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Background: High sodium intake is an important risk factor for hypertension and cardiovascular disease. However, the association between gut microbiota composition and metabolomic profiles with dietary sodium intake and blood pressure (BP) is not well-understood. The metabolome, microbiome, and dietary salt intervention (MetaSalt) study aimed to investigate microbial and metabolomic profiles related to dietary sodium intake and BP regulation. Methods: This family-based intervention study was conducted in four communities across three provinces in rural northern China in 2019. Probands with untreated prehypertension or stage-1 hypertension were identified through community-based BP screening, and family members including siblings, offspring, spouses, and parents were subsequently included. All participants participated in a 3-day baseline examination with usual diet consumption, followed by a 10-day low-salt diet (3 g/d of salt or 51.3 mmol/d of sodium) and a 10-day high-salt diet (18 g/d of salt or 307.8 mmol/d of sodium). Differences in mean BP levels were compared according to the intervention phases using a paired Student's t-test. Results: A total of 528 participants were included in this study, with a mean age of 48.1 years, 36.7% of whom were male, 76.8% had a middle school (69.7%) or higher (7.1%) diploma, 23.4% had a history of smoking, and 24.4% were current drinkers. The mean arterial pressure at baseline was 97.2 ± 10.5 mm Hg for all participants, and significantly decreased during the low-salt intervention (93.8 ± 9.3, P

Background. Gastric cancer is the most common malignant tumor of the digestive system. It has a poor prognosis and is clinically challenging to treat. Ferroptosis is a newly defined mode of programmed cell death. The roles and prognostic value of ferroptosis-related long noncoding RNAs (lncRNAs) in gastric cancer remain unknown. Results. In the current study, 20 ferroptosis-related lncRNAs were identified via univariate Cox analysis, least absolute shrinkage, and selection operator Cox regression analysis and used to construct a prognostic signature and classify gastric cancer patients into high-risk and low-risk groups. The signature was validated using TCGA training and testing cohorts. The risk signature was an independent prognostic indicator of survival and accurately predicted the prognoses of patients with gastric cancer. It was also associated with immune cell infiltration. Gene set enrichment analysis was used to investigate underlying mechanisms that the 20 ferroptosis-related lncRNAs were involved in. Chemosensitivity and immune checkpoint inhibitor analyses indicated that high-risk patients were more sensitive to the immune checkpoint inhibitor programmed cell death protein 1. Conclusions. The important role of ferroptosis-related lncRNAs in immune infiltration identified in the current study may assist the determination of personalized prognoses and treatments in patients with gastric cancer. These 20 lncRNAs can be used as the diagnostic and prognostic markers for gastric cancer.

Chemoradiotherapy (CRT) has been widely applied in patients with advanced nasopharyngeal carcinoma (ANPC). However, limited imaging modality exists on the evaluation of early response to CRT. The purpose of this study was therefore to investigate whether 3D pseudo-continuous arterial spin labeling (3D pCASL) perfusion imaging could predict early response to CRT in ANPC patients.Seventy ANPC patients who received CRT underwent pre-treatment MRI including 3D pCASL perfusion measurements, and were categorized into response group (RG) and no-response group (NRG) according to RECIST 1.1. Pre-treatment 3D pCASL derived cerebral blood flow (CBF) values in tumors were compared between RG and NRG patients. Receiver-operating characteristic (ROC) analysis was performed to determine the optimal diagnostic cutoff value for CBF in predicting tumor response to CRT. Clinicopathological variables were also analyzed by using univariate and binary logistic regression. The corresponding obtained variables with statistical significance were further applied to create a nomogram in which the bootstrap resampling method was used for calibration.Forty-eight patients in RG had significantly higher pre-treatment CBF values in tumors compared with 22 patients in NRG (P 0.001). CBF showed the high area under the ROC curve (AUC = 0.843) in distinguishing RG from NRG patients. The corresponding cutoff value for CBF was 103.68 ml/100 g/min, with respective accuracy, sensitivity and specificity of 82.86%, 87.50% and 72.73%. The nomogram was generated by binary logistic regression results, incorporating three variables: CBF value, clinical stage and pathological type. The AUC, accuracy, sensitivity and specificity of the nomogram was respectively 0.893, 84.28%, 81.25% and 90.91% in predicting tumor response to CRT. Moreover, as shown in the calibration curve, a strong agreement was observed between nomogram prediction probability and actual clinical findings (P = 0.309).3D pCASL derived CBF in tumor could act as a noninvasive effective biomarker to predict tumor response to CRT in ANPC patients before clinical treatment. Furthermore, the nomogram combining CBF and clinicopathological variables could serve as a novel clinical analysis tool for treatment response prediction.

Cross-sectional studies have reported that high sodium sensitivity is more common among individuals with hypertension. Experimental studies have also reported various animal models with sodium-resistant hypertension. It is unknown, however, whether sodium sensitivity and resistance precede the development of hypertension. We conducted a feeding study, including a 7-day low-sodium diet (1180 mg/day) followed by a 7-day high-sodium diet (7081 mg/day), among 1718 Chinese adults with blood pressure (BP) P P =0.006 for nonlinear trend). Furthermore, a J-shaped association between systolic BP responses to sodium intake and incident hypertension was identified ( P

ObjectiveTo construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.MethodsUsing a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.ResultsDuring a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66–2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%–27.7%) and 13.6% (95% CI 11.6%–15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%–49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).ConclusionsOur metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.Classification of EvidenceThis study provides Class I evidence that metaPRS is predictive of stroke risk.

The rational design and construction of noble-metal-free electrocatalysts with high activity and robust durability for oxygen evolution reactions (OERs) have aroused immense interest in the past decades, but challenges remain. Herein, a reduction-induced dissolution–recrystallization (RIDR) strategy was developed to fabricate a defect-rich yolk–shell Prussian-blue analogue (YS-PBA) by a solvothermal process in isopropyl alcohol (IPA) in the presence of polyvinylpyrrolidone (PVP). The experimental result indicated that the defect-rich YS-PBA was formed via phase transformation from Co3[FeIII(CN)6]2 to Co2FeII(CN)6 induced by the reduction potential of the IPA-PVP couple. The newly synthesized YS-PBA exhibited outstanding OER performance with a low overpotential of 293 mV to deliver a current density of 10 mA cm−2 and long-term durability (120 h) in alkaline media. Both experimental and density functional theory (DFT) results unveiled that the defects formed in YS-PBA cause a dramatic positive effect on the improvement of the OER activity.

What is already known about this topic? Short-term PM2.5 exposure has been associated with hourly, 24-hour, daytime, and nighttime blood pressure (BP) levels, and further studies focusing whether and how the associations with other ambulatory BP monitoring indicators are warranted. What is added by this report? This study observed that short-term PM2.5 exposure was associated with BP elevations and was the first to report the associations of short-term PM2.5 exposure with BP variability. Circadian rhythm of BP and BP load among hypertensive patients were found to be modified by controlled BP status or taking angiotensin receptor blockers (ARBs). What are the implications for public health practice? This study suggested that antihypertensive therapy, especially with well-controlled BP status may be potential measurements to attenuate adverse impacts of PM2.5 for hypertensive patients with intermediate-to-high risk of cardiovascular disease (CVD).

Ablation of carbon/carbon (C/C) composites was investigated in a nitrogen plasma torch with a heat flux of ∼25 MW/m2. The reaction products of carbon in C/C composites and nitrogen plasma jet were calculated based on the principle of free energy minimum. The calculated results show that the thermal chemical ablation and sublimation of carbon occur and Cn(g) (n = 1–3), CN(g), C2N(g) and C2N2(g) may be the major reaction products consuming carbon. Ablation is apt to begin at the interfaces, especially the fibre-matrix interface and interfaces inside the matrix. Ablation of C/C composites is mainly controlled by the thermal chemical ablation, sublimation of carbon, and mechanical breakage. The formation of needle-shaped fibres and shell-shaped matrices is attributed to both the thermal chemical ablation and sublimation of carbon, while carbon fragments and fractured fibres or matrices result from the mechanical breakage.

BACKGROUND Differentiating nasopharyngeal carcinoma (NPC) from nasopharyngeal lymphoma (NPL) is useful for deciding the appropriate treatment. However, the diagnostic accuracy of current imaging methods is low. PURPOSE To explore the feasibility of arterial spin labeling (ASL) perfusion imaging in the qualitative and quantitative differentiation between NPC and NPL to improve the diagnosis of malignancies in the nasopharynx. STUDY TYPE Retrospective. POPULATION Ninety seven patients: NPC (65 cases) and NPL (32 cases), histologically confirmed. FIELD STRENGTH/SEQUENCE 3T/3D fast spin echo pseudo-continuous ASL imaging with spiral readout scheme, 3D inverse recovery- fast spoiled gradient recalled echo brain volume (BRAVO) imaging. ASSESSMENT Cerebral blood flow (CBF) images from ASL perfusion imaging were assessed by three radiologists. Each tumor was visually scored based on CBF images. Intratumoral CBF and intramuscular CBF values were obtained from intratumoral and lateral pterygoid muscle areas, respectively. Through dividing intratumoral CBF by intramuscular CBF, normalized CBF (nCBF) was further calculated. STATISTICAL TESTS Fleiss's kappa and intraclass correlation coefficients (ICCs) were used to assess interobserver agreement among the three readers. The Mann-Whitney U-test was used to compare visual scoring, and an unpaired t-test was performed to compare CBF value between the NPC and NPL groups. The area under the curve (AUC) value was used to quantify the diagnostic ability of each parameter. RESULTS Good interobserver agreements were validated by high Fleiss's kappa and ICC values (all >0.80). NPCs showed significantly higher visual scores than NPLs (P

Although emerging studies from high-income countries investigated the relationship between sedentary behavior (SB) and cardiovascular risk, little evidence came from developing countries. Moreover, the benefits of reallocating time from SB to physical activity (PA) on incident cardiovascular disease (CVD) are unknown. Using three cohorts from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project, we included 93 110 adults who were free from CVD at baseline. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD, including stroke, coronary heart disease, and CVD death. Isotemporal substitution models were applied to estimate the per-hour effects of replacing SB with PA. After 5.8 years follow-up, 3799 CVD cases were identified. A gradient positive association between sedentary time and incident CVD was observed. Relative to those with

Objective To investigate the function of discoidin domain receptor 1 (DDR1) in hepatocellular carcinoma (HCC) and to further clarify the underlying mechanism. Results DDR1 was significantly increased in HCC tissues and cells, which was related to clinical staging and prognosis of HCC. Upregulation of DDR1 promoted EMT and glutamine metabolism in HCC cells, while loss of DDR1 showed the opposite effects. STAT3 bound with the promoter of DDR1, and facilitated the phosphorylation of STAT3. In turn, activation of STAT3 increased the expression of DDR1. Silencing of STAT3 removed the promoting effect of DDR1 on proliferation, migration and invasion of HCC cells. The in vivo tumor growth assay showed that the cross-talk between DDR1 and STAT3 promoted HCC tumorigenesis. Conclusions Our research revealed the positive feedback of DDR1 and STAT3 promoted EMT and glutamine metabolism in HCC, which provided some experimental basis for clinical treatment or prevention of HCC. Materials and methods The mRNA expression of DDR1 was detected by qRT-PCR. CCK8 assay, wound healing assay and transwell assay were used to detect the DDR1/ STAT3 function on proliferation, migration and invasion in HCC cells. Western blot was used to calculate protein level of DDR1, STAT3, epithelial-mesenchymal transition (EMT) related proteins.

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding., Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.

Background:. The association of milk intake with cardiovascular disease (CVD) and cause-specific mortality remained controversial and evidence among the Chinese population was limited. We aimed to study the relationship between milk intake and CVDs among general Chinese adults. Methods:. A total of 104,957 participants received questionnaire survey. Results of physical examination such as anthropometric measurements and biochemical tests during 2007 to 2008, demographic data and their information on milk intake were collected through standardized questionnaires. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of CVD incidence, cause-specific mortality and all-cause mortality related to milk intake. Restricted cubic splines (RCSs) were applied to examine dose-response associations. Results:. Among the 91,757 participants with a median follow-up period of 5.8 years, we documented 3877 CVD cases and 4091 all-cause deaths. Compared with participants who never consumed milk, the multivariate-adjusted HRs (95% CIs) of CVD incidence for 1 to 150 g/day, 151 to 299 g/day, and ≥300 g/day were 0.94 (0.86–1.03) (P > 0.05), 0.77 (0.66–0.89) (P

A novel blue-emitting Mg₂La8(SiO₄)6O₂:Ce3+ phosphor with apatite-type nanostructure has been successfully synthesized via a conventional solid-state reaction. X-ray diffraction (XRD) and photoluminescence (PL) spectroscopy were used to characterize the as-prepared samples. The phosphor exhibited an absorption band ranging from 220 to 400 nm in the ultraviolet range and generated bright blue emission at 425 nm and 510 nm under different excitation wavelengths. The critical Ce3+ quenching concentration (QC) was determined to be about 7 mol%, and the corresponding QC mechanism was verified to be the dipole-dipole interactions.

Real-time assessment of therapeutic response in patients with advanced lung cancer presents a major challenge throughout the treatment process. Currently, computed tomography imaging is often used; however, it is radiation-based and hysteretic and is not suitable for repeated use as a real-time assessment. Blood biomarkers represent a novel solution for assessing therapeutic response in patients with advanced lung cancer. In the present study, the efficacy of a methylation marker [methylated prostaglandin E receptor 4 (mPTGER4)] and four protein markers [carcinoma antigen 125 (CA125), carcinoembryonic antigen (CEA), cytokeratin 19-fragments (cyfra21-1) and neuron-specific enolase (NSE)] were simultaneously evaluated to determine their potential in facilitating therapeutic response monitoring as well as their prognostic values in patients with stage IV lung cancer. The results indicated that, following treatment, the blood levels of methylated PTGER4 and NSE had significantly decreased, and mPRGER4, CA125, CEA and NSE exhibited a significant decrease in percentage level. Since mPTGER4 exhibited a higher rate of positive detection prior to therapy, and a greater response of sensitivity to therapy compared to the protein markers, it may represent an improved marker for the monitoring of therapeutic response. The efficacy of the markers in predicting the overall survival (OS) rate of patients with stage IV lung cancer was also assessed. Results from the follow-up of patients (up to 891 days) revealed that the blood levels of mPTGER4, CA125 and NSE before treatment were able to predict overall survival (OS) rate. Additionally, the percentage change in expression levels of CA125, CEA and NSE was also able to predict the OS rate. In conclusion, the present results indicate that mPTGER4 represents an improved biomarker for monitoring therapeutic efficacy compared with CA125, CEA, Cyfra21-1 and NSE. In predicting the long-term survival of patients with stage IV lung cancer; however, the pre-treatment levels of mPTGER4, CA125 and NSE and the percentage changes of CA125, CEA and NSE may be used as the markers.

Background Evidence of the effects of long-term fine particulate matter (PM2.5) exposure on cardiovascular diseases (CVDs) is rare for populations exposed to high levels of PM2.5 in China and in other countries with similarly high levels. Objectives The aim of this study was to assess the CVD risks associated with long-term exposure to PM2.5 in China. Methods A nationwide cohort study, China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China), was used, with 116,972 adults without CVD in 2000 being included. Participants were followed until 2015. Satellite-based PM2.5 concentrations at 1-km spatial resolution during the study period were used for exposure assessment. A Cox proportional hazards model with time-varying exposures was used to estimate the CVD risks associated with PM2.5 exposure, adjusting for individual risk factors. Results Annual mean concentrations of PM2.5 at the China-PAR sites ranged from 25.5 to 114.0 μg/m3. For each 10 μg/m3 increase in PM2.5 exposures, the multivariate-adjusted hazard ratio was 1.251 (95% confidence interval: 1.220 to 1.283) for CVD incidence and 1.164 (95% confidence interval: 1.117 to 1.213) for CVD mortality. The slopes of concentration-response functions of PM2.5 exposure and CVD risks were steeper at high PM2.5 levels. In addition, older residents, rural residents, and never smokers were more prone to adverse effects of PM2.5 exposure. Conclusions This study provides evidence that elevated long-term PM2.5 exposures lead to increased CVD risk in China. The effects are more pronounced at higher PM2.5 levels. These findings expand the current knowledge on adverse health effects of severe air pollution and highlight the potential cardiovascular benefits of air quality improvement in China and other low- and middle-income countries.

This meta-analysis was performed to quantitatively evaluate the dose-response association between obstructive sleep apnea (OSA) and risk of type 2 diabetes mellitus (T2DM).PubMed, Embase, and Web of Science were searched up to 12 December 2018 for articles that assessed the OSA-T2DM association. Random effects models were used to analyze the quantitative association between OSA and risk of T2DM. Restricted cubic splines were used to model the dose-response association between apnea-hypopnea index (AHI), used to assess the severity of OSA according to events/h, and risk of T2DM.We included 16 cohort studies in our meta-analysis. During a median follow-up of 10.5 years (range: 3.0-22.0), 19 355 T2DM cases were reported among 338 912 study participants. The pooled relative risk of T2DM was 1.40 (95% CI, 1.32-1.48) for OSA in the binary meta-analysis and 1.08 (1.01-1.14) for each 5-event/h increase in AHI value. We found a positive linear association between OSA and T2DM risk.Our dose-response meta-analysis revealed a linear association between OSA and T2DM.背景: 该研究对阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea, OSA)和2型糖尿病发病风险的关系进行定量评价, 并探索其潜在的剂量-反应关系。 方法: 检索PubMed、Embase和 Web of Science数据库中2018年12月12日前发表的关于OSA和2型糖尿病的相关性研究。采用随机效应模型定量分析OSA和2型糖尿病发病风险的关系。通过限制性立方样条模型评估呼吸暂停低通气指数(基于次数/小时评价OSA严重程度的指标)和2型糖尿病发病风险的剂量-反应关系。 结果: 本研究共纳入16个队列研究, 包括研究对象 338,912人, 随访时间为中位数10.5年(范围为3.0-22.0年), 随访期间19,355名研究对象确诊2型糖尿病。二元meta分析显示OSA使2型糖尿病的发病相对风险度为1.40 ( 95%CI:1.32-1.48), 呼吸暂停低通气指数每增加5次/小时, 2型糖尿病的发病相对风险度为1.08(95%CI:1.01-1.14)。OSA与2型糖尿病的发病风险成线性正相关。 结论: OSA的严重程度和2型糖尿病的发病风险有关, 且存在线性剂量-反应关系。.

Human dental pulp stem cells (hDPSCs), which are characterized by self-renewal capacity and the ability of multilineage differentiation, have gained increased attention in regenerative medicine recently. Histone acetylation modulator proteins (HAMPs) are a protein family that mediates the modification and identification of histone acetylation and participates in various critical cellular processes. Here, we comprehensively surveyed the expression profile of HAMPs during osteoblast differentiation of hDPSCs and found that the HDAC class III pathway was upregulated, whereas the signal transducer and activator of transcription 3 (STAT3) signaling was downregulated during osteogenesis. Further laboratory research demonstrated that Sirtuin-1 (SIRT1), a class III HDAC, was upregulated and STAT3 activation was downregulated during osteogenic differentiation. SIRT1 counteracted the activation of STAT3 to promote osteogenic differentiation of hDPSCs at 7 and 21 days in both Western blot assay and chemical staining, which highlights the promising utility of SIRT1 activators in hDPSCs-based therapies for bone augmentation strategies and provides clinical insights that may lead to the development of osteogenic agents.

Background The association of psychological factors with postoperative pain has been well documented. The incorporation of psychoeducational intervention into a standard analgesia protocol seems to be an attractive approach for the management of acute postoperative pain. Our study aimed to evaluate the impact of psychoeducational intervention on acute postoperative pain in pulmonary nodule (PN) patients treated with thoracoscopic surgery. Methods In this study, 76 PN patients treated with thoracoscopic surgery and intravenous patient-controlled analgesia (IV-PCA) plus psychoeducational evaluation and intervention were selected as the psychoeducational intervention group (PG). Another 76 PN patients receiving IV-PCA without psychoeducational intervention after thoracoscopic surgery, treated as the control group (CG), were identified from the hospital database and matched pairwise with PG patients according to age, sex, preoperative body mass index (BMI), opioid medications used for IV-PCA and the educational attainment of patients. Results The most common psychological disorders were anxiety and interpersonal sensitivity, which were recorded from 82.9% (63/76) and 63.2% (48/76) of PG patients. The numerical rating scale (NRS) pain scores of the PG patients were significantly lower than those of the CG patients at 2 and 24 h after surgery (P P = 0.038). PG patients had a significantly lower incidence of rescue analgesia than CG patients (28.9% vs. 44.7%, P = 0.044). Nausea/vomiting was the most common side effect of opioid medications, recorded for 3 (3.9%) PG patients and 10 (13.2%) CG patients (P = 0.042). In addition, no significant difference was observed between PG and CG patients in terms of grade 2 or higher postoperative complications (10.5% vs. 17.1%, P = 0.240). Conclusions Psychoeducational intervention for PN patients treated with thoracoscopic surgery resulted in reduced acute postoperative pain, less opioid consumption and fewer opioid-related side effects.

Jianfeng Huang,* Wenzheng Chen,* Changyu Chen,* Zhigang Jie, Tao Xiao Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhigang Jie; Tao Xiao, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, No. 1519 Dongyue Road, Nanchang, 330006, Jiangxi, People’s Republic of China, Email Jiezg123@126.com; xiaotao@ncu.edu.cnPurpose: N6-methyladenosine (m6A) RNA modification plays an important role in regulating tumor microenvironment (TME) infiltration. However, the relationship between the expression pattern of m6A-related long non-coding RNAs (lncRNAs) and the immune microenvironment of gastric cancer (GC) is unclear.Methods: In this study, 23 m6A-related lncRNAs were identified by Pearson’s correlation analysis and univariate Cox regression analysis. According to the expression of these lncRNAs, we identified two distinct molecular clusters by consensus clustering and compared the differences of the TME and enriched pathways between the two clusters. We further constructed a prognostic risk signature and verified it using The Cancer Genome Atlas training and testing cohorts.Results: The results showed that cluster 1 was associated with tumor-related and immune activation-related pathways. In addition, cluster 1 was also associated with higher ImmuneScore, StromalScore, and ESTIMATEScore. The results of the stratified survival analysis and independent prognosis analysis indicated that the risk signature is an independent prognostic indicator for patients with GC. In addition, it can effectively predict survival status in patients with different clinical characteristics. Furthermore, we found that the risk signature was associated with a variety of tumor-infiltrating immune cells, and that low risk scores were significantly correlated with high expression of programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), as well as sensitivity to chemotherapeutic drugs (eg, fluorouracil and oxaliplatin).Conclusion: This evidence contributes to our understanding of the regulation of TME infiltration by m6A-related lncRNAs and may lead to more effective immunotherapy and chemotherapy for patients with GC.Keywords: N6-methyladenosine, gastric cancer, tumor microenvironment, lncRNA risk signature, prognostic

Simple Summary There is strong evidence that locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) carries a significantly better prognosis than HPV negative OPSCC, suggesting the possibility of treatment de-escalation and, therefore, toxicity reduction in this patient population. The lack of success in clinical trials towards this end presses the need to risk stratify locally advanced HPV+ OPSCC patients who can safely have treatment de-escalated. The present study had recourse to radiomics for this purpose and showed that radiomics has the ability to discriminate patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone. The implications of this study aid in demonstrating the potential pivotal role of radiomics in predictive risk assessment and personalizing therapy for this patient population. Abstract (1) Background and purpose: clinical trials have unsuccessfully tried to de-escalate treatment in locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with the goal of reducing treatment toxicity. The aim of this study was to explore the role of radiomics for risk stratification in this patient population to guide treatment. (2) Methods: the study population consisted of 225 patients with locally advanced HPV+ OPSCC treated with curative-intent radiation or chemoradiation therapy. Appearance of distant metastasis was used as the endpoint event. Radiomics data were extracted from the gross tumor volumes (GTVs) identified on the planning CT, with gray level being discretized using three different bin widths (8, 16, and 32). The data extracted for the groups with and without distant metastasis were subsequently balanced using three different algorithms including synthetic minority over-sampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and borderline SMOTE. From these different combinations, a total of nine radiomics datasets were derived. Top features that minimized redundancy while maximizing relevance to the endpoint were selected individually and collectively for the nine radiomics datasets to build support vector machine (SVM) based predictive classifiers. Performance of the developed classifiers was evaluated by receiver operating characteristic (ROC) curve analysis. (3) Results: of the 225 locally advanced HPV+ OPSCC patients being studied, 9.3% had developed distant metastases at last follow-up. SVM classifiers built for the nine radiomics dataset using either their own respective top features or the top consensus ones were all able to differentiate the two cohorts at a level of excellence or beyond, with ROC area under curve (AUC) ranging from 0.84 to 0.95 (median = 0.90). ROC comparisons further revealed that the majority of the built classifiers did not distinguish the two cohorts significantly better than each other. (4) Conclusions: radiomics demonstrated discriminative ability in distinguishing patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone and may serve to risk stratify this patient population with the purpose of guiding the appropriate therapy.

Worldwide, the incidence rate of gastric cancer ranks fifth, and the mortality rate of gastric cancer ranks third among all malignant tumors. However, the pathogenesis of gastric cancer remains poorly understood. In this study, we demonstrated that the expression level of NELFE is higher in human gastric cancer tissues than in adjacent nontumor tissues. A high level of NELFE is associated with worse postoperative overall survival (OS) and relapse-free survival (RFS) rates in patients with gastric cancer. Moreover, the expression of NELFE is correlated with high tumor grade and lymph node metastasis in gastric cancer patients. Knockdown of NELFE dramatically inhibits the cell proliferation and metastasis of gastric cancer xenografts in vivo. Furthermore, we found that NELFE binding to the 3’UTR of E2F2 affects the mRNA stability of E2F2 to regulate the expression level of E2F2. In gastric cancer, E2F2 also acts as an oncogene to inhibit the proliferation and migration of gastric cancer cells by knocking down the expression level of E2F2. However, overexpressing E2F2 in cells with NELFE knockdown significantly reverses the inhibition of cell proliferation and migration induced by NELFE knockdown. Therefore, NELFE at least partially functions as an oncogene through E2F2. Moreover, CIBERSORTx analysis of the proportion of tumor-infiltrating immune cells (TICs) revealed that immune cells are correlated with NELFE and E2F2 expression, suggesting that NELFE and E2F2 might be responsible for the preservation of the immunodominant status for gastric cancer. In conclusion, NELFE acts as an oncogene in gastric cancer and can be used as a potential therapeutic target.

Although emerging researches have linked ambient fine particulate matter (PM(2.5)) to obesity, evidence from high-polluted regions is still lacking. We thus assessed the long-term impacts of PM(2.5) on body mass index (BMI) and the risk of the prevalence of overweight/obesity (BMI≥25 kg/m(2)), by incorporating the well-established Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project comprising 77,609 participants with satellite-based PM(2.5) estimates at 1-km spatial resolution. The average of long-term PM(2.5) level was 70.4 μg/m(3), with the range of 32.1–94.2 μg/m(3). Each 10 μg/m(3) increment of PM(2.5) was associated with 0.421 kg/m(2) (95% confidence interval [CI]: 0.402, 0.439) and 13.5% (95% CI: 12.8%, 14.3%) increased BMI and overweight/obesity risk, respectively. Moreover, compared with the lowest quartile of PM(2.5) (≤57.5 μg/m(3)), the relative risk of the prevalence of overweight/obesity from the highest quartile (>85.9 μg/m(3)) was 1.611 (95% CI: 1.566, 1.657). The exposure-response curve suggested a non-linear relationship between PM(2.5) exposure and overweight/obesity. Besides, the association was modified by age, diabetes mellitus, hypertension and dyslipidemia status. Our study provides the evidence for the adverse impacts of long-term PM(2.5) on BMI and overweight/obesity in China, and the findings are important for policy development on air quality, especially in severely polluted areas.

Objective We aimed to evaluate whether hypertriglyceridemic waist-to-height ratio (HWHtR) and its dynamic status was associated with hypertension (HTN). Methods We examined data for 10 312 nonhypertensive participants aged at least 18 years from the Rural Chinese Cohort Study at the baseline examination who were followed until 2014 with a median follow-up of 6 years. HWHtR was defined by combined triglyceride level and waist-to-height ratio (WHtR). Multiple logistic regression models were used to examine the probability of incident HTN according to HWHtR and its transformation, estimating odds ratios (ORs) and 95% confidence intervals (CIs). Results A total of 127 men and 225 women with high triglyceride level and high WHtR (HTHWH) had incident HTN during follow-up. After adjusting for potential confounders, the probability of HTN was increased with HTHWH for men [OR 1.49 (95% CI 1.01-2.20)] but this association was not significant for women [1.21 (0.88-1.66)]. The results of the sensitivity analyses were robust for men and women. The ORs were generally consistent on subgroup analysis by age,BMI, SBP and DBP for men. As compared with persistent normal triglyceride level and normal WHtR (NTNWH), the transformation from baseline NTNWH to follow-up HTHWH was associated with increased probability of HTN for men [OR 4.16 (95% CI 2.21-7.84)]. However, for women, the association of changed HWHtR from baseline to follow-up with probability of HTN was not significant for almost all transformation groups. Conclusion HWHtR and its dynamic status was associated with incident HTN for rural Chinese men. From this cohort study, HWHtR may be an indicator for interventions aiming to reduce HTN among these men.

Background and Purpose— Previous results on the association between lipids and stroke were controversial. We investigated the association of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C ), high-density lipoprotein cholesterol (HDL-C), and triglyceride with stroke. Methods— Six cohort studies in China with 267 500 participants were included. Cox proportional hazards regression models and restricted cubic spline analyses were used to estimate hazard ratios and 95% CIs and explore linear and nonlinear relationships of lipids and stroke, respectively. Results— The median follow-up duration ranged from 6 to 19 years. During 2 295 881 person-years, 8072 people developed stroke. Multivariable adjusted hazard ratios (95% CIs) per 1 mmol/L increase in TC, LDL-C, triglyceride were 1.08 (1.05–1.11), 1.08 (1.04–1.11), 1.07 (1.05-1.09) for ischemic stroke, respectively. Compared with participants with TC 160-199.9 mg/dL, hazard ratios (95% CIs) were 1.43 (1.11–1.85) for hemorrhagic stroke in those with TC P P =0.029 and P >0.05). Conclusions— TC, LDL-C, and triglyceride showed positive associations with ischemic stroke. The risk of hemorrhagic stroke was higher when TC was lower than 120 mg/dL. LDL-C and triglyceride showed no association with hemorrhagic stroke. The risks of ischemic and hemorrhagic stroke might be higher when HDL-C was lower than 50 mg/dL.

Objective To evaluate the impact of systematic nutrition management (SNM) on nutritional status, treatment-related toxicity, quality of life (QoL), response rates, and survival in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) treated by radiotherapy (RT). Methods In this retrospective study, 56 patients with LA-NPC were selected as nutrition management group (NG) for SNM during RT till 1 month later. Another 56 patients with LA-NPC receiving RT without SNM as control group (CG) were identified from the hospital database and matched pairs with NG patients according to age, gender, stage, and body mass index (BMI) prior to RT. Results At 1 month after RT, the percentage of malnourished patients with BMI 0.05) for the 2-year progression-free survival and overall survival (84.2% versus 79.5% and 94.7% versus 92.3%, respectively.). Conclusion SNM for LA-NPC patients treated by RT resulted in better nutritional status, reduced treatment-related toxicity and improved QoL.

Primary ciliary dyskinesia (PCD) is a rare phenotypically and genetically heterogeneous disorder resulting from abnormal cilia ultrastructure and function. Few studies have reported the phenotype and genetic characteristics of PCD caused by mutations in DNAAF3. In this study, four PCD patients with DNAAF3 mutations underwent extensive clinical assessments, cilia ultrastructural and motion evaluations. All patients presented with situs inversus totalis, neonatal respiratory distress, and sinusitis; however, they did not have recurrent infections of the lower airways. The nasal nitric oxide level of these patients was markedly reduced. The respiratory cilia were found to be uniformly immotile, with their dynein arms defects. A total of 7 (5 novel) variants in DNAAF3 were identified and cosegregated in their families by Trio-based whole-exome sequencing. As the first report on DNAAF3 mutations in PCD patients in China, our study not only contributes to a deeper appreciation of the phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis of and counseling for PCD.

The risk of incident hypertension associated with long-term exposure to fine particulate matter (PM 2.5 ) was still unclear by studies conducted in North America and Europe, and this relationship has rarely been quantified at higher ambient concentrations typically found in developing countries. We aimed to investigate the association between PM 2.5 and incident hypertension using the large-scale prospective cohorts in China. We included 59 456 participants without hypertension aged ≥18 years from the China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China) project. Data on ambient PM 2.5 at participants’ residential address were obtained during 2004 to 2015 using a satellite-based spatial-temporal model. Hazard ratios and 95% CIs were calculated for incident hypertension using stratified Cox proportional hazards models with adjustment of potential confounders. The findings indicated that average PM 2.5 concentration from 2004 to 2015 at study participants’ address was 77.7 μg/m 3 . During the follow-up of 364 947 person-years, we identified 13 981 incident hypertension cases. Compared with the lowest quartile exposure of PM 2.5 , participants in the highest quartile had an increased risk of incident hypertension with a hazard ratio (95% CI) of 1.77 (1.56–2.00). Each 10 μg/m 3 increment of PM 2.5 concentration could increase 11% risk of hypertension (hazard ratio, 1.11; 95% CI, 1.05–1.17). This cohort study provided the first evidence from China that long-term exposure to PM 2.5 was independently associated with incident hypertension at relatively high ambient concentrations. Stringent strategies on PM 2.5 pollution control are warranted to improve the air quality and contribute to the reduction of disease burden of hypertension in China.

Purpose: Lung adenocarcinoma (LUAD) is a main subtype of lung cancer, which is the leading cause of cancer-related deaths. The five-year survival rates of lung cancer patients are still comparatively low. Therefore, potential therapeutic targets are urgently needed to improve the survival of lung cancer patients. In this study, we identified FAM111B as an oncogene and potential therapeutic target for LUAD. Methods: The TCGA database and tissue microarray analysis were used to compare the expression of FAM111B in tumor tissue and normal tissues and evaluate the relationship between FAM111B expression and clinical survival. FAM111B was knocked down and overexpressed to observe whether FAM111B could affect the proliferation, migration, cell cycle, and apoptosis of LUAD cells in vivo and in vitro. Results: FAM111B was highly expressed in tumor tissues compared with normal tissues (P

Elevated resting heart rate (RHR) is associated with risk of type 2 diabetes mellitus (T2DM). However, the association of change in RHR (ΔRHR) and incident T2DM is not fully elucidated. We aimed to assess the dose-response association between 6-year ΔRHR and T2DM.A total of 12155 non-T2DM participants ≥18 years old were enrolled during 2007-2008 and followed up during 2013-2014. ΔRHR was calculated by subtracting the baseline RHR from the RHR value at 6-year follow-up. Age-, sex-, and RHR-specific relative risks (RRs) and 95% confidence intervals (CIs) for the effect of ΔRHR on incident T2DM were calculated by using modified Poisson regression models. As compared with ΔRHR of 0 beats/min, the adjusted risk of T2DM was significantly increased with RHR increment and reduced with RHR reduction. ΔRHR was positively associated with future risk of T2DM [RR per unit increase: 1.03 (1.03-1.04)]. As compared with stable change in RHR group (-5ΔRHR5 beats/min), for ΔRHR ≤ -10 beats/min, -10ΔRHR ≤ -5 beats/min, 5≤ΔRHR10 beats/min, and ΔRHR ≥10 beats/min groups, the pooled adjusted RR (95% CI) of T2DM was 0.69 (0.55-0.86), 0.90 (0.73-1.11), 1.31 (1.07-1.61), and 1.90 (1.59-2.26), respectively. This significant association still existed on subgroup analyses based on age, sex, and baseline RHR and sensitivity analyses.Dynamic RHR change was significantly associated with incident T2DM. Our study suggests that RHR may be a non-invasive clinical indicator for interventions aiming to reduce incident T2DM in the general population.

Background Although cancer has become one of the leading health burdens, to the authors' knowledge, evidence regarding its relationship with a healthy lifestyle in the Chinese population remains limited. Methods The authors evaluated the association between clustering of healthy lifestyle factors and cancer risk using 3 prospective cohort studies with 101,208 Chinese adults from the general population. Hazard ratios (HRs) and corresponding 95% confidential intervals (95% CIs) related to healthy lifestyle factors were calculated using Cox proportional hazard models, and population-attributable risk percentages were estimated further. Results The results demonstrated that each additional healthy lifestyle factor was associated with a 6% (range, 3%-9%) lower risk of overall cancer. Compared with having none to 3 healthy lifestyle factors, HRs related to adherence to all 6 healthy lifestyle factors were 0.78 (95% CI, 0.60-1.02) and 0.82 (95% CI, 0.67-1.00), respectively, for men and women. It was estimated that approximately 18.4% and 2.3%, respectively, of overall cancer cases for men and women were attributable to nonadherence to all 6 healthy lifestyle factors. Conclusions The results of the current study indicate that adherence to clustering of healthy lifestyle factors was associated with a reduced risk of cancer incidence among Chinese adults. Greater efforts urgently are needed to promote the adoption of multiple healthy lifestyle behaviors to reduce the increasing burden of cancer.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Previous studies revealed that fine particulate matter (PM 2.5 ) exposure adversely affected blood pressure (BP), but factors that might attenuate this association were still unclear. Using a multicenter panel study among 277 hypertensive participants with intermediate-to-high risk of cardiovascular disease from 4 cities in China, we aimed to explore whether BP control status and antihypertensive medications were potential modifying factors. Each participant carried personal-portable monitors to record individual real-time PM 2.5 levels and 24-hour ambulatory BP up to 3× within 1 year. Generalized linear mixed model with individual-specific random intercept was used to assess effect sizes. We identified adverse impacts of short-term PM 2.5 exposure on BP. However, these impacts were attenuated among patients with controlled BP. For example, per interquartile range (43.78 µg/m 3 ) increment in the prior 10-hour moving average of PM 2.5 , systolic BP increased −0.20 (95% CI, −0.57 to 0.18) mm Hg and 0.85 (95% CI, 0.36–1.35) mm Hg among those with controlled and uncontrolled BP, respectively ( P interaction , 0.0009). Furthermore, among those with uncontrolled BP, treatment with angiotensin receptor blocker would potentially lower BP in responses to PM 2.5 , with systolic BP associated with per interquartile range increment in 10-hour moving average PM 2.5 of 0.32 (95% CI, −0.37 to 1.00) mm Hg and 1.53 (95% CI, 0.74–2.33) mm Hg among those taking angiotensin receptor blocker or not, respectively ( P interaction , 0.0229). In conclusion, although PM 2.5 exposure would increase BP, keeping well-controlled BP status and using angiotensin receptor blockers might attenuate these adverse impacts, which might provide supporting evidence for guiding hypertensive patients who live in areas with high level of PM 2.5 .

Altered expression of miR-182 has been observed in various types of human cancer. The purpose of this study was to investigate the expression of miR-182 and its role in prostate cancer (PCa). Expression of miR-182 and ST6GALNAC5 in tumor tissues and the Du145 PCa cell line was analyzed. Cell proliferation assay, colony formation assay, transwell assay, and wound healing assay were performed. The impact of miR-182 on tumor growth was investigated using a xenograft model. The results indicated that expression of miR-182 was higher in PCa tissues and cell lines, while ST6GALNAC5 was decreased. Downregulating miR-182 significantly inhibited the capacities of proliferation and invasion of PC3 and Du145 cells. ST6GALNAC5 was demonstrated to be a target of miR-182 by luciferase assay, and western blot results indicated PI3K/Akt pathway was involved in miR-182 associated effects on PC3 and Du145 cells. The animal experiment suggested that knockdown of miR-182 inhibited tumor growth. Our study proved that miR-182 participated in the proliferation and invasion of PCa cells via mediating expression of ST6GALNAC5 and established a miR-182/ST6GALNAC5/PI3K/AKT axis in regulation of tumor progression. Our investigation provided a basis for further exploration of the application of miR-182 or ST6GALNAC5-associated therapies for PCa patients.

Introduction Studies investigating the effect of high-density lipoprotein cholesterol (HDL-C) on stroke and stroke subtypes have reached inconsistent conclusions. The purpose of our study was to clarify the dose–response association between HDL-C level and risk of total stroke and stroke subtypes by a systematic review and meta-analysis. Methods We performed a systematic search of PubMed, Embase, and Web of Science databases through July 30, 2020, for prospective cohort studies that reported the HDL-C–stroke association and extracted the estimate that was adjusted for the greatest number of confounding factors. Restricted cubic splines were used to evaluate the linear and nonlinear dose–response associations. Results We included 29 articles, which reported on 62 prospective cohort studies including 900,501 study participants and 25,678 with stroke. The summary relative risk per 1-mmol/L increase in HDL-C level for total stroke was 0.82 (95% CI, 0.76–0.89; I 2 = 42.9%; n = 18); ischemic stroke (IS), 0.75 (95% CI, 0.69–0.82; I 2 = 50.1%; n = 22); intracerebral hemorrhage (ICH), 1.21 (95% CI, 1.04–1.42; I 2 = 33.4%; n = 10); and subarachnoid hemorrhage (SAH), 0.98 (95% CI, 0.96–1.00; I 2 = 0%; n = 7). We found a linear inverse association between HDL-C level and risk of total stroke and SAH, a nonlinear inverse association for IS risk, but a linear positive association for ICH risk. The strength and the direction of the effect size estimate for total stroke, IS, ICH, and SAH remained stable for most subgroups. We found no publication bias with Begg’s test and Egger’s test for the association of HDL-C level with risk of total stroke, IS, and ICH. Conclusion A high HDL-C level is associated with reduced risk of total stroke and IS and an increased risk of ICH.

Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity., p62 is a signaling hub protein that contributes to the control of energy expenditure. Here the authors investigate the relative roles of p62 and a similar protein, NBR1, and show that NBR1 is required for the repression of thermogenesis in adipocytes occurring in the absence of p62.

Aims. To compare the relationship between the nonperfusion area (NPA) on ultra-widefield fluorescein angiography (UWFFA) and the nonflow area (NFA) on optical coherence tomographic angiography (OCTA) in retinal vein occlusion (RVO). Methods. Cross-sectional study. 46 eyes of 46 RVO patients who underwent UWFFA and OCTA. NPA and ischemic index (ISI) were quantified on UWWFA. NFA, vessel density (VD) of the superficial capillary plexus (SCP), the deep capillary plexus (DCP), and the size foveal avascular zone (FAZ) on 3 ∗ 3 mm OCTA were measured. The association of the NPA and ISI on UWWFA and the parameters on OCTA were analyzed. Spearman correlation was used for statistical testing. Results. The NPA and ISI on UWFFA were significantly correlated with the NFA on OCTA in RVO, and r values were 0.688 ( p < 0.01 ) and 0.680 ( p < 0.01 ), respectively. VD in the SCP of the temporal quadrant was negatively correlated with NPA and ISI, and r values were −0.346 ( p < 0.05 ) and −0.337 ( p < 0.05 ), respectively. VD in the DCP of the temporal quadrant was negatively correlated with the NPA, and the r value was −0.246 ( p < 0.05 ). No significant correlation was found between the NPA and ISI on UWFFA and VD of other quadrants in the SCP or DCP and the FAZ area on OCTA. Conclusion. NPA in the peripheral retina was correlated with NFA in macula. NFA detected by OCTA could be an indicator of the ischemic status in RVO.

Background World Health Organization (WHO) released region-specific cardiovascular disease (CVD) risk prediction charts recently, but the extent to which the charts can apply to Chinese population is unknown. We aimed to validate the WHO CVD risk charts for East Asia, and evaluate their practicability combining with China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China) equations among Chinese adults. Methods The China-PAR cohort with 93,234 participants aged 40–80 years was followed up during 1992–2015, including 29,337 participants from three sub-cohorts with follow-up period of over 10 years. We validated the WHO CVD risk charts using the China-PAR cohort by assessment of the predicted number of events, C index, calibration χ², and calibration plots, further elaborated the concordance between the China-PAR equations and the WHO risk charts. Findings During an average follow-up of 13•64 years, 1849 incident CVD cases were identified from 29,337 participants. Both the laboratory-based and non-laboratory-based charts overestimated CVD events by 59% and 58% in men, and by 72% and 85% in women, respectively. However, 92% of participants identified as high risk by the China-PAR equations could be successfully detected by the laboratory-based charts at the cut-off point of 10%. We also observed that the non-laboratory-based charts demonstrated the poor performance for diabetic population, with high proportion of high-risk individuals (17% for men, 31% for women) would be missed. Interpretation Although the WHO CVD risk charts for East Asia apparently overestimated CVD risk among Chinese population, they could be pragmatic pre-selection tools, as potential supplement to the China-PAR equations. The widespread use of the WHO risk charts along with the China-PAR equations might facilitate the implementation of the risk-based CVD prevention in China. Funding Full funding sources are listed at the end of the paper (see Acknowledgments).

Aims Chemerin is abundant in patients with high body mass index and metabolic syndrome possibly due to its activation in adipogenesis and glucose intolerance. It has reported that sera chemerin is positively associated with fatty liver with little known underlying mechanisms. Our aim is to study the role of chemerin in hepatic lipid metabolism. Main methods Oil Red O staining and TG quantitative assay were used to detect intracellular lipid accumulation. PCR, QPCR and western blot were applied to measure lipid metabolism-related genes, CMKLR1, GPR1 and inflammation marker genes. Luciferase reporter assay was employed to uncover the down-regulation of proximate promoter activities of CMKLR1 and GPR1 by SREBP1c. Antibody neutralization assay was used to address the effects of chemerin on hepatic lipid synthesis. Key findings Over-expression of chemerin led to passive lipid accumulation, in human hepatoma cell line HepG2. The disable form of chemerin (chemerin 21–158) and active chemerin (chemerin 21–157) performed strongly effects on lipid metabolism in HepG2 cells. Heterologous expression of CMKLR1 or G-protein coupled receptor1 (GPR1) played similar roles in hepatocyte lipid metabolism as chemerin. Chemerin exerted its effects on lipid metabolism via GPR1 in HepG2 cells. Furthermore, free fatty acids and high concentration insulin inhibited chemerin expression. Consistently, the key lipogenic transcription factor Sterol regulatory element binding protein 1c suppressed chemerin mRNA expression and proximate promoter activities of CMKLR1 and GPR1. Significance It implied the existence of negative feed-back regulation and further confirmed the involvement of chemerin in hepatic lipid metabolism.

Background Glycine-N-acyltransferase-like 1 (GLYATL1), which is involved in the detoxification of endogenous and exogenous acyl-CoA, promotes glutamine metabolism in xenobiotic metabolism. Recent evidence suggests an association between GLYATL1 and tumors. However, there are few comprehensive analyses of GLYATL1 in cancers. We evaluated the expression and prognostic value of GLYATL1 and explored the mechanism underlying the association between GLYATL1 and cancers. Methods GLYATL1 mRNA expression across cancers was investigated in the Oncomine database and confirmed in the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Next, its prognostic value in different cancers was revealed by PrognoScan and Kaplan-Meier plotter. According to clinicopathologic features, we conducted a subgroup analysis of the prognosis of GLYATL1 in a cohort of hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas (TCGA) and the GSE116174 dataset. We further investigated the GLYATL1 promoter methylation profile in HCC. Next, a protein-protein interaction (PPI) network was constructed via the Search Tool for the Retrieval of Interacting Genes (STRING) database. Finally, we utilized gene set enrichment analysis (GSEA) to identify significantly enriched pathways and confirmed their associations using the Tumor Immune Estimation Resource (TIMER) and GEPIA databases. Results GLYATL1 is downregulated in many cancers and indicates a poor prognosis. Specifically, low GLYATL1 expression was associated with short overall survival (OS) in HCC patients. Interestingly, GLYATL1 expression was associated with poor OS in stage I-II HCC patients and was revealed as an independent prognostic factor. The promoter methylation level of GLYATL1 in HCC tissue was significantly higher than that in normal liver tissue. The PPI network suggested that GLYATL1 is co-expressed with ten genes, including CNGA3 and GNB5. GSEA revealed that GLYATL1 is predominantly negatively enriched in xenobiotic metabolism, and the gene association analysis in TIMER and GEPIA showed a significantly negative association between the expression of GLYATL1 and the expression of most genes involved in mitochondrial glutamine metabolism, including SLC1A5 and SLC1A11. Conclusions Our study is the first to shed light on the expression and prognostic value of GLYATL1 in cancers and provide a potential regulatory mechanism underlying HCC development.

Highlights • Sedentary behavior is associated with higher risks of cancer incidence, cancer mortality and all-cause mortality, as well as earlier onset of cancer and shorter life expectancy, among the Chinese population. • J-shaped dose–response relationships were observed between daily sedentary time and risks of cancer incidence and mortality, and the lowest risks were seen at 6 h/day. • Significant adverse effects of sedentary behavior on cancer incidence and mortality are independent of the level of moderate-to-vigorous physical activity. • The present study indicates that a reduction in sedentary behavior, in addition to an increase in physical activity, is recommended for the prevention of cancer and mortality., Background Inconsistent results have been reported in developed countries for relationships between sedentary behavior and cancer incidence and mortality, and evidence from the Chinese population is scarce. This study aimed to investigate such relationships in large Chinese population-based prospective cohorts and to explore the joint effect and interaction of sedentary behavior and moderate-to-vigorous physical activity (MVPA) on these relationships. Methods We included 95,319 Chinese adults without cancer from 3 large cohorts and assessed their sedentary behavior and physical activity with a unified questionnaire. Cancer incidence and mortality were confirmed by interviewing participants or their proxies and checking hospital records and death certificates. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) for cancer and mortality were estimated using Cox proportional hazards regression models. Results During 559,002 person-years of follow-up, 2388 cancer events, 1571 cancer deaths, and 4562 all-cause deaths were recorded. Sedentary behavior was associated with increased risk of developing cancer and deaths in a dose–response manner. The multivariable-adjusted HRs (95%CIs) were the following: HR = 1.16, 95%CI: 1.01‒1.33; HR = 1.24, 95%CI: 1.04‒1.48; and HR = 1.15, 95%CI: 1.04‒1.28 for cancer incidence, cancer mortality, and all-cause mortality, respectively, for those having ≥10 h/day of sedentary time compared with those having, Graphical abstract Image, graphical abstract

Background: Pharmacologic targeting of components of the MAPK/ERK pathway in differentiated thyroid carcinoma (DTC) is often limited due to the development of adaptive resistance. However, the detailed mechanism of MEK inhibitor (MEKi) resistance is not fully understood. Methods: RNA-seq of the constructed MEKi-resistant DTC cell line BCPAP-R (compared with the BCPAP line) was performed to investigate the intrinsic mechanism of drug resistance. Colony formation assays, cell viability assays, and cell cycle analysis were performed, and various murine models, including xenograft models, long-term MEKi-treated models, and transgenic model were used to evaluate the treatment effect of combination therapy (SHP099 and selumetinib). Findings: MEKi-resistant models were constructed successfully, in which multiple receptor tyrosine kinases (RTKs) signaling pathways and Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream target of many RTKs, we first found that blockade of SHP2 enhanced the sensitivity to MEKi in constructed MEKi-resistant thyroid cancer models (including constructed cell lines and a long-term MEKi-treated murine model). Interestingly, we also found that compared with MEKi treatment alone, MEKi in combination with an SHP2 inhibitor markedly suppressed the reactivation of the MEK/ERK pathway; thus, the addition of the SHP2 inhibitor significantly improved the anti-tumor effects of MEKi. The synergistic suppression of DTC upon treatment with both inhibitors was futher confirmed in xenograft models and transgenic models. Interpretation: RTKs activation leads to reactivation of the MAPK pathway and resistance to MEKi in DTC, which is reversed by SHP2 blockade. As a novel active inhibitor of SHP2, SHP099 in combination with selumetinib is a promising therapeutic approach for advanced DTC and MEKi-resistant one. Funding Statement: This work was partially supported by grants from the National Natural Science Foundation of China (GRANT no. 81872169), Tianjin Key Research and Development Program Science and Technology Support Key Projects (grant no. 17YFZCSY00690), and Tianjin Municipal Science and Technology Project (grant no. 19JCYBJC27400). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: All animal experiments were approved by the Tianjin Medical University Cancer Institute and the Hospital Animal Care and Use Committee and performed according to the IACUC protocol.

Background. The tumor microenvironment (TME) is associated with disease outcomes and treatment response in colon cancer. Here, we constructed a TME-related gene signature that is prognosis of disease survival and may predict response to immunotherapy in colon cancer. Methods. We calculated immune and stromal scores for 385 colon cancer samples from The Cancer Genome Atlas (TCGA) database using the ESTIMATE algorithm. We identified nine TME-related prognostic genes using Cox regression analysis. We evaluated associations between protein expression, extent of immune cell infiltrate, and patient survival. We calculated risk scores and built a clinical predictive model for the TME-related gene signature. Receiver operating characteristic (ROC) curves were generated to assess the predictive power of the signature. We estimated the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs in patients using the pRRophetic algorithm. The expression of immune checkpoint genes was evaluated. Results. High immune and stromal scores are significantly associated with poor overall survival ( p < 0.05 ). We identified 773 differential TME-related prognostic genes associated with survival; these genes were enriched in immune-related pathways. Nine key prognostic genes were identified and were used to construct a TME-related prognostic signature: CADM3, LEP, CD1B, PDE1B, CCL22, ABI3BP, IGLON5, SELE, and TGFB1. This signature identified a high-risk group with worse survival outcomes, based on Kaplan-Meier analysis. A nomogram composed of clinicopathological factors and risk score exhibited good accuracy. Drug sensitivity analysis identified no difference in sensitivity between the high-risk and low-risk groups. High-risk patients had higher expression of PD-1, PDL-1, and CTLA-4 and lower expression of LAG-3 and VSIR. Infiltration of dendritic cells was higher in the high-risk group. Conclusions. We identified a novel prognostic TME-related gene expression signature in colon cancer. Stratification of patients based on this gene signature could be used to improve outcomes and guide better therapy for colon cancer patients.

MiR-520b belongs to the miR-373/520 family, is expressed only in human and nonhuman primates. Previous reports indicated that the expression of miR-520b was repressed in human atherosclerotic plaque tissue compared with healthy vessels. However, the role of miR-520b in coronary artery disease still remains to be uncovered. In this study, we demonstrated that endothelial cells (ECs) in human atherosclerotic plaques expressed miR-520b and aimed to elucidate the impact of miR-520b on EC activation and inflammatory response. To determine the potential targets of miR-520b, we performed RNA-seq analysis by transfecting miR-520b mimics in ECs. The quantitative real-time PCR (qPCR) validation suggested that miR-520b over-expression reduced pro-inflammatory gene expression (e.g. ICAM1, VCAM1, SELE) while the inhibition of miR-520b induced their expression. By combining bioinformatics prediction and functional assays, we identified that RELA (Nuclear Factor-κB (NF-κB) Transcription Factor P65) was a direct target of miR-520b. Moreover, miR-520b mimics attenuated monocyte adhesion and monocyte trans-endothelial migration (the initial steps of atherosclerotic formation) in response to lipopolysaccharides (LPS) stimulation. Re-expression of a non-miR-targetable version of p65 could rescue the reduced monocyte cell attachment, suggesting that this process is NF-κB p65 dependent. MiR-520b reduced the abundance of NF-κB p65 in cytoplasmic fractions without corresponding increase in nuclear fractions, indicating that this regulation is independent of p65 translocation process. MiR-520b mimics attenuated the activity of VCAM-1 promoter, whereas miR-520b inhibitor activated its activity. However, miR-520b inhibitor had no effect on promoter activity containing the mutated NF-κB p65 binding sites, strongly demonstrating that the impact of miR-520b on VCAM1 gene is mediated by NF-κB p65. Thus, we concluded that miR-520b suppressed EC inflammation and the cross-talk between monocytes and ECs by down-regulating NF-κB p65-ICAM1/VCAM1 axis and might serve as a potential therapeutic target for EC dysfunction and atherosclerosis.

Background While the relationship between ambient air pollution and diabetes mellitus has recently been reported, data on the association between fine particulate matter (PM2.5) and diabetic complications are limited, especially in microvascular diseases such as diabetic retinopathy. Objectives To investigate the associations between long-term exposure to PM2.5 and the prevalence of diabetic retinopathy in adult diabetic patients in rural China. Methods The study population was based on the Rural Epidemiology for Glaucoma in China (REG-China), a national cross-sectional survey conducted in rural China. This analysis selected diabetic patients with or without diabetic retinopathy. A satellite-based spatiotemporal model was used to estimate personal PM2.5 exposure. Logistic regression models were used to investigate the effect of long-term PM2.5 exposure on diabetic retinopathy. Results The analysis included 3111 diabetic participants, 329 of whom were diagnosed with diabetic retinopathy. The median level of exposure to PM2.5 from 2000 to2016 was 59.9 μg/m3. For each 10 μg/m3 increase in PM2.5, the adjusted odds ratio (95% confidence interval) for diabetic retinopathy was 1.41 (1.27, 1.57). In subgroup analyses, the effect of PM2.5 on diabetic retinopathy was significantly stronger in participants who self-reported alcohol consumption. Conclusion These findings suggest that long-term exposure to high PM2.5 was associated with the risk of diabetic retinopathy among diabetic patients in rural China.