Olink Proteomics-Based Exploration of Immuno-Oncology-Related Biomarkers Leading to Lung Adenocarcinoma Progression.

INTRODUCTION: It is crucial to investigate the distinct proteins that contribute to the advancement of lung cancer. MATERIAL AND METHODS: We analyzed the expression levels of 92 immuno-oncology-related proteins in 96 pairs of lung adenocarcinoma tissue samples using Olink proteomics. The differentially expressed proteins (DEPs) were successively screened in tumor and paraneoplastic groups, early and intermediate-late groups by a nonparametric rank sum test, and the distribution and expression levels of DEPs were determined by volcano and heat maps, etc., and the area under the curve was calculated. RESULTS: A total of 24 DEPs were identified in comparisons between tumor and paracancerous tissues. Among them, interleukin-8 (IL8) and chemokine (C-C motif) ligand 20 (CCL20) as potential markers for distinguishing tumor tissues. Through further screening, it was found that interleukin-6 (IL6) and vascular endothelial growth factor A (VEGFA) may be able to lead to tumor progression through the JaK-STAT signaling pathway, Toll-like receptor signaling pathway and PI3K/AKT signaling pathway. Interestingly, our study revealed a down-regulation of IL6 and VEGFA in tumor tissues compared to paracancerous tissues. CONCLUSIONS: IL8 + CCL20 (AUC: 0.7056) have the potential to differentiate tumor tissue from paracancerous tissue; IL6 + VEGFA (AUC: 0.7531) are important protein markers potentially responsible for tumor progression.

AKT1 Promotes Tumorigenesis and Metastasis by Directly Phosphorylating Hexokinases.

The importance of protein kinase B (AKT) in tumorigenesis and development is well established, but its potential regulation of metabolic reprogramming via phosphorylation of the hexokinase (HK) isozymes remains unclear. There are two HK family members (HK1/2) and three AKT family members (AKT1/2/3), with varied distribution of AKTs exhibiting distinct functions in different tissues and cell types. Although AKT is known to phosphorylate HK2 at threonine 473, AKT-mediated phosphorylation of HK1 has not been reported. We examined direct binding and phosphorylation of HK1/2 by AKT1 and identified the phosphorylation modification sites using coimmunoprecipitation, glutathione pull-down, western blotting, and in vitro kinase assays. Regulation of HK activity through phosphorylation by AKT1 was also examined. Uptake of 2-[1,2-3H]-deoxyglucose and production of lactate were investigated to determine whether AKT1 regulates glucose metabolism by phosphorylating HK1/2. Functional assays, immunohistochemistry, and tumor experiments in mice were performed to investigate whether AKT1-mediated regulation of tumor development is dependent on its kinase activity and/or the involvement of HK1/2. AKT interacted with and phosphorylated HK1 and HK2. Serine phosphorylation significantly increased AKT kinase activity, thereby enhancing glycolysis. Mechanistically, the phosphorylation of HK1 at serine 178 (S178) by AKT significantly decreased the Km and enhanced the Vmax by interfering with the formation of HK1 dimers. Mutations in the AKT phosphorylation sites of HK1 or HK2 significantly abrogated the stimulatory characteristics of AKT on glycolysis, tumorigenesis, and cell migration, invasion, proliferation, and metastasis. HK1-S178 phosphorylation levels were significantly correlated with the occurrence and metastasis of different types of clinical tumors. We conclude that AKT not only regulates tumor glucose metabolism by directly phosphorylating HK1 and HK2, but also plays important roles in tumor progression, proliferation, and migration.

Global, regional, and national burden of trachea, bronchus, and lung cancer among women of reproductive age, 1990-2019.

BACKGROUND: Trachea, bronchus, and lung (TBL) cancer has demonstrated a discernible feminization and a tendency towards younger onset in recent decades. Therefore, our objective is to examine the most recent patterns in the worldwide prevalence of TBL among women of reproductive age on a global, regional, and national scale. METHODS: To assess the prevalence trends of TBL in women of reproductive age, we calculated the estimated annual percentage change (EAPC), age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and disability-adjusted life years (DALYs) for 204 countries and territories from 1990 to 2019. These calculations were based on the Global Burden of Disease (GBD) 2019 database. RESULTS: From 1990 to 2019, there was a global increase in the absolute number of incidence cases, deaths, and DALYs of TBL in women of reproductive age. However, the ASIR, ASDR, and age-standardized DALY rates were decreasing over this period, with EAPC of -0.77 (95 % confidence interval [CI]: -1.03 to -0.51), -1.08 (95 % CI: -1.34 to -0.82), and -1.10 (95 % CI: -1.36 to -0.84), respectively. This trend was observed even in regions with higher Socio-Demographic Index (SDI). East Asia consistently had the highest ASIR, ASDR, and age-standardized DALY rate, but there was a decreasing trend. Conversely, Eastern Sub-Saharan Africa displayed an increasing burden pattern. When examining countries individually, Monaco, Greenland, and Palau had the highest ASIR. Moreover, in most countries, the ASIR for TBL increased with age, particularly among women aged 35-49 years. CONCLUSIONS: Despite a global decline in ASIR, ASDR, and age-standardized DALY rates for TBL in women of reproductive age over the past three decades, there is still a troubling increase observed in low- and low-middle SDI regions. It is crucial to implement effective preventive and curative measures in these regions in order to address this concerning trend.

Methods and clinical biomarker discovery for targeted proteomics using Olink technology.

PURPOSE: This paper is to offer insights for designing research utilizing Olink technology to identify biomarkers and potential therapeutic targets for disease treatment. EXPERIMENTAL DESIGN: We discusses the application of Olink technology in oncology, cardiovascular, respiratory and immune-related diseases, and Outlines the advantages and limitations of Olink technology. RESULTS: Olink technology simplifies the search for therapeutic targets, advances proteomics research, reveals the pathogenesis of diseases, and ultimately helps patients develop precision treatments. CONCLUSIONS: Although proteomics technology has been rapidly developed in recent years, each method has its own disadvantages, so in the future research, more methods should be selected for combined application to verify each other.

Predicting the risk of lung cancer using machine learning: A large study based on UK Biobank.

In response to the high incidence and poor prognosis of lung cancer, this study tends to develop a generalizable lung-cancer prediction model by using machine learning to define high-risk groups and realize the early identification and prevention of lung cancer. We included 467,888 participants from UK Biobank, using lung cancer incidence as an outcome variable, including 49 previously known high-risk factors and less studied or unstudied predictors. We developed multivariate prediction models using multiple machine learning models, namely logistic regression, naïve Bayes, random forest, and extreme gradient boosting models. The performance of the models was evaluated by calculating the areas under their receiver operating characteristic curves, Brier loss, log loss, precision, recall, and F1 scores. The Shapley additive explanations interpreter was used to visualize the models. Three were ultimately 4299 cases of lung cancer that were diagnosed in our sample. The model containing all the predictors had good predictive power, and the extreme gradient boosting model had the best performance with an area under curve of 0.998. New important predictive factors for lung cancer were also identified, namely hip circumference, waist circumference, number of cigarettes previously smoked daily, neuroticism score, age, and forced expiratory volume in 1 second. The predictive model established by incorporating novel predictive factors can be of value in the early identification of lung cancer. It may be helpful in stratifying individuals and selecting those at higher risk for inclusion in screening programs.

Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study.

Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

Development and validation of a prediction model for early screening of people at high risk for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a serious threat worldwide. Although early screening is suggested to be the most effective method to prevent and control CRC, the current situation of early screening for CRC is still not optimistic. In China, the incidence of CRC in the Yangtze River Delta region is increasing dramatically, but few studies have been conducted. Therefore, it is necessary to develop a simple and efficient early screening model for CRC. AIM: To develop and validate an early-screening nomogram model to identify individuals at high risk of CRC. METHODS: Data of 64448 participants obtained from Ningbo Hospital, China between 2014 and 2017 were retrospectively analyzed. The cohort comprised 64448 individuals, of which, 530 were excluded due to missing or incorrect data. Of 63918, 7607 (11.9%) individuals were considered to be high risk for CRC, and 56311 (88.1%) were not. The participants were randomly allocated to a training set (44743) or validation set (19175). The discriminatory ability, predictive accuracy, and clinical utility of the model were evaluated by constructing and analyzing receiver operating characteristic (ROC) curves and calibration curves and by decision curve analysis. Finally, the model was validated internally using a bootstrap resampling technique. RESULTS: Seven variables, including demographic, lifestyle, and family history information, were examined. Multifactorial logistic regression analysis revealed that age [odds ratio (OR): 1.03, 95% confidence interval (CI): 1.02-1.03, P < 0.001], body mass index (BMI) (OR: 1.07, 95%CI: 1.06-1.08, P < 0.001), waist circumference (WC) (OR: 1.03, 95%CI: 1.02-1.03 P < 0.001), lifestyle (OR: 0.45, 95%CI: 0.42-0.48, P < 0.001), and family history (OR: 4.28, 95%CI: 4.04-4.54, P < 0.001) were the most significant predictors of high-risk CRC. Healthy lifestyle was a protective factor, whereas family history was the most significant risk factor. The area under the curve was 0.734 (95%CI: 0.723-0.745) for the final validation set ROC curve and 0.735 (95%CI: 0.728-0.742) for the training set ROC curve. The calibration curve demonstrated a high correlation between the CRC high-risk population predicted by the nomogram model and the actual CRC high-risk population. CONCLUSION: The early-screening nomogram model for CRC prediction in high-risk populations developed in this study based on age, BMI, WC, lifestyle, and family history exhibited high accuracy.

No causal association between plasma cystatin C and cardiovascular diseases: Mendelian randomization analyses in UK biobank.

Background: We aimed to determine whether the plasma cystatin C is a causal risk factor for cardiovascular events, stroke, myocardial infarction (MI), and cardiovascular disease (CVD) mortality by conducting Mendelian randomization (MR) designs. Methods: Our study included 277,057 individuals free of CVDs or cancer at baseline in the UK Biobank. The genetic scores of plasma cystatin C comprising 67 single-nucleotide polymorphisms were calculated on the basis of data from a large genome-wide association study. By stratifying the genetic score, we conducted cox regression to assess the relationship between plasma cystatin C and CVDs. In this study, linear MR analysis was used to estimate the causal association between plasma cystatin C and CVDs. Results: Observational analyses showed that plasma cystatin C concentrations were associated with the risk of CVDs [hazard ratios (HR) per standard deviation (SD) 1.09, 95% confidence interval (CI); 1.07-1.10] and CVD mortality (1.14, 1.11-1.17). Among CVDs, plasma cystatin C were associated with stroke (1.10, 1.08-1.11) and MI (1.08, 1.07-1.10). Linear MR analysis did not provide evidence of a causal association between plasma cystatin C and the risk of CVDs [odds ratio (OR) per SD 0.96, 95% CI;0.90-1.03], stroke (0.96, 0.93-1.01), MI (0.97, 0.91-1.03), and CVD mortality (0.98, 0.96-1.01), with consistent estimates from sensitivity analyses. Conclusion: Observational findings indicated that higher plasma cystatin C is associated with a higher risk of CVDs; According to MR studies, there is no causal association between plasma cystatin C and the risk of CVDs and CVD mortality.

Aurantimonas marianensis sp. nov., isolated from deep-sea sediment of the Mariana Trench.

A novel strain, designated as LRZ36T, was isolated from deep-sea sediment (from a depth of 5400 m) from the Mariana Trench. Cells of this strain are rod-shaped, Gram-stain-negative, strictly aerobic and non-motile. Phylogenetic analysis of LRZ36T based on 16S rRNA gene sequences revealed a lineage in the family Aurantimonadaceae but distinct from the most closely related species Aurantimonas marina CGMCC 1.17725T, 'Aurantimonas litoralis' KCTC 12094 and Aurantimonas coralicida DSM 14790T with sequence identities of 99.4 %, 98.0 and 97.9 %, respectively. The genome of LRZ36T was 3.8 Mbp in size with a DNA G+C content of 64.8 %, containing 3623 predicted coding genes. LRZ36T showed average nucleotide identity values of 89.8 %, 78.7 and 78.5 % and digital DNA-DNA hybridization values of 38.9 %, 21.7 and 21.6 % with A. marina CGMCC 1.17725T, 'A. litoralis' KCTC 12094 and A. coralicida DSM 14790T, respectively. The major respiratory quinone was ubiquinone-10 (Q-10), and the predominant fatty acids were C18 : 1ω7c (74.4 %) and C16 : 0 (12.1 %). The polar lipids in LRZ36T are diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylcholine, phosphatidylinositol mannoside, an unidentified aminophospholipid, three unidentified lipids, three unidentified phospholipids and two unidentified aminolipids. On the basis of genotypic and phenotypic evidence, LRZ36T represents a novel species of the genus Aurantimonas, for which the name Aurantimonas marianensis sp. nov. is proposed. The type strain is LRZ36T (= KCTC 92065T = GDMCC 1.2985T=MCCC 1K07227T).

Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: a large UK population-based cohort.

BACKGROUND/OBJECTIVES: The evidence of relationship between dietary intake of folate, vitamin B6 and vitamin B12 and cardiovascular diseases (CVD) in UK populations is limited. We aimed to analyze the association of dietary intake of folate, vitamin B6, and vitamin B12 with CVD events [stroke, myocardial infarction (MI)] and CVD mortality. METHODS: We included 115,664 participants, aged 40-70 years, with no CVD events or cancer at baseline, enrolled between 2006 and 2010 and followed up to the end of 2018. Dietary intake was measured with an online 24-h dietary assessment. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations. RESULTS: After multivariate adjustment, higher dietary folate intake was inversely associated with CVDs with hazard ratios of 0.99, 0.92, and 0.88 in groups 2-4 compared with group 1 (the lowest group); inversely associated with stroke with hazard ratios of 0.94, 0.90, and 0.86 groups 2-4 compared to group 1 (lowest group); inversely associated with MI with hazard ratios of 1.01, 0.90 and 0.86 groups 2-4 compared to group 1 (lowest group); inversely associated with CVD mortality with hazard ratios of 0.95, 0.80 and 0.74 Groups 2-4 compared to group 1 (lowest group). Each tablespoon/day higher intake of raw vegetable intake, pieces/day higher intake of fresh fruit intake bowls/week higher intake of cereal intake, and g/day higher intake of dietary fiber were associated with higher intakes of folate every 0.02,0.06,0.05, and 0.08 SD, respectively. E-value analysis suggested robustness to unmeasured confounding. CONCLUSIONS: Each increase in folate intakes was related to 5% lower risks of total CVD events and 10% lower risks of CVD mortality. Our findings support that strengthening dietary folate intake as a primary prevention strategy for CVD events and CVD mortality.

Corrigendum: No causal association between plasma cystatin C and cardiovascular diseases: Mendelian randomization analyses in UK biobank.

[This corrects the article DOI: 10.3389/fmed.2023.1191675.].

Educational level differences in the primary and secondary prevention of stroke.

The aim of this study is to estimate the educational level differences in the primary and secondary prevention of stroke among the Chinese population. Data were obtained from the China Kadoorie Biobank (CKB) survey of 512,891 people aged 30-79 years in 10 geographic regions of China, which was conducted from 2002 to 2008. The Prediction for Atherosclerotic Cardiovascular Disease Risk in China model was used to identify individuals with a high estimated 10-year stroke risk. A total of 8884 participants (1.7%) had established stroke and 218,972 (42.7%) had a high stroke risk. In both primary and secondary prevention, the participants' educational level was positively associated with the control of smoking, blood pressure, consuming a healthy diet, and the use of antiplatelet, BP-lowering medications but negatively associated with higher physical activity levels (all Ptrend < 0.001). In addition, the positive associations were observed with the control of drinking and use of anti-hyperglycaemia medication for primary prevention (all Ptrend < 0.001) and with the use of lipid-lowering medication for secondary prevention (Ptrend = 0.019). The results of the interaction between education level and prevention level showed that, compared with participants in primary prevention, educational level disparities in those with secondary prevention had significantly higher use of antiplatelets and lipid-lowering drugs, achieving the physical activity goal and non-current drinker (all Pfor interaction < 0.05). A higher education level was associated with an increased acceptance of primary and secondary prevention strategies (not smoking or drinking, consuming a healthier diet) except for engaging in a suitable level of physical activity.

Global, Regional, and National Burden of Cancer in Children Younger Than 5 Years, 1990-2019: Analysis of the Global Burden of Disease Study 2019.

Objectives: To quantify the burden and variation trends of cancers in children under 5 years at the global, regional, and national levels from 1990 to 2019. Methods: Epidemiological data for children under 5 years who were diagnosed with any one childhood cancer were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) from 1990 to 2019. The outcomes were the absolute numbers and rates of incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) for different types of cancer. Results: In 2019, 8,774,979.1 incident cases (95% uncertainty interval [UI]: 6,243,599.2 to11,737,568.5) and 8,956,583.8 (6,446,323.9 to 12,364,520.8) prevalent cases of cancer in children under 5 years were identified worldwide; these cancers resulted in 44,451.6 (36,198.7 to 53,905.9) deaths and 3,918,014.8 (3,196,454.9 to 4,751,304.2) DALYs. From 1990 to 2019, although the numbers of incident and prevalent cases only decreased by -4.6% (-7.0 to -2.2) and -8.3% (-12.6 to -3.4), respectively, the numbers of deaths and DALYs clearly declined by -47.8% (-60.7 to -26.4) and -47.7% (-60.7 to -26.2), respectively. In 2019, the middle sociodemographic index (SDI) regions had the highest incidence and prevalence, whereas the low SDI regions had the most mortality and DALYs. Although all of the SDI regions displayed a steady drop in deaths and DALYs between 1990 and 2019, the low-middle and low SDI regions showed increasing trends of incidence and prevalence. Leukemia remained the most common cancer globally in 2019. From 1990 to 2019, the burdens of leukemia, liver cancer, and Hodgkin's lymphoma declined, whereas the incidence and prevalence of other cancers grew, particularly testicular cancer. Conclusions: The global childhood cancer burden in young children has been steadily decreasing over the past three decades. However, the burdens and other characteristics have varied across different regions and types of cancers. This highlights the need to reorient current treatment strategies and establish effective prevention methods to reduce the global burden of childhood cancer.

Non-alcoholic Fatty Liver Disease Is Associated With Aortic Calcification: A Cohort Study With Propensity Score Matching.

Objectives: Non-alcoholic fatty liver disease (NAFLD) greatly affects cardiovascular disease, but evidence on the associations between NAFLD and markers of aortic calcification is limited. We aim to evaluate the association between NAFLD and aortic calcification in a cohort of Chinese adults using propensity score-matching (PSM) analysis. Methods: This prospective cohort study involved adults who underwent health-screening examinations from 2009 to 2016. NAFLD was diagnosed by abdominal ultrasonography at baseline, and aortic calcification was identified using a VCT LightSpeed 64 scanner. Analyses included Cox proportional-hazards regression analysis and PSM with predefined covariates (age, gender, marital and smoking status, and use of lipid-lowering drugs) to achieve a 1:1 balanced cohort. Results: Of the 6,047 eligible participants, 2,729 (45.13%) were diagnosed with NAFLD at baseline, with a median age of 49.0 years [interquartile range, 44.0-55.0]. We selected 2,339 pairs of participants with and without NAFLD at baseline for the PSM subpopulation. Compared with those without NAFLD, patients with NAFLD were at a higher risk of developing aortic calcification during follow-up; significant results were observed before and after matching, with the full-adjusted hazard ratios and corresponding 95% confidence intervals being 1.19 (1.02-1.38) and 1.18 (1.01-1.38), respectively (both p < 0.05). In subgroup analyses, no interaction was detected according to age, gender, smoking status, body mass index, total cholesterol, low-density lipoprotein cholesterol, use of lipid-lowering drugs, hypertension, or type 2 diabetes. Conclusions: NAFLD may be independently associated with aortic calcification. Further studies are warranted to elucidate the possible underlying mechanisms.

Associations of Serum Biomarkers of Fruit and Vegetable Intake With the Risk of Cause-Specific Mortality and All-Cause Mortality: A National Prospective Cohort Study.

Objective: The purpose of this study was to evaluate the associations of serum biomarkers of fruit and vegetable intake (vitamin C and carotenoids) with cause-specific mortality and all-cause mortality in a nationally representative sample of US adults. Methods: We analyzed data from 12,530 participants from the National Health and Nutrition Examination Survey III (1988-1994). The Cox proportional hazards models with restricted cubic spline were used for the analysis. Results: During 246,027 person-years of follow-up, 4,511 deaths occurred, including 1,395 deaths from cardiovascular disease, 1,072 deaths from heart disease, 323 deaths from cerebral disease, and 954 deaths from cancer. The serum vitamin C was significantly associated with the cancer and all-cause mortality, with hazard ratios (HRs) (95% CIs) for each one SD of 0.80 (0.71-0.91) and 0.91 (0.86-0.96). The serum alpha-carotene was significantly associated with the cancer mortality, with HRs (95% CIs) of 0.70 (0.54-0.90), 0.68 (0.48-0.95), 0.64 (0.43-0.95), and 0.44 (0.33-0.60) for comparisons of groups 2-5 with group 1 in model 2, respectively. The change for each one SD in the composite biomarker score, equivalent to a 0.483 times/month difference in total fruits and vegetables intake, gave an HR of 0.79 (0.69-0.90) for cancer mortality. Conclusion: Inverse associations were found between serum vitamin C, carotenoids, and composite biomarker score and outcomes expect for cerebral disease, heart disease, and cardiovascular disease mortality. This finding supports an increase in dietary fruit and vegetable intake as a primary prevention strategy for cancer and all-cause mortality.

Predictive Utility of Mortality by Aging Measures at Different Hierarchical Levels and the Response to Modifiable Life Style Factors: Implications for Geroprotective Programs.

Background: Aging, as a multi-dimensional process, can be measured at different hierarchical levels including biological, phenotypic, and functional levels. The aims of this study were to: (1) compare the predictive utility of mortality by three aging measures at three hierarchical levels; (2) develop a composite aging measure that integrated aging measures at different hierarchical levels; and (3) evaluate the response of these aging measures to modifiable life style factors. Methods: Data from National Health and Nutrition Examination Survey 1999-2002 were used. Three aging measures included telomere length (TL, biological level), Phenotypic Age (PA, phenotypic level), and frailty index (FI, functional level). Mortality information was collected until December 2015. Cox proportional hazards regression and multiple linear regression models were performed. Results: A total of 3,249 participants (20-84 years) were included. Both accelerations (accounting for chronological age) of PA and FI were significantly associated with mortality, with HRs of 1.67 [95% confidence interval (CI) = 1.41-1.98] and 1.59 (95% CI = 1.35-1.87), respectively, while that of TL showed non-significant associations. We thus developed a new composite aging measure (named PC1) integrating the accelerations of PA and FI, and demonstrated its better predictive utility relative to each single aging measure. PC1, as well as the accelerations of PA and FI, were responsive to several life style factors including smoking status, body mass index, alcohol consumption, and leisure-time physical activity. Conclusion: This study demonstrates that both phenotypic (i.e., PA) and functional (i.e., FI) aging measures can capture mortality risk and respond to modifiable life style factors, despite their inherent differences. Furthermore, the PC1 that integrated phenotypic and functional aging measures outperforms in predicting mortality risk in comparison with each single aging measure, and strongly responds to modifiable life style factors. The findings suggest the complementary of aging measures at different hierarchical levels and highlight the potential of life style-targeted interventions as geroprotective programs.

Does healthy lifestyle attenuate the detrimental effects of urinary polycyclic aromatic hydrocarbons on phenotypic aging? An analysis from NHANES 2001-2010.

Existing evidence has showed that exposure to polycyclic aromatic hydrocarbons (PAHs) increases the risk of many chronic diseases. Given the close connection between aging (a major risk factor) and chronic diseases, however, very few studies have evaluated the association between PAHs and aging. Furthermore, whether modifiable healthy lifestyle could attenuate the detrimental effect of PAHs on aging remains unknown. Therefore, we conducted this study, aiming to: (1) examine the associations of urinary monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) and lifestyle with Phenotypic Age Acceleration (PhenoAge.Accel), a novel aging measure that captures morbidity and mortality risk; and (2) evaluate the potential interaction effects of OH-PAHs and lifestyle on PhenoAge.Accel. Cross-sectional data of 2,579 participants (aged 20-84 years, n = 1,292 females) from the National Health and Nutrition Examination Survey for years 2001-2010 were analyzed. A lifestyle index was constructed based on five components (drinking, smoking, body mass index, physical activity, and diet), ranging from 0 to 5. We calculated PhenoAge.Accel using algorithms developed previously. General linear regression models were used to examine the associations. We observed strong associations of OH-PAHs and lifestyle with PhenoAge.Accel. For instance, one unit increase in ∑NAP (sum of 1- and 2-hydroxynaphthalene) was associated with 0.37 year (95% confidence interval [CI]: 0.26, 0.48) increase in PhenoAge.Accel. We did not observe statistically significant interaction effects between OH-PAHs and lifestyle on PhenoAge.Accel. After stratified by sex, we observed strong associations as well as statistically significant interactions of OH-PAHs and lifestyle with PhenoAge.Accel among females. In conclusion, both OH-PAHs and lifestyle were independently associated with phenotypic aging and there were statistically significant interactions between OH-PAHs and lifestyle on phenotypic aging among females. The findings highlight the importance of adherence to a healthy lifestyle to attenuate the detrimental effects of exposures to PAHs on phenotypic aging among females.

Multivitamin/mineral supplementation and the risk of cardiovascular disease: a large prospective study using UK Biobank data.

PURPOSE: Despite the widespread use of multivitamin/mineral supplements, the effects of multivitamin/mineral on cardiovascular disease (CVD) remain inconclusive. We aimed to prospectively investigate how multivitamin/mineral use is associated with CVD. METHODS: This population-based cohort study included 465,278 men and women who participated in the UK Biobank and were free from CVD at baseline. Participants were enrolled between 2006 and 2010 and followed-up until the end of 2018. Data on supplement use including multivitamin/mineral were collected using self-reported questionnaires. Cox proportional hazards models were used to estimate the hazard ratios of CVD events in relation to multivitamin/mineral use. RESULTS: During the follow-up, we identified 25,772 cases of CVD events, 4754 cases of CVD mortality, 18,728 cases of coronary heart disease, 6726 cases of myocardial infarction, and 4561 cases of stroke. The multivariable-adjusted hazard ratios associated with multivitamin/mineral use were 0.96 (95% CI: 0.93, 0.99) for CVD events, 0.92 (0.86, 1.00) for CVD mortality, 0.96 (0.93, 0.99) for coronary heart disease, and 0.92 (0.86, 0.97) for myocardial infarction. Subgroup analysis suggested that multivitamin/mineral use was associated with a significantly lower risk of CVD events in participants aged < 60 years and in former and current smokers (P for interaction ≤ 0.01). Sensitivity analyses showed no substantial change in the results when we excluded participants who developed CVD events during the first 2 years of follow-up. CONCLUSION: Multivitamin/mineral supplementation was associated with very modest reductions in CVD events. Age and smoking might modify these associations.

Primary cardiac undifferentiated pleomorphic sarcoma is associated with TP53 mutation during lack of MDM2 amplification, and targeted sequencing analysis reveals potentially actionable targets.

Cardiac undifferentiated pleomorphic sarcoma (UPS) is a rare malignancy. Several studies have revealed frequent MDM2, CDK4, PDFGRA, and KIT amplifications and CDKN2A and CDKN2B deletions. Cases lacking the above copy number alterations may harbor alternative driver mutations; however, little is known about such occurrences. This study was conducted to gain further insights into the molecular features of cardiac UPS using targeted sequencing of 560 cancer-related genes, and fluorescence in situ hybridization and immunohistochemistry of MDM2, CDK4, CDKN2A, TP53, and RB1 in 9 cardiac UPS cases. TP53 mutation or CDKN2A deletion was found in cases lacking MDM2 amplification. Further, p53 overexpression was detected in the case with TP53 mutation, while p16 expression was completely lost in the case with CDKN2A homozygous deletion. p16 overexpression was found in cases with MDM2 and CDK4 amplification but without CDKN2A deletion. Immunohistochemistry of MDM2, CDK4, p53, and p16 is expected to be preliminarily used for gene status analysis. As cardiac UPS and intimal sarcomas are merging into a single spectrum, mutation data for 3 cardiac UPS and 9 intimal sarcomas from the literature, as well as data for 5 cardiac UPS in our study were evaluated, and known recurrently mutated cancer driver genes, including PDGFRB, TP53, ALK, PTCH1, RET, ERBB4, JAK3, GATA1, PIK3CG, and RARA, were identified. Several new potentially actionable mutations, including those in RARA, ALK, PTCH1, RET, ROS1, ABL1, and MET, were also found. These findings improve the molecular understanding of this rare malignancy and are expected to provide a basis for developing precision therapeutics for cardiac UPS and intimal sarcomas.

Gremlin1 and TGF-ß1 protect kidney tubular epithelial cells from ischemia-reperfusion injury through different pathways.

BACKGROUND: Gremlin1 belongs to the superfamily members of transforming growth factor (TGF)-ß1, playing a profibrotic role in chronic kidney diseases (CKD) and the transition from the late stage of acute kidney injury (AKI) to CKD, but the effect it plays in the early stage of AKI is unclear. This study aimed to investigate the role of Gremlin1on apoptosis in renal tubular epithelial cells under ischemia-reperfusion (I/R) induction. METHODS: We detected Gremlin1 and TGF-ß1 expression in the kidneys of mice undergoing renal ischemia-reperfusion injury bilaterally. We induced apoptosis through depletion and reperfusion of oxygen and serum in human kidney tubular epithelial cells (HKCs), mimicking I/R injury in vivo, and detected the role and pathways of Gremlin1 and TGF-ß1on HKCs injury. RESULTS: Mice undergoing bilateral I/R surgery presented AKI with a significant increase in serum creatinine, obvious renal tubular injuries, and increased macrophage cell and T-cell infiltration in interstitial areas. Gremlin1 expression was significantly increased along with TGF-ß1 in the kidneys of AKI mice compared to sham mice. Exogenous Gremlin1 inhibited I/R-induced caspase3 expression in HKCs, which was blocked by a VEGFR2 kinase inhibitor III (SU5416). TGF-ß1 also inhibited I/R-induced cell apoptosis in HKCs but had no synergic effect with Gremlin1. The TGF-ß1's inhibitory effect could be blocked by the TGF-ß1 type I receptor (activin receptor-like kinase 5, and ALK5)-specific inhibitor SB431542. CONCLUSIONS: Gremlin1 and TGF- ß1 protect kidney tubular epithelial cells from ischemia-reperfusion-induced apoptosis through VEGFR2 and Smad2 signaling pathways.