subgroup analysis indicated that the association between XPD751 and lung cancer could only be found in Europeans and Americans. The publication bias analysis had no statistically significant results. Conclusion Polymorphisms of XPD codons 312 and 751 seem to be involved in elevated risk of lung cancer.

Background and objective Twist has been identified as a promoting factor for epithelialmesenchymal transition (EMT), which enhances the metastatic potential of cancer. The aim of this study is to detect the expression of Twist in lung cancer tissues and cell lines, and analyze its relationship with clinicopathologiccharacteristics and biological behavior of lung cancer. Methods Twist expression was examined in 68 lung cancer specimens and 8 normal lung specimens using immunohistochemistry (S-P method). Expression levels of Twist1 and Twist2 mRNA were detected using transcription-polymerase chain reaction (RT-PCR) in HBE and 8 lung cancer cell lines. Immunofluorescence was used to detect the Twist protein expression levels and subcellular localization in lungcancer cells and HBE (human normal bronchi epithelium) cells. Results Among 68 lung cancer specimens, 9 samples showed weak expression of Twist 13.24% (9 of 68), 75.00% (51 of 68) lung cancer specimens showed moderate to strong Twist staining whereas 8 corresponding normal lung specimens showed weak staining extent. Twist expression level was positively correlated with differentiation (P =0.002) and age (P =0.012). Twist1 and Twist2 mRNA expression levels were incompatible in different histology types. The fluorescence signal of Twist protein was conspicuous in lung squamous cell carcinoma cells and adencarcinoma cells, primarily in cytoplasm, but low in HBE. Conclusion High expression of Twist in lung cancer was associated with differentiation. Twist could be used as a valuable biomarker to evaluate the progressionof lung cancer.

Cases of hemorrhagic fever with renal syndrome (HFRS) are widely distributed in eastern Asia, especially in China, Russia, and Korea. It is proved to be a difficult task to eliminate HFRS completely because of the diverse animal reservoirs and effects of global warming. Reliable forecasting is useful for the prevention and control of HFRS.Two hybrid models, one composed of nonlinear autoregressive neural network (NARNN) and autoregressive integrated moving average (ARIMA) the other composed of generalized regression neural network (GRNN) and ARIMA were constructed to predict the incidence of HFRS in the future one year. Performances of the two hybrid models were compared with ARIMA model.The ARIMA, ARIMA-NARNN ARIMA-GRNN model fitted and predicted the seasonal fluctuation well. Among the three models, the mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) of ARIMA-NARNN hybrid model was the lowest both in modeling stage and forecasting stage. As for the ARIMA-GRNN hybrid model, the MSE, MAE and MAPE of modeling performance and the MSE and MAE of forecasting performance were less than the ARIMA model, but the MAPE of forecasting performance did not improve.Developing and applying the ARIMA-NARNN hybrid model is an effective method to make us better understand the epidemic characteristics of HFRS and could be helpful to the prevention and control of HFRS.

Both genetic polymorphisms and environmental risk factors play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of interaction between polymorphisms in pre-miRNA genes and cooking oil fume exposure on the risk of lung cancer.A hospital-based case-control study of 258 cases and 310 controls was conducted. Six polymorphisms in miRNAs were determined by Taqman allelic discrimination method. The gene-environment interactions were assessed on both additive and multiplicative scale. The statistical analyses were performed mostly with SPSS.The combination of the risk genotypes of five miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-608 rs4919510, miR-27a rs895819 and miR-423 rs6505162) with risk factor (cooking oil fume exposure) contributed to a significantly higher risk of lung cancer, and the corresponding ORs (95% confidence intervals) were 1.91(1.04-3.52), 1.94 (1.16-3.25), 2.06 (1.22-3.49), 1.76 (1.03-2.98) and 2.13 (1.29-3.51). The individuals with both risk genotypes of miRNA SNPs and exposure to risk factor (cooking oil fumes) were in a higher risk of lung cancer than persons with only one of the two risk factors (ORs were 1.91, 1.05 and 1.41 for miR-146a rs2910164, ORs were 1.94, 1.23 and 1.34 for miR-196a2 rs11614913, ORs were 2.06, 1.41 and 1.68 for miR-608 rs4919510, ORs were 1.76, 0.82 and 1.07 for miR-27a rs895819, and ORs were 2.13, 1.15 and 1.02 for miR-423 rs6505162, respectively). All the measures of biological interaction indicate that there were not indeed biological interactions between the six SNPs of miRNAs and exposure to cooking oil fumes on an additive scale. Logistic models suggested that the gene-environment interactions were not statistically significant on a multiplicative scale.The interactions between miRNA SNPs and cooking oil fume exposure suggested by ORs of different combination were not statistically significant.

BACKGROUND: Previous studies on the association of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg399Gln, and Arg280His polymorphisms with head and neck cancer (HNC) have produced inconsistent results. The aim of the present study was to evaluate the effects of these three polymorphic variants on HNC risk. METHODS: The PubMed and EMBASE databases were searched for genetic association studies on the XRCC1 Arg194Trp, Arg399Gln, and Arg280His polymorphisms and HNC risk. (The most recent search was conducted on 20 August, 2013.) Twenty-six studies were identified and meta-analysis was performed to evaluate the association between the polymorphism and HNC by calculating combined odds ratios and 95% confidence intervals. RESULTS: No significant association was found under the allelic, homozygous, heterozygote, and dominant genetic models in the overall comparison. Further, no significant association between the XRCC1 Arg399Gln and Arg280His polymorphisms and HNC risk was detected under the four genetic models in subgroup analyses based on ethnicity, cancer site, and whether or not the studies had been adjusted for cigarette smoking and alcohol. However, in stratified analyses based on cancer site, a significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer under the allelic, heterozygote, and dominant models. The XRCC1 Arg194Trp polymorphism was significantly associated with HNC risk in studies that were adjusted for smoking and alcohol under the homozygous and heterozygote models. CONCLUSION: The meta-analysis results suggest that the XRCC1 Arg399Gln and Arg280His polymorphisms are probably not associated with the risk of HNC, but the XRCC1 Arg194Trp polymorphism was associated with increased risk of HNC in the subgroup analysis of studies adjusted for smoking and alcohol and with increased risk of oral cancer in the stratified analyses based on cancer site. Further studies with larger samples are needed to confirm these findings.

BACKGROUND: The morbidity and mortality of cancer increase remarkably every year. It's a heavy burden for family and society. The detection of prognostic biomarkers can help to improve the theraputic effect and prolong the lifetime of patients. microRNAs have an influential role in cancer prognosis. The results of articles discussing the relationship between microRNA polymorphisms and cancer prognosis are inconsistent. METHODS: We conduct a meta-analysis of 19 publications concerning the association of four common polymorphisms, mir-146a rs2910164, mir-149 rs2292832, mir-196a2 rs11614913 and mir-499 rs3746444, with cancer prognosis. Pooled Hazard Ratios with 95% Confidence Intervals for the relationship between four genetic polymorphisms and Overall Survival, Recurrence-free Survival, Disease-free survival, recurrence are calculated. Subgroup analysis by population and type of tumor are conducted. RESULTS: GG genotype of mir-146a may be the protective factor for overall survival, especially in Caucasian population. C-containing genotypes of mir-196a2 act as a risk role for overall survival. The same result exists in Asian population, in Non-Small Cell Lung Cancer and digestive cancer. The patients with C allele of mir-149 have a better overall survival, especially in Non-Small Cell Lung Cancer. No significant results are obtained for mir-499 polymorphisms. CONCLUSIONS: Genetic polymorphisms in mir-146a, mir-196a2 and mir-149 may be associated with overall survival. This effect varies with different types of cancer. Genetic polymorphism in mir-499 may have nothing to do with cancer prognosis.

OBJECTIVE: Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed. METHODS: We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers. RESULTS: Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.23-1.61) in Asian children, and 1.70(1.19-2.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis. CONCLUSIONS: The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations.