Exploring the link between walking and lung cancer risk: a two-stage Mendelian randomization analysis.

BACKGROUND: Previous observational research showed a potential link between physical activities such as walking and the risk of lung cancer. However, Mendelian randomization (MR) studies suggested there was no association between moderate to vigorous physical activity and lung cancer risk. We speculated that specific physical activities may be associated with lung cancer risk. Consequently, we conducted an MR study to examine the potential relationship between walking and the risk of lung cancer. METHODS: We collected genetic summary data from UK Biobank. After excluding SNPs with F values less than 10 and those associated with confounding factors, we conducted a MR analysis to assess the causal effects between different types of walk and lung cancer. We also performed sensitivity analysis to validate the robustness of our findings. Finally, we analyzed the possible mediators. RESULTS: MR analysis showed number of days/week walked for 10 + minutes was associated with a reduced risk of lung cancer risk (OR = 0.993, 95% CI = 0.987-0.998, P = 0.009). Additionally, usual walking pace was identified as a potentially significant factor in lowering the risk (OR = 0.989, 95% CI = 0.980-0.998, P = 0.015). However, duration of walks alone did not show a significant association with lung cancer risk (OR = 0.991, 95%CI = 0.977-1.005, P = 0.216). The sensitivity analysis confirmed the robustness of these findings. And number of days/week walked for 10 + minutes could affect fed-up feelings and then lung cancer risk. There was a bidirectional relationship between usual walking pace and sedentary behaviors (time spent watching TV). CONCLUSION: The study unveiled a genetically predicted causal relationship between number of days/week walked for 10 + minutes, usual walking pace, and the risk of lung cancer. The exploration of potential mediators of walking phenotypes and their impact on lung cancer risk suggests that specific physical activities may reduce the risk of lung cancer.

Integrative analysis of DNA methylomes reveals novel cell-free biomarkers in lung adenocarcinoma.

Lung cancer is a leading cause of cancer-related deaths worldwide, with a low 5-year survival rate due in part to a lack of clinically useful biomarkers. Recent studies have identified DNA methylation changes as potential cancer biomarkers. The present study identified cancer-specific CpG methylation changes by comparing genome-wide methylation data of cfDNA from lung adenocarcinomas (LUAD) patients and healthy donors in the discovery cohort. A total of 725 cell-free CpGs associated with LUAD risk were identified. Then XGBoost algorithm was performed to identify seven CpGs associated with LUAD risk. In the training phase, the 7-CpGs methylation panel was established to classify two different prognostic subgroups and showed a significant association with overall survival (OS) in LUAD patients. We found that the methylation of cg02261780 was negatively correlated with the expression of its representing gene GNA11. The methylation and expression of GNA11 were significantly associated with LAUD prognosis. Based on bisulfite PCR, the methylation levels of five CpGs (cg02261780, cg09595050, cg20193802, cg15309457, and cg05726109) were further validated in tumor tissues and matched non-malignant tissues from 20 LUAD patients. Finally, validation of the seven CpGs with RRBS data of cfDNA methylation was conducted and further proved the reliability of the 7-CpGs methylation panel. In conclusion, our study identified seven novel methylation markers from cfDNA methylation data which may contribute to better prognosis for LUAD patients.

TIMELESS promotes the proliferation and migration of lung adenocarcinoma cells by activating EGFR through AMPK and SPHK1 regulation.

BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present. METHODS: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis. RESULTS: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells. CONCLUSIONS: Our study revealed that siTIM could inhibit EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and altering the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD.

Prognostic value of different N1 lymph node zones in pN1M0 non-small cell lung cancer: a systematic review and meta-analysis.

The IASLC lymph node map grouped the lymph node stations into "zones" for prognostic analyses. In the N1 lymph nodes group, N1 nodes are divided into the Hilar/Interlobar zone (N1h) and Peripheral zone (N1p). There is no consensus on the different prognostic values of N1 lymph nodes in N1h and N1p. Therefore, we conducted a systematic review and meta-analysis to assess the survival difference between N1h and N1p in patients of pN1M0 NSCLC. Medline, the Cochrane Library, Embase, and the Web of science were systematically searched to identify relevant studies published up to April 4th, 2020. A retrospective and prospective cohort study comparing N1h versus N1p to the pN1M0 NSCLC was included. Hazard ratios (HRs) for OS were aggregated according to a fixed or random-effect model. Ten publications for 1946 patients of pN1M0 NSCLC were included for the meta-analysis.The 5-year OS was lower for patients with N1h (HR: 1.67, 95% CI 1.44-1.94; P < 0.001). The pooled 5-year OS in N1h and N1p were 40% and 56%, respectively. The patients in pN1M0 NSCLC have different survival according to different N1 lymph node zones involvement: patients with N1p metastasis have a better prognosis than those with N1h metastasis.

ESRP1 as a prognostic factor of non-small-cell lung cancer is related to the EMT transcription factor of Twist.

OBJECTIVE: Non-small-cell lung cancer (NSCLC) is one of the most common fatal cancers in the world. Although the treatment of NSCLC has been significantly improved, there is still an unmet need to identify novel targets for developing therapeutic agents and diagnostic/prognostic markers. The aim of this study is explore the role and underlying mechanism of the epithelial splicing regulatory protein (ESRP1) in the development and progression of NSCLC. METHODS: A total of 115 participants, 65 cases of NSCLC, 20 cases of precancerous lesions, and 30 cases of benign lung nodules, were included in this study. The expressions of ESRP1 and related transcription factor Twist in enrolled lung tissues were evaluated by histochemistry and immunohistochemistry assay. The survival analysis and related prognosis factors were evaluated by the Kaplan-Meier curve and Cox regression. In addition, the expression of ESRP1 and epithelial-mesenchymal transition (EMT)related transcription factor Twist and EMT markers E-cadherin and N-cadherin were ascertained by immunohistochemical and immunoblotting assay on A549 lung adenocarcinoma cell lines that were exposed to transforming growth factor ß1 (TGFß1). RESULTS: Compared with normal lung tissues, the abundance of ESRP1 protein was significantly increased in precancerous lesions and lung cancer. Correlation analysis demonstrated that ESRP1 was an independent prognostic factor in NSCLC. The expression of ESRP1 and Twist was positively correlated in lung tissues (r = 0.285, p < 0.001). In vitro analysis further showed that TGFß1 could upregulate the expression of EMT transcription factor Twist while downregulating ESRP1. CONCLUSIONS: Our data suggest that the aberrant expression of ESRP1 is an early event in the development of NSCLC. The ESRP1 could serve as a prognostic biomarker for NSCLC, particularly when combined with Twist. The Twist negatively regulated the expression of ESRP1, emphasizing the role of the TGFß/ESRP1 pathway in the development of NSCLC, which warrants further investigation.

Incidence and related risk factors of radiographic knee osteoarthritis: a population-based longitudinal study in China.

OBJECTIVE: To explore the incidence and risk factors for radiographic knee osteoarthritis (ROA) in a suburban area of China. METHODS: Shunyi Osteoarthritis Study was a population-based, longitudinal study of knee osteoarthritis in Shunyi, a suburban area of Beijing, China. A total of 1295 residents aged over 50 years were recruited with fully informed by randomized cluster sampling and were followed up 3 years later. At the time of baseline and follow-up visits, participants completed a home interview questionnaire and received a clinical examination including height, weight, range of motion (ROM), chair stand test, 50-foot walk test, and weight-bearing posterior-anterior semi-flexed view of radiographs at tibiofemoral joints. The incident ROA for a knee was defined if its KL grade was no more than grade 1 at baseline visit and no less than grade 2 at the follow-up visit. A patient without ROA in both knees at the baseline visit and with ROA in at least one knee at the follow-up visit was viewed as an incident case of ROA in patient level. Generalized linear model and generalized estimating equation were performed to examine the association between socio-demographic factors, physical function as well as baseline knee joint condition, and incident ROA in patient and knee level. RESULTS: A total of 1295 residents were recruited at baseline in 2014, and 962 (74.3%) residents were followed in 2017. The annual cumulative incidence of ROA was 3.6% at knee level and 5.7% at patient level. Older age (per year, adjusted odds ratio (OR) = 1.079; 95% confidence interval (CI), 1.042-1.117), overweight (adjusted OR = 2.086; 95% CI, 1.286-3.385), female (adjusted OR = 1.756; 95% CI, 1.074-2.877), less ROM (per degree, adjusted OR = 0.952; 95% CI, 0.923-0.983) and Kellgren and Lawrence (KL) grade 1 at baseline (adjusted OR = 8.527; 95% CI, 5.489-13.246) were risk factors for incident ROA. CONCLUSION: The incidence of knee ROA in Chinese suburban area was high. Advanced age, female, overweight, less range of motion, and KL grade 1 at baseline were associated with an increased risk of incident ROA.

The role of EGFR-TKIs as adjuvant therapy in EGFR mutation-positive early-stage NSCLC: A meta-analysis.

BACKGROUND: The role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is not clear in early-stage nonsmall-cell lung cancer (NSCLC) patients. This meta-analysis aims to compare the efficacy and safety of EGFR-TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations. PATIENTS AND METHODS: Pubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease-free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged. RESULTS: Seven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22-0.63), in favor of EGFR-TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31-1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third-generation EGFR-TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09-0.94). The possibility of severe adverse events for the first-generation drugs was significantly lower than for third-generation drugs. CONCLUSION: In EGFR mutation-positive patients with stage IB-IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR-TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR-TKIs had more favorable tolerability than chemotherapy, especially with the usage of first-generation drugs.

The prevalence of rheumatoid arthritis in middle-aged and elderly people living in Naqu City, Tibet, Autonomous Region of China.

OBJECTIVE: To estimate the prevalence of rheumatoid arthritis (RA) in the Tibet Autonomous Region (China). METHODS: A population-based cross-sectional survey was conducted on 1458 residents of Luoma Town, Tibet Autonomous Region, who were aged ≥ 40 years old. We interviewed participants using questionnaires, and rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), and C-reactive protein (CRP) were determined. The identification of RA in this study was on the basis of criteria issued by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guideline. RESULTS: Herein, 782 participants completed all items of RA. The overall prevalence of RA was 4.86%, and the prevalence was higher in women than that in men (7.14% vs. 2.56%, p = 0.005). The age-standardized prevalence of RA was 6.30% (95% confidence interval (CI) 4.20-8.64%), which was 2.46% (95% CI 1.04%, 4.10%) and 9.59% (95% CI 5.93%, 13.77%) in men and women, respectively. CONCLUSION: The prevalence of RA is relatively higher in the Tibet than that in other areas of China.

The prevalence of gout and hyperuricemia in middle-aged and elderly people in Tibet Autonomous Region, China: A preliminary study.

OBJECTIVE: Gout and hyperuricemia are common public health problem. There has been no epidemiological survey of gout and hyperuricemia in Tibet Autonomous Region, the southwest of China. Therefore, we estimated the prevalence of gout and hyperuricemia in Luoma Town, Naqu City, Tibet Autonomous Region of China. METHODS: A population-based cross-sectional survey was conducted among 1458 residents of Luoma Town, Tibet Autonomous Region, age ≥40 years. We used questionnaires in face-to-face interviews, anthropometric measurements and serum uric acid test. Hyperuricemia was defined as serum uric acid level ≥7 mg/dl in men and ≥6 mg/dl in women. The definition of gout in this study was on the basis of new 2015ACR/EULAR classification criteria. RESULTS: Nine hundred eighty-nine participants completed all items of gout and 818 participants attended to be taken blood samples for serum UA levels test. The overall crude prevalence of gout and hyperuricemia was 0.30% and 1.83% respectively. It was more prevalent in men than in women (2.86% vs 0.75%, P = .034) in hyperuricemia group. Tibetan had a lower age-standardized prevalence of gout 0.26% (95% confidence interval (CI): 0%-0.60%) and hyperuricemia 2.05% (95% confidence interval (CI): 0.99%-3.44%) compared with the China Health and Retirement Longitudinal Study results. CONCLUSION: This is the first large-scale population-based survey to demonstrate the prevalence of gout and hyperuricemia of the middle-aged and elderly population in Tibet Autonomous Region, China. The prevalence of gout and hyperuricemia is relatively lower than other places in China, and that might be influenced by ethnicity, genetic and environment factors. These findings will be useful for the future researches and health care strategies.

Burden of osteoarthritis in China, 1990-2017: findings from the Global Burden of Disease Study 2017.

BACKGROUND: China has seen a remarkable epidemiological and demographic transition during the past three decades. We aimed to describe the prevalence of osteoarthritis as well as years lived with disability (YLDs) due to osteoarthritis in China, according to age, sex, and geographical location, from 1990 to 2017. METHODS: Data were obtained from systematic reviews of symptomatic osteoarthritis of the knee and hip in the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017). Three categories of sequelae (mild, moderate, and severe) of osteoarthritis were defined to indicate the degrees of severity and functional loss associated with the condition. A Bayesian meta-regression tool was applied to estimate the prevalence of osteoarthritis and the distribution of its severity. YLDs were calculated by multiplying the prevalence of osteoarthritis sequelae by their corresponding disability weights. All data were analysed by age-sex-province-year groups in China. FINDINGS: Around 26·1 million individuals in China had osteoarthritis in 1990, and this number rose to 61·2 million in 2017. The age-standardised prevalence of osteoarthritis increased from 2·9% (95% uncertainty interval 2·5-3·3) in 1990 to 3·1% (2·7-3·4) in 2017. The total YLDs due to osteoarthritis increased from 0·84 million (0·42-1·69) in 1990 to 1·97 million (0·98-3·94) in 2017, while the age-standardised YLD rate increased from 92·5 (45·7-185·6) per 100 000 people to 98·8 (49·4-197·6) per 100 000. Osteoarthritis prevalence and YLDs were higher in females than in males, and YLD rate increased with age. Osteoarthritis was the 24th most common cause of YLDs in China in 2017, accounting for 1·08% (0·64-2·02) of all YLDs. INTERPRETATION: Osteoarthritis is prevalent in China. Between 1990 and 2017, disease burden increased and varied greatly according to geographical location. Appropriate prevention and treatment strategies, predominantly those targeted at women, older people, and underdeveloped areas, must be developed to reduce the burden of the disease. FUNDING: National Natural Science Foundation of China, China National Key Research and Development Programme.

Imaging features in incident radiographic patellofemoral osteoarthritis: the Beijing Shunyi osteoarthritis (BJS) study.

BACKGROUND: The present study aims to describe the imaging features in incident radiographic patellofemoral osteoarthritis (RPFOA) population in a Chinese suburban area. METHODS: The Beijing Shunyi osteoarthritis (BJS) study was a population-based, longitudinal and prospective study. Residents were recruited by randomized cluster sampling in 2014 and were followed 3 years later. Home interviews and clinical examinations were performed; weight-bearing posterior-anterior semi-flexed (45-degree) views of the tibiofemoral (TF) joints and skyline (45-degree) views of the patellofemoral (PF) joints were included. For each batch of study films (n = 100), 20 films from the year 2014 and 20 previously read PF radiographs were fed back to test inter-/intra-reader repeatability. The imaging features of incident RPFOA were analyzed. Narrative statistics, independent-sample t-tests, and nonparametric tests were performed. RESULTS: A total of 1295 participants (2590 knees) were recruited at baseline in 2014, and 967 (74.7%) residents were followed in 2017. Of all the knees (n = 1537) without RPFOA at baseline, 139 knees (13.3%) across 119 people developed incident RPFOA. Compared with the whole population, age (p = 0.031), body mass index (BMI, p = 0.042), and incidence of knee pain symptoms (p < 0.01) were significantly different in the incident RPFOA population, while range of motion (ROM, p = 0.052) and gender (0/1, p = 0.203) showed no significance. In the incident population, the changes of each imaging indicator grade were evaluated-lateral patellofemoral osteophyte (LPOST, increased by 1.02), medial patellofemoral osteophyte (MPOST, increased by 0.49), lateral joint space narrowing (LJSN, increased by 0.30), medial joint space narrowing (MJSN, increased by 0.06); indicator grade progress decreases, respectively. The progress of LPOST was the fastest among the four indicators (p < 0.01). CONCLUSIONS: In this population-based longitudinal study, among the incident RPFOA population, the imaging indicators show that marginal patellofemoral osteophyte is more pronounced than patellofemoral joint space narrowing. LPOST is the fastest-progressing indicator among all the radiographic features, which is also the most common imaging manifestation of RPFOA. In the incident RPFOA population, the proportion of elders, women, higher-BMI individuals, and people suffering knee pain is more than the normal population.