Verification of the expression trend and interaction prediction of innate immune cells and immune-checkpoint molecules in the process of oral mucosal carcinogenesis.

OBJECTIVES: This study aimed to explore the expression trends of innate immune cells and immune-checkpoint molecules validated by data calculation in the process of oral mucosal carcinogenesis, as well as to explore methods of suppressing oral mucosal carcinogenesis based on immunotherapy by predicting their interactions. Me-thods 1) The cancer genome atlas (TCGA) database comprehensively scores immune cells and immune-checkpoint molecules in the process of oral mucosal carcinogenesis and screens out intrinsic immune cells and immune-checkpoint molecules that interfere with tumor immune escape. 2) Clinical patient blood routine data were collected for the statistical analysis of peripheral blood immune cells during the progression of oral mucosal carcinogenesis. Immune cells in peripheral blood that may affect the progression of oral mucosal carcinogenesis were screened. 3) Immunohistochemical staining was performed on intrinsic immune cells and immune-checkpoint molecules validated based on data calculation in various stages of oral mucosal carcinogenesis. 4) Special staining was used to identify innate immune cells in various stages of oral mucosal carcinogenesis based on data-calculation verification. 5) Survival analysis was conducted on intrinsic immune cells and immune-checkpoint molecules validated based on data calculation during the process of oral mucosal carcinogenesis. The association of intrinsic immune cells and immune-checkpoint molecules with the prognosis of oral squamous cell carcinoma was verified. RESULTS: The expression of monocytes and neutrophils increased during the process of oral mucosal carcinogenesis. The expression of eosinophils showed a single peak trend of up and down. The expression of mast cells decreased. In the process of oral mucosal carcinogenesis, the expression of the immune-checkpoint molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death-ligand (PD-L1) increased. The expression trends of monocytes, neutrophils, and eosinophils were positively correlated with those of CTLA4 and PD-L1 immune-checkpoint molecules. The expression trend of mast cells was negatively correlated with the expression of CTLA4 and PD-L1. Monocytes, neutrophils, and eosinophils may promote tumor immune escape mediated by CTLA4 and/or PD-L1, thereby accelerating the progression of oral mucosal carcinogenesis. Mast cells may inhibit tumor immune escape mediated by CTLA4 and/or PD-L1, delaying the progression of oral mucosal carcinogenesis. CONCLUSIONS: Therefore, interference with specific immune cells in innate immunity can regulate the expression of CTLA4 and/or PD-L1 to a certain extent, inhibit tumor immune escape, and delay the progression of oral mucosal carcinogenesis.

Risk factors associated with heatwave mortality in Chinese adults over 65 years.

Aging populations are susceptible to heat-related mortality because of physiological factors and comorbidities. However, the understanding of individual vulnerabilities in the aging population is incomplete. In the Chinese Longitudinal Healthy Longevity Survey, we assessed daily heatwave exposure individually for 13,527 participants (median age = 89 years) and 3,249 summer mortalities during follow-up from 2008 to 2018. The mortality risk during heatwave days according to relative temperature is approximately doubled (hazard ratio (HR) range = 1.78-1.98). We found that heatwave mortality risks were increased for individuals with functional declines in mobility (HR range = 2.32-3.20), dependency in activities of daily living (HR range = 2.22-3.27), cognitive impairment (HR = 2.22) and social isolation reflected by having nobody to ask for help during difficulties (HR range = 2.14-10.21). Contrary to current understanding, older age was not predictive of heatwave mortality risk after accounting for individual functional declines; no statistical differences were detected according to sex. Beyond age as a risk factor, our findings emphasize that functional aging is an underlying factor in enhancing heatwave resilience. Assessment of functional decline and implementing care strategies are crucial for targeted prevention of mortality during heatwaves.

Acidity-induced ITGB6 promote migration and invasion of lung cancer cells by epithelial-mesenchymal transition and focal adhesion.

Non-small cell lung cancer (NSCLC) is a prevalent tumor and acidic tumor microenvironment provides an energy source driving tumor progression. We previously demonstrated significantly upregulated Integrin ß6 (ITGB6) in NSCLC cells. This study was designed to investigate the role of ITGB6 in NSCLC metastasis and explore the potential mechanisms. The expression of ITGB6 was evaluated in patients with NSCLC. Migration and invasion assays were utilized to investigate the role of ITGB6, and ChIP-qPCR and dual-luciferase reporter experiments preliminarily analyzed the relationship between ETS proto-oncogene 1 (ETS1) and ITGB6. Bioinformatics analysis and rescue models were performed to explore the underlying mechanisms. The results demonstrated that ITGB6 was upregulated in NSCLC patients and the difference was even more pronounced in patients with poor prognosis. Functionally, acidity-induced ITGB6 promoted migration and invasion of NSCLC cells in vitro, and epithelial-mesenchymal transition (EMT) and focal adhesion were the important mechanisms responsible for ITGB6-involved metastasis. Mechanistically, we revealed ETS1 enriched in the ITGB6 promoter region and promoted transcription to triggered the activation of subsequent signaling pathways. Moreover, ChIP-qPCR and dual-luciferase reporter experiments demonstrated that ETS1 played an important role in directly mediating ITGB6 expression. Furthermore, we found ITGB6 was responsible for the acidic microenvironment-mediated migration and invasion processes in NSCLC by performing rescue experiments with ITGB6 knockdown. Our findings indicated acidic microenvironment directly induced ETS1 to regulate the expression of ITGB6, and then the highly expressed ITGB6 further mediate EMT and activates the downstream focal adhesion pathways, eventually promotes the invasion and migration in NSCLC progression and metastasis.

Real-World Evidence of Multiple Air Pollutants and Mortality: A Prospective Cohort Study in an Oldest-Old Population.

We aimed to report real-world longitudinal ambient air pollutants levels compared to WHO Air Quality Guidelines (AQG) and analyze multiple air pollutants' joint effect on longevity, and the modification and confounding from the climate and urbanization with a focus on the oldest-old. This study included 13,207 old participants with 73.3% aged 80 and beyond, followed up from 2008 to 2018 in 23 Chinese provinces. We used the Cox-proportional hazards model and quantile-based g-computation model to measure separate and joint effects of the multiple pollutants. We adjusted for climate and area economic factors based on a directed acyclic graph. In 2018, no participants met the WHO AQG for PM2.5 and O3, and about one-third met the AQG for NO2. The hazard ratio (HR) for mortality was 1.07 (95% confidence interval-CI: 1.05, 1.09) per decile increase in all three pollutants, with PM2.5 being the dominant contributor according to the quantile-based g-computation model. In the three-pollutant model, the HRs (95% CI) for PM2.5 and NO2 were 1.27 (1.25, 1.3) and 1.08 (1.05, 1.12) per 10 µg/m3 increase, respectively. The oldest-old experienced a much lower mortality risk from air pollution compared to the young-old. The mortality risk of PM2.5 was higher in areas with higher annual average temperatures. The adjustment of road density considerably intensified the association between NO2 and mortality. The ambient PM2.5 and O3 levels in China exceeded the WHO AQG target substantially. Multiple pollutants coexposure, confounding, and modification of the district economic and climate factors should not be ignored in the association between air pollution and mortality.

Equilibrative nucleotide transporter ENT3 (SLC29A3): A unique transporter for inherited disorders and cancers.

As a crucial gene associated with diseases, the SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). ENT3 plays an essential regulatory role in transporting intracellular hydrophilic nucleosides, nucleotides, hydrophilic anticancer and antiviral nucleoside drugs, energy metabolism, subcellular localization, protein stability, and signal transduction. The mutation and inactivation of SLC29A3 are intimately linked to the occurrence, development, and prognosis of various human tumors. Moreover, many hereditary human diseases, such as H syndrome, pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome, Faisalabad histiocytosis (FHC), are related to SLC29A3 mutations. This review explores the mechanisms of SLC29A3 mutations and expression alterations in inherited disorders and cancers. Additionally, we compile studies on the inhibition of ENT3, which may serve as an effective strategy to potentiate the anticancer activity of chemotherapy. Thus, the synopsis of genetics, permeant function and drug therapy of ENT3 provides a new theoretical and empirical foundation for the diagnosis, prognosis of evaluation and treatment of various related diseases.

Trade-offs between cold protection and air pollution-induced mortality of China's heating policy.

The winter heating policy in northern China was designed to safeguard households from the harsh subfreezing temperatures. However, it has inadvertently resulted in seasonal spikes in air pollution levels because of the reliance on coal as an energy source. While the loss of life years attributable to mortality from air pollution caused by winter heating has been estimated, the beneficial effect of protection from cold temperatures has not been assessed, primarily due to a lack of individual-level data linking these variables. Our study aims to address this research gap. We provide individual-level empirical evidence that quantifies the impact of protection from cold temperatures and air pollution on mortality, studying 5,334 older adults living around the Huai River during the period between 2000 and 2018. Our adjusted Cox-proportional hazard models show that winter heating was associated with a 22% lower mortality rate (95% CI: 16-28%). Individuals residing in areas without access to winter heating are subjected to heightened mortality risks during periods of cold temperatures. The protective effect is offset by a 27.8% rise attributed to elevated PM2.5 levels. Our results imply that the equilibrium between the effects of these two factors is achieved when PM2.5 concentration exceeds 24.3 µg/m3 (95% CI: 18.4-30.2). Our research suggests that while the existing winter heating policy significantly mitigates winter mortality by lessening the detrimental effects of cold temperatures, future air pollution reduction could provide further health benefits.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

Purpose: This study aimed to explore the clinical efficacy of transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (triple therapy) compared to TACE alone (monotherapy) for advanced hepatocellular carcinoma (HCC). Material and Methods: Data of consecutive advanced HCC patients receiving triple therapy or monotherapy at our center between January 2019 and December 2022 were collected and retrospectively analyzed. Propensity score matching (PSM) and subgroup analyses were performed to reduce the bias between the two groups. The primary outcomes of the study were the overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: A total of 104 patients were enrolled in this study: 41 in the triple therapy group and 63 in the monotherapy group. After PSM analysis, each group included 37 patients. The median OS and PFS were significantly longer in the triple therapy group than in the monotherapy group in the whole cohort (median OS, 18.8 vs 11.7 months, P = 0.022; median PFS, 10.5 vs 6.4 months, P = 0.012) and after PSM (median OS, 19.6 vs 12.5 months, P = 0.030; median PFS, 10.5 vs 6.7 months, P = 0.008). Furthermore, the treatment modality was an independent prognostic factor for OS (hazard ratio [HR]: 0.449, 95% confidence interval [CI]: 0.240-0.840, P = 0.012) and PFS (HR: 0.406, 95% CI: 0.231-0.713, P = 0.002) according to the multivariate cox regression analysis. A greater ORR was also observed in the triple therapy group (ORR: 56.7% vs 32.4%, P = 0.035). No significant difference was observed in DCR between the two groups (83.7% vs 72.9%, P = 0.259). Conclusion: The triple therapy was superior to the monotherapy regarding OS, PFS, and ORR of advanced HCC patients.

China's public health initiatives for climate change adaptation.

China's health gains over the past decades face potential reversals if climate change adaptation is not prioritized. China's temperature rise surpasses the global average due to urban heat islands and ecological changes, and demands urgent actions to safeguard public health. Effective adaptation need to consider China's urbanization trends, underlying non-communicable diseases, an aging population, and future pandemic threats. Climate change adaptation initiatives and strategies include urban green space, healthy indoor environments, spatial planning for cities, advance location-specific early warning systems for extreme weather events, and a holistic approach for linking carbon neutrality to health co-benefits. Innovation and technology uptake is a crucial opportunity. China's successful climate adaptation can foster international collaboration regionally and beyond.

Biophilic classroom environments on stress and cognitive performance: A randomized crossover study in virtual reality (VR).

The emerging Metaverse will likely increase time expenditure in indoor virtual environments, which could impact human health and well-being. The biophilia hypothesis suggests that humans have an innate tendency to seek connections with the natural world and there is increasing evidence that biophilic design such as the incorporation of green plants can yield health benefits. Recently, virtual reality (VR) has been used to regulate stress and improve overall wellness, particularly by incorporating natural settings. In this randomized crossover study, we designed five virtual classroom scenes with different biophilic elements and turbidity in VR and investigated whether the visual stimulations can affect the stress levels and cognitive functions of 30 young adults from a university in China. We measured their physiological indicators of stress reaction by wearable biomonitoring sensors (blood pressure (BP), heart rate (HR), heart rate variability (HRV), and skin conductance level (SCL)), conducted verbal cognitive tests on attention and creativity, and evaluated subjective/perceived (self-reported) stress levels and connection with nature. Albeit our results suggested no significant change in physiological stress reactions or cognitive functions induced by the biophilic and turbid interventions in VR, the addition of biophilic elements in the Metaverse could benefit students' health due to significantly decreased perceived stress levels and increased connections with nature.

Environmental greenspace, subjective well-being, and all-cause mortality in elderly Chinese: Association and mediation study in a prospective cohort.

BACKGROUND: Subjective well-being (SWB) measures mental health and happiness. Greenspace can have a positive impact on mental health, and higher SWB is associated with lower all-cause mortality. We conducted a mediation analysis on greenspace and all-cause mortality through improving SWB, in a prospective cohort of Chinese older adults. METHODS: We included older adults over 65 from the 2008-2014 Chinese Longitudinal Healthy Longevity Survey (CLHLS). We used satellite-derived normalized difference vegetation index (NDVI) to measure greenspaces and calculated SWB measured by eight items. Three main statistical approaches were used. First, we used generalized estimating equations (GEE) and Cox proportional hazard models to examine NDVI-SWB and SWB-mortality relationships. Second, we conducted a causal mediation analysis to investigate the mediating effect of greenspace on all-cause mortality through SWB. Third, we conducted subgroup analyses to discover effect modification. FINDINGS: Among 13,133 participants, the mean SWB score and NDVI in 2008 were 28·9 (SD 4·34) and 0·41 (SD 0·14), respectively. We found SWB partially mediated the relationship between residential greenspace and mortality in the adjusted model (average causal mediation effect = 0·11, p = 0·04; average direct effect = 1·96, p < 0·001; total effect = 2·07, p < 0·001) with varying proportions in subgroups. The protective influence was more evident for people with impaired cognitive function, living in rural areas and towns, and with lower income. INTERPRETATION: We found a positive association between greenspace, SWB, and mortality. Greenness in the living environment confers better mental health and promotes longevity in the elderly population.

A Case of Insidious Onset of Kimura Disease-associated Immunoglobulin A Nephropathy without Eosinophil Infiltration in the Renal Tissue.

Kimura disease (KD), also known as eosinophilic lymphogranuloma, is a rare chronic inflammatory or allergic disease. It can present with immune-related diseases such as nephrotic syndrome, asthma, and ankylosing spondylitis. In this study, we report a case of KD combined with immunoglobulin A nephropathy that first presented as a mass in the inguinal region, followed by recurrent renal involvement. Previous reports suggested that renal involvement caused by KD was due to direct infiltration of eosinophils; however, in this case, no eosinophil infiltration was found in the renal tissue after renal biopsy. This observation reminds us to approach the case from an immune-related molecular perspective to investigate the exact cause of renal damage due to KD.

NO2 and PM2.5 air pollution co-exposure and temperature effect modification on pre-mature mortality in advanced age: a longitudinal cohort study in China.

BACKGROUND: There is a discourse on whether air pollution mixture or air pollutant components are causally linked to increased mortality. In particular, there is uncertainty on whether the association of NO2 with mortality is independent of fine particulate matter (PM2.5). Furthermore, effect modification by temperature on air pollution-related mortality also needs more evidence. METHODS: We used the Chinese Longitudinal Healthy Longevity Study (CLHLS), a prospective cohort with geographical and socio-economic diversity in China. The participants were enrolled in 2008 or 2009 and followed up in 2011-2012, 2014, and 2017-2018. We used remote sensing and ground monitors to measure nitrogen dioxide (NO2), fine particulate matter (PM2.5) , and temperature. We used the Cox-proportional hazards model to examine the association between component and composite air pollution and all-cause mortality, adjusted for demographic characteristics, lifestyle, geographical attributes, and temperature. We used the restricted cubic spline to visualize the concentration-response curve. RESULTS: Our study included 11 835 individuals with an average age of 86.9 (SD: 11.4) at baseline. Over 55 606 person-years of follow-up, we observed 8 216 mortality events. The average NO2 exposure was 19.1 µg/m3 (SD: 14.1); the average PM2.5 exposure was 52.8 µg/m3 (SD: 15.9). In the single pollutant models, the mortality HRs (95% CI) for 10 µg/m3 increase in annual average NO2 or PM2.5 was 1.114 (1.085, 1.143) and 1.244 (1.221, 1.268), respectively. In the multi-pollutant model co-adjusting for NO2 and PM2.5, the HR for NO2 turned insignificant: 0.978 (0.950, 1.008), but HR for PM2.5 was not altered: 1.252 (1.227, 1.279). PM2.5 and higher mortality association was robust, regardless of NO2. When acccounting for particulate matter, NO2 exposure appeared to be harmful in places of colder climates and higher seasonal temperature variation. CONCLUSIONS: We see a robust relationship of PM2.5 exposure and premature mortality in advance aged individuals, however, NO2 exposure and mortality was only harmful in places of colder climate such as northeast China, indicating evidence of effect modification by temperature. Analysis of NO2 without accounting for its collinearity with PM2.5, may lead to overestimation.

A Review of the Role of Extracellular Polymeric Substances (EPS) in Wastewater Treatment Systems.

A review of the characterization and functions of extracellular polymeric substances (EPS) of microbial aggregates in biological wastewater treatment systems is presented in this paper. EPS represent the complex high-molecular-weight mixture of polymers excreted by microorganisms generated from cell lysis as well as adsorbed inorganic and organic matter from wastewater. EPS exhibit a three-dimensional, gel-like, highly hydrated matrix that facilitates microbial attachment, embedding, and immobilization. EPS play multiple roles in containments removal, and the main components of EPS crucially influence the properties of microbial aggregates, such as adsorption ability, stability, and formation capacity. Moreover, EPS are important to sludge bioflocculation, settleability, and dewatering properties and could be used as carbon and energy sources in wastewater treatment. However, due to the complex structure of EPS, related knowledge is incomplete, and further research is necessary to understand fully the precise roles in biological treatment processes.

Assessing the effects of ultraviolet radiation, residential greenness and air pollution on vitamin D levels: A longitudinal cohort study in China.

Vitamin D metabolism is essential in aging and can be affected by multiple environmental factors. However, most studies conducted single exposure analyses. We aim to assess the individual and combined effects of ultraviolet (UV) radiation, residential greenness, fine particulate matter (PM2.5), and ozone (O3) on vitamin D levels in a national cohort study of older adults in China. We used the 2012 and 2014 Chinese Longitudinal Healthy Longevity Survey data, and measured the environmental exposure in the same year. We interpolated the UV radiation from monitoring stations, measured residential greenness through satellite-derived Normalized Difference Vegetation Index (NDVI), modeled PM2.5 with satellite data, and estimated O3 using machine learning. We dichotomized serum 25-hydroxy vitamin D (25(OH)D), the primary circulating form of vitamin D, into non-deficiency (≥50 nmol/L) and deficiency (<50 nmol/L) categories. We used the generalized estimating equation for analysis, adjusted for sociodemographic information, lifestyle, physical condition, and season of blood draw, and calculated joint odds ratios based on the Cumulative Risk Index. We also explored the interaction between interested exposures, modification of participants' characteristics, and potential mediation. We included 1,336 participants, with a mean age of 83 at baseline. In single exposure models, the odds ratios of vitamin D deficiency (VDD) for per interquartile range increase in UV radiation, NDVI, PM2.5, and O3 and decrease were 0.39 (95 % CI:0.33,0.46), 0.90 (0.81,1.00), 1.65 (1.53,1.78), 1.67 (1.46,1.92), respectively. UV radiation mediated nearly 48 % and 78 % of the relationship between VDD and PM2.5 and O3, respectively. The association between UV radiation and VDD was stronger in females than men (OR: 2.25 vs 1.22). UV radiation, residential greenness can protect against VDD, while, PM2.5 and O3 increase the risk of VDD. UV radiation partly mediated the association between air pollution and VDD.

Air pollution, residential greenness, and metabolic dysfunction biomarkers: analyses in the Chinese Longitudinal Healthy Longevity Survey.

BACKGROUND: We hypothesize higher air pollution and fewer greenness exposures jointly contribute to metabolic syndrome (MetS), as mechanisms on cardiometabolic mortality. METHODS: We studied the samples in the Chinese Longitudinal Healthy Longevity Survey. We included 1755 participants in 2012, among which 1073 were followed up in 2014 and 561 in 2017. We used cross-sectional analysis for baseline data and the generalized estimating equations (GEE) model in a longitudinal analysis. We examined the independent and interactive effects of fine particulate matter (PM2.5) and Normalized Difference Vegetation Index (NDVI) on MetS. Adjustment covariates included biomarker measurement year, baseline age, sex, ethnicity, education, marriage, residence, exercise, smoking, alcohol drinking, and GDP per capita. RESULTS: At baseline, the average age of participants was 85.6 (SD: 12.2; range: 65-112). Greenness was slightly higher in rural areas than urban areas (NDVI mean: 0.496 vs. 0.444; range: 0.151-0.698 vs. 0.133-0.644). Ambient air pollution was similar between rural and urban areas (PM2.5 mean: 49.0 vs. 49.1; range: 16.2-65.3 vs. 18.3-64.2). Both the cross-sectional and longitudinal analysis showed positive associations of PM2.5 with prevalent abdominal obesity (AO) and MetS, and a negative association of NDVI with prevalent AO. In the longitudinal data, the odds ratio (OR, 95% confidence interval-CI) of PM2.5 (per 10 µg/m3 increase) were 1.19 (1.12, 1.27), 1.16 (1.08, 1.24), and 1.14 (1.07, 1.21) for AO, MetS and reduced high-density lipoprotein cholesterol (HDL-C), respectively. NDVI (per 0.1 unit increase) was associated with lower AO prevalence [OR (95% CI): 0.79 (0.71, 0.88)], but not significantly associated with MetS [OR (95% CI): 0.93 (0.84, 1.04)]. PM2.5 and NDVI had a statistically significant interaction on AO prevalence (pinteraction: 0.025). The association between PM2.5 and MetS, AO, elevated fasting glucose and reduced HDL-C were only significant in rural areas, not in urban areas. The association between NDVI and AO was only significant in areas with low PM2.5, not under high PM2.5. CONCLUSIONS: We found air pollution and greenness had independent and interactive effect on MetS components, which may ultimately manifest in pre-mature mortality. These study findings call for green space planning in urban areas and air pollution mitigation in rural areas.

miR-7/TGF-ß2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis.

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-ß2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-ß2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-ß2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-ß2; the expressions of both miR-7-5p and TGF-ß2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-ß2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Chronic kidney disease biomarkers and mortality among older adults: A comparison study of survey samples in China and the United States.

OBJECTIVES: Among older adults in China and the US, we aimed to compare the biomarkers of chronic-kidney-diseases (CKD), factors associated with CKD, and the correlation between CKD and mortality. SETTING: China and the US. STUDY DESIGN: Cross-sectional and prospective cohorts. PARTICIPANTS: We included 2019 participants aged 65 and above from the Chinese Longitudinal Healthy Longevity Study (CLHLS) in 2012, and 2177 from US National Health and Nutrition Examination Survey (NHANES) in 2011-2014. OUTCOMES: Urinary albumin, urinary creatinine, albumin creatinine ratio (ACR), serum creatinine, blood urea nitrogen, plasma albumin, uric acid, and estimated glomerular filtration rate (eGFR). CKD (ACR ≥ 30 mg/g or eGFR< 60 ml/min/1.73m2) and mortality. ANALYTICAL APPROACH: Logistic regression and Cox proportional hazard models. Covariates included age, sex, race, education, income, marital status, health condition, smoking and drinking status, physical activity and body mass index. RESULTS: Chinese participants had lower levels of urinary albumin, ACR, and uric acid than the US (mean: 25.0 vs 76.4 mg/L, 41.7 vs 85.0 mg/g, 292.9 vs 341.3 µmol/L). In the fully-adjusted model, CKD was associated with the risk of mortality only in the US group (hazard ratio [HR], 95% CI: 2.179, 1.561-3.041 in NHANES, 1.091, 0.940-1.266 in CLHLS). Compared to eGFR≥90, eGFR ranged 30-44 ml/min/1.73m2 was only associated with mortality in the US population (HR, 95% CI: 2.249, 1.141-4.430), but not in the Chinese population (HR, 95% CI: 1.408, 0.884-2.241). CONCLUSIONS: The elderly participants in the US sample had worse CKD-related biomarker levels than in China sample, and the association between CKD and mortality was also stronger among the US older adults. This may be due to the biological differences, or co-morbid conditions.

Effect of FOXO3 and Air Pollution on Cognitive Function: A Longitudinal Cohort Study of Older Adults in China From 2000 to 2014.

Forkhead Box O 3 (FOXO3) genotype is strongly associated with human longevity and may be protective against neurodegeneration. Air pollution is a risk factor for cognitive decline and dementia. We aimed to study the individual and combined effects of FOXO3 and air pollution on cognitive function in a large prospective cohort with up to 14 years of follow-up. We measured cognitive function and impairment using the Mini-Mental State Examination (MMSE). We used tagging SNPs rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene, of which roughly half of the population had the longevity-associated polymorphism. We matched annual average fine particulate matter (PM2.5) concentrations within a 1 km2 grid. We conducted cross-sectional and longitudinal analyses using multivariable linear and logistic regression models and generalized estimating equations. At baseline, carriers of the longevity-associated homozygous minor alleles of FOXO3 SNPs had a higher MMSE score than the carriers of homozygous major alleles. In the longitudinal follow-up, carriers of FOXO3 homozygous minor alleles had lower odds of cognitive impairment compared with noncarriers. Higher PM2.5 was associated with a lower MMSE score and higher odds of cognitive impairment. The positive effects of FOXO3 were the strongest in females, older people, and residents in areas with lower air pollution.

Sex Difference and Interaction of SIRT1 and FOXO3 Candidate Longevity Genes on Life Expectancy: A 10-Year Prospective Longitudinal Cohort Study.

SIRT1 and FOXO3 are both associated with longevity. Molecular biology research in many organisms (yeast, nematode worm Caenorhabditis elegans, and mice mammalian models) shows SIRT1 acts on the FOXO family of forkhead transcription factors to respond to oxidative stress better, shifting processes away from cell death toward stress resistance. Human population studies need epidemiologic evidence. We used an open cohort of 3 166 community-dwelling participants in China with follow-up from 2008 to 2018. The mean age at baseline was 84.6 years. In 16 375 person-years of follow-up, there were 1 968 mortality events. SIRT1 and FOXO3 exhibited Mendelian randomization as there was no correlation with each other and with baseline study population characteristics. Some SIRT1 and FOXO3 single-nucleotide polymorphisms showed protective effects for mortality risk. The FOXO3 protective effect was stronger in females, and the SIRT1 protective effect was stronger in male study participants. We did not see evidence of a synergistic effect of being carriers of both SIRT1 and FOXO3 advantageous alleles.

Comparing Effects of FOXO3 and Residing in Urban Areas on Longevity: A Gene-Environment Interaction Study.

Forkhead box O3 (FOXO3) is a candidate longevity gene. Urban residents are also positively associated with longer life expectancy. We conducted a gene-environment interaction to assess the synergistic effect of FOXO3 and urban/rural environments on mortality. We included 3 085 older adults from the Chinese Longitudinal Healthy Longevity Survey. We used single-nucleotide polymorphisms (SNPs) rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene and classified residential locations as "urban" and "rural." Given the open cohort design, we used the Cox-proportional hazard regression models to assess the mortality risk. We found the minor allele homozygotes of FOXO3 to have a protective effect on mortality (HR [95% CI] for rs4946936 TT vs CC: 0.807 [0.653-0.996]; rs2802292 GG vs TT: 0.812 [0.67-0.985]; rs2253310 CC vs GG: 0.808 [0.667-0.978]). Participants living in urban areas had a lower risk of mortality (HR of the urban vs the rural: 0.854 [0.759-0.962]). The interaction between FOXO3 and urban and rural regions was statistically significant (pinteraction < .01). Higher air pollution (fine particulate matter: PM2.5) and lower residential greenness (Normalized Difference Vegetation Index [NDVI]) both contributed to higher mortality. After adjusting for NDVI and PM2.5, the protective effect size of FOXO3 SNPs was slightly attenuated while the protective effect size of living in an urban environment increased. The effect size of the beneficial effect of FOXO3 on mortality is roughly equivalent to that of living in urban areas. Our research findings indicate that the effect of places of residence and genetic predisposition of longevity are intertwined.