Proteogenomic Analysis Identifies a Causal Association between Plasma Apolipoprotein B Levels and Liver Cancer Risk.

Liver oncogenesis is accompanied by discernible protein changes in the bloodstream. By employing plasma proteomic profiling, we can delve into the molecular mechanisms of liver cancer and pinpoint potential biomarkers. In this nested case-control study, we applied liquid chromatography-tandem mass spectrometry for proteome profiling in baseline plasma samples. Differential protein expression was determined and was subjected to functional enrichment, network, and Mendelian randomization (MR) analyses. We identified 193 proteins with notable differential levels between the groups. Of these proteins, MR analysis offered a compelling negative association between apolipoprotein B (APOB) and liver cancer. This association was further corroborated in the UK Biobank cohort: genetically predicted APOB levels were associated with a 31% (95% CI 19-42%) decreased risk of liver cancer; and phenotypic analysis indicated an 11% (95% CI 8-14%) decreased liver cancer risk for every 0.1 g/L increase of circulating APOB levels. Multivariable MR analysis suggested that the hepatic fat content might fully mediate the APOB-liver cancer connection. In summary, we identified some plasma proteins, particularly APOB, as potential biomarkers of liver cancer. Our findings underscore the intricate link between lipid metabolism and liver cancer, offering hints for targeted prophylactic strategies and early detection.

Nonlinear relationships of circulating polyunsaturated fatty acids with the complications of liver cirrhosis: A prospective, longitudinal cohort study.

BACKGROUND & AIMS: The role of circulating polyunsaturated fatty acids (PUFAs) in preventing liver cirrhosis complications remains unclear. METHODS: Between 2006 and 2010, 273,834 UK Biobank participants with plasma PUFA quantification data were enrolled and followed up until October 31, 2022. Plasma PUFAs were quantified using a high-throughput nuclear magnetic resonance-based metabolic profiling platform. Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with hepatocellular carcinoma. RESULTS: During a median follow-up of 13.9 years, 2026 participants developed liver cirrhosis complications. Total plasma PUFAs, omega-3 PUFAs, docosahexaenoic acid (DHA), omega-6 PUFAs, and linoleic acid (LA) were inversely associated with the risk of liver cirrhosis complications, whereas the plasma omega-6/omega-3 ratio was positively associated. Nonparametrically restricted cubic spline regression showed nonlinear associations of plasma PUFAs with liver cirrhosis complications. The inflection points were 4.78 mmol/L for total PUFAs, 0.73 mmol/L for omega-3 PUFAs, 0.25 mmol/L for DHA, 4.07 mmol/L for omega-6 PUFAs, and 2.99 mmol/L for LA. Plasma omega-3 PUFAs were negatively associated with the risk of liver cirrhosis complications when omega-3 PUFAs were <0.73 mmol/L (adjusted hazard ratio [HR], 0.11 [0.08-0.16]), whereas the association was inverted when omega-3 PUFAs were ≥0.73 mmol/L (adjusted HR, 1.87 [1.20-2.92]). CONCLUSIONS: The protective effect of plasma omega-3 PUFAs on liver cirrhosis complications is reversed after passing the corresponding inflection point, suggesting an optimal dietary omega-3 PUFA supplementation dose.

Enhancing myocardial infarction treatment through bionic hydrogel-mediated spatial combination therapy via mtDNA-STING crosstalk modulation.

Myocardial infarction (MI)-induced impaired cardiomyocyte (CM) mitochondrial function and microenvironmental inflammatory cascades severely accelerate the progression of heart failure for compromised myocardial repair. Modulation of the crosstalk between CM mitochondrial DNA (mtDNA) and STING has been recently identified as a robust strategy in enhancing MI treatment, but remains seldom explored. To develop a novel approach that can address persistent myocardial injury using this crosstalk, we report herein construction of a biomimetic hydrogel system, Rb1/PDA-hydrogel comprised of ginsenoside Rb1/polydopamine nanoparticles (Rb1/PDA NPs)-loaded carboxylated chitosan, 4-arm-PEG-phenylboronic acid (4-arm-PEG-PBA), and 4-arm-PEG-dopamine (4-arm-PEG-DA) crosslinked networks. An optimized hydrogel formulation presents not only desired adhesion properties to the surface of the myocardium, but also adaptability for deep myocardial injection, resulting in ROS scavenging, CM mitochondrial function protection, M1 macrophage polarization inhibition through the STING pathway, and angiogenesis promotion via an internal-external spatial combination. The enhanced therapeutic efficiency is supported by the histological analysis of the infarcted area, which shows that the fibrotic area of the MI rats decreases from 58.4% to 5.5%, the thickness of the left ventricular wall increases by 1-fold, and almost complete recovery of cardiac function after 28 days of treatment. Overall, this study reported the first use of a strong adhesive and injectable hydrogel with mtDNA and STING signaling characteristics for enhanced MI treatment via an internal-external spatial combination strategy.

Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease.

BACKGROUND: Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored. METHODS: We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality. RESULTS: 96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e - 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15-6.85), 2.82-fold (1.69-4.72), and 4.41-fold (3.04-6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome. CONCLUSIONS: Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions.

Healthy lifestyles are associated with alleviating the single-nucleotide polymorphism-based genetic risks of ischaemic stroke, intracerebral haemorrhage and myocardial infarction.

BACKGROUND: Both genetic and lifestyle factors contribute to myocardial infarction (MI) and stroke, including ischaemic stroke (IS) and intracerebral haemorrhage (ICH). We explored how and the extent to which a healthy lifestyle, by considering a comprehensive list, could counteract the genetic risk of those diseases, respectively. METHODS: 315 044 participants free of stroke and MI at baseline were identified from the UK Biobank. Genetic risk scores (GRS) for those diseases were constructed separately and categorised as low, intermediate and high by tertile. Lifestyle risk scores (LRS) were constructed separately using smoking, alcohol intake, physical activity, dietary patterns and sleep patterns. Similarly, participants were categorised into low, intermediate and high LRS. The data were analysed using Cox proportional hazard models. RESULTS: Over a median follow-up of 12.8 years, 4642, 1046 and 9485 participants developed IS, ICH and MI, respectively. Compared with participants with low levels of GRS and LRS, the HRs of those with high levels of GRS and LRS were 3.45 (95% CI 2.71 to 4.41), 2.32 (95% CI 1.40 to 3.85) and 4.89 (95% CI 4.16 to 5.75) for IS, ICH and MI, respectively. Moreover, among participants with high GRS, the standardised 14-year rates of IS events were 4.40% (95% CI 3.45% to 5.36%) among those with high LRS. In contrast, it is only 1.78% (95% CI 1.63% to 1.94%) among those with low LRS. Similarly for MI, the high LRS group had standardised rates of 8.60% (95% CI 7.38% to 9.81%), compared with 3.34% (95% CI 3.12% to 3.56%) in low LRS. Among the high genetic risk group of ICH, the rate is reduced by about half compared low LRS to high LRS, although the rate was low for both (0.36% (95% CI 0.31% to 0.42%) and 0.71% (95% CI 0.36% to 1.05%), respectively). CONCLUSION: Healthy lifestyles were substantially associated with a reduction in the risk of IS, ICH and MI and attenuated the genetic risk of IS, ICH and MI by at least half, respectively.

Associations of sleep behaviors and genetic risk with risk of incident osteoporosis: A prospective cohort study of 293,164 participants.

BACKGROUND: Unhealthy sleep behaviors are associated with higher risks of osteoporosis (OP), while prospective evidence is limited. This study aimed to prospectively investigate this association, quantify the attributable burden of OP incidence reduction due to unhealthy sleep behaviors, and explore potential modifications by genetic risk factors. METHODS: This longitudinal cohort study was conducted utilizing data from the UK Biobank, comprising 293,164 participants initially free of OP and with requisite sleep behaviors data at baseline. We followed the participants after recruitment until November 30, 2022, to ascertain incident OP. We assessed the associations of five sleep behaviors including sleep duration, chronotype, insomnia, daytime napping, and morning wake-up difficulties, as well as sleep behavior patterns identified based on the above sleep behaviors, with the risk of OP, using Cox models adjusted for multiple confounders. The analyses were then performed separately among individuals with different OP susceptibility, indexed by standard polygenetic risk scores(PRS) for OP. Our secondary outcome was OP with pathologic fracture. Subgroup and sensitivity analyses were performed. Additionally, attributable risk percent in the exposed population (AR%) and population attributable fraction (PAF) of sleep behaviors were calculated. RESULTS: Over a median follow-up of 13.7 years, 8253 new-onset OP cases were documented. Unhealthy sleep behaviors, such as long or short sleep duration, insomnia, daytime napping, morning wake-up difficulties, and unhealthy sleep patterns, were associated with elevated risks of OP (HRs ranging from 1.14 to 1.46, all P-value <0.001) compared to healthy sleep behaviors. Similar associations were observed for OP with pathologic fractures. Insomnia exhibited the largest AR% of 39.98 % (95%CI: 36.46, 43.31) and PAF of 33.25 % (95%CI: 30.00, 36.34) among healthy sleep patterns and components. A statistically significant multiplicative interaction was noted between sleep behaviors and OP PRS on OP risk (all P-interaction <0.001). CONCLUSIONS: Four unhealthy sleep behaviors and sleep behavior patterns were associated to increased OP risk, with insomnia contributing the most to OP incidence, while genetic risk for OP modified this association. These findings underscore the crucial role of adhering to healthy sleep behaviors for effective OP prevention.

Association between biological aging and the risk of mortality in individuals with non-alcoholic fatty liver disease: A prospective cohort study.

BACKGROUND: The biological process of aging plays an important role in nonalcoholic fatty liver disease (NAFLD) development. However, epidemiological evidence about the association of biological aging with mortality risk among people with NAFLD is limited. METHODS: A total of 2199 participants with NAFLD from the National Health and Nutrition Examination Surveys (NHANES) III were included. The outcomes were all-cause and cause-specific (cardiovascular disease [CVD], cancer, and diabetes) mortality. We computed three BA measures, the Klemera-Doubal method (KDM) age, Phenotypic age, and homeostatic dysregulation (HD), by using 18 age-associated clinical biomarkers, and assessed their associations with mortality risk using Cox proportional hazards (CPH) models. RESULTS: After a median follow-up of 16 years, a total of 1077 deaths occurred. People with NAFLD who died during follow-up period exhibited higher baseline biological age (BA) and biological age accelerations (BAAs). The multivariate-adjusted CPH suggested that a one-standard deviation (SD) increase in KDM age acceleration, Phenotypic age acceleration, or HD was associated with a 3 %, 7 %, or 39 % elevated risk of all-cause mortality, respectively. The results of age-varying HRs showed that the associations of KDM age accelerations (AAs) and Phenotypic AAs with all-cause mortality appeared to be stronger in people with NAFLD younger than 45 years. CONCLUSIONS: Biological aging was positively associated with both all-cause and cause-specific mortality among people with NAFLD, particularly among younger individuals.

Machine-learning-based plasma metabolomic profiles for predicting long-term complications of cirrhosis.

BACKGROUND AND AIMS: The complications of liver cirrhosis occur after long asymptomatic stages of progressive fibrosis and are generally diagnosed late. We aimed to develop a plasma metabolomic-based score tool to predict these events. APPROACH AND RESULTS: We enrolled 64,005 UK biobank participants with metabolomic profiles. Participants were randomly divided into the training (n=43,734) and validation cohorts (n=20,271). Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with HCC. An interpretable machine-learning framework was applied to learn the metabolomic states extracted from 168 circulating metabolites in the training cohort. An integrated nomogram was developed and compared to conventional and genetic risk scores. We created 3 groups: low-risk, middle-risk, and high-risk through selected cutoffs of the nomogram. The predictive performance was validated through the area under a time-dependent receiver operating characteristic curve (time-dependent AUC), calibration curves, and decision curve analysis. The metabolomic state model could accurately predict the 10-year risk of liver cirrhosis complications in the training cohort (time-dependent AUC: 0.84 [95% CI: 0.82-0.86]), and outperform the fibrosis-4 index (time-dependent AUC difference: 0.06 [0.03-0.10]) and polygenic risk score (0.25 [0.21-0.29]). The nomogram, integrating metabolomic state, aspartate aminotransferase, platelet count, waist/hip ratio, and smoking status showed a time-dependent AUC of 0.930 at 3 years, 0.889 at 5 years, and 0.861 at 10 years in the validation cohort, respectively. The HR in the high-risk group was 43.58 (95% CI: 27.08-70.12) compared with the low-risk group. CONCLUSIONS: We developed a metabolomic state-integrated nomogram, which enables risk stratification and personalized administration of liver-related events.

Prevalence of nonalcoholic fatty liver disease and liver cirrhosis in Chinese adults with type 2 diabetes mellitus.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and liver cirrhosis are significant clinical concerns, especially among individuals with type 2 diabetes mellitus (T2DM). However, in China, there is a paucity of reliable evidence detailing the characteristics of NAFLD and liver cirrhosis in T2DM. Furthermore, the relationship between blood glucose levels and NAFLD prevalence remains unclear. METHODS: Data from the Shanghai Suburban Adult Cohort and Biobank were analyzed, including 6621 participants with T2DM. NAFLD was diagnosed by ultrasonography and liver cirrhosis was performed according to the health information systems. Logistic regression and restricted cubic spline analysis were used to explore the potential risk factors for NAFLD and liver cirrhosis. RESULTS: The prevalence of NAFLD was 59.36%, and liver cirrhosis was 1.43% among T2DM patients. In these patients, factors like age, being female, marital status, and obesity significantly increased the risk of NAFLD. Specifically, obesity had a strong positive association with NAFLD (odds ratio [OR] = 4.70, 95% confidence interval [CI]: 4.13-5.34). The higher glycated hemoglobin (HbA1c) quartile was associated with a heightened NAFLD risk compared to the lowest quartile (all p < .001). The HbA1c-NAFLD relationship displayed a linear that mimicked an inverted L-shaped pattern. A significant positive association existed between HbA1c levels and NAFLD for HbA1c <8.00% (OR = 1.59, 95% CI: 1.44-1.75), but this was not observed for HbA1c >8.00% (OR = 1.03, 95% CI: 0.92-1.15). CONCLUSION: Systematic screening for NAFLD is essential in T2DM patients, especially with poor glucose control and obesity in female.

Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline: A Community-Based Cohort Study.

Cardiovascular health metrics are now widely recognized as modifiable risk factors for cognitive decline and dementia. Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia. Circulating metabolites profiling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline. In a prospective community-based cohort in China (n = 725), 312 serum metabolic phenotypes were quantified, and cardiovascular health score was calculated including smoking, exercise, sleep, diet, body mass index, blood pressure, and blood glucose. Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline. A better cardiovascular health was significantly associated with lower risk of concentration decline and orientation decline (hazard ratio (HR): 0.84-0.90; p < 0.05). Apolipoprotein-A1, high-density lipoprotein (HDL) cholesterol, cholesterol ester, and phospholipid concentrations were significantly associated with a lower risk of longitudinal memory and orientation decline (p < 0.05 and adjusted-p < 0.20). Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and -3 (proportion of mediation: 7.68-8.21%, both p < 0.05). Cardiovascular risk factors were associated with greater risks of cognitive decline, which were found to be mediated by circulating lipoproteins, particularly the medium-size HDL components. These findings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00120-2.

Low thyroid function is associated with metabolic dysfunction-associated steatotic liver disease.

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is recently introduced to better highlight the pathogenic significance of cardiometabolic dysfunction, as compared with non-alcoholic fatty liver disease. This study aimed to investigate the association between low thyroid function and MASLD in the new context. Methods: We recruited 2901 participants for our retrospective cohort study from 2016 to 2021. Participants were divided into strict-normal thyroid function and low thyroid function groups (low-normal thyroid function, subclinical hypothyroidism) based on initial thyroid stimulating hormone (TSH) levels, respectively. Cox regression models were used to estimate the hazard ratios (HRs) and 95% CI. Results: During a median follow-up of 15.6 months, 165 (8.9%) strict-normal thyroid function subjects and 141 (13.4%) low thyroid function subjects developed MASLD; this result was statistically relevant (P < 0.05). Univariate regression analysis showed that low thyroid function and subclinical hypothyroidism were statistically significantly associated with MASLD (low thyroid function: HR1.53; 95% CI 1.22-1.92; subclinical hypothyroidism: HR1.95; 95% CI 1.47-2.60). Conclusions: MASLD is associated with low thyroid function and the relationship between MASLD and low thyroid function is independent.

Prognostic factors for competing risk in patients with AIDS-related Kaposi's sarcoma: A SEER population-based study.

OBJECTIVES: Despite the improved survival of patients with AIDS and Kaposi's sarcoma (KS), competing events are a non-negligible issue affecting the survival of such patients. In this study, we explored the prognostic factors of KS-specific and non-KS-specific mortality in patients with AIDS-related KS (AIDS-KS), accounting for competing risk. METHODS: We identified 17 103 patients with AIDS-KS aged 18-65 years between 1980 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) 18 registry database. Prognostic factors for KS-specific and non-KS-specific mortality were determined by the Fine and Grey proportional subdistribution hazard model. We built competing risk nomograms and assessed their predictive performance based on the identified prognostic factors. RESULTS: In total, 12 943 (75.68%) patients died, 1965 (15.50%) of whom died from competing events. The KS-specific mortality rate was 14 835 per 100 000 person-years, and the non-KS specific mortality rate was 2719 per 100 000 person-years. Specifically, age >44 years was associated with an 11% decrease in the subdistribution hazard of KS-specific mortality compared with age <43 years but a 50% increase in the subdistribution hazard of non-KS-specific mortality. Being male was associated with a 26% increase in the subdistribution hazard of KS-specific mortality compared with being female but a 32% decrease in the subdistribution hazard of non-KS-specific mortality. Notably, being in the antiretroviral therapy (ART) era consistently showed a decrease in the subdistribution hazard of both KS-specific and non-KS-specific mortality than being in the pre-ART era. CONCLUSIONS: Competing events commonly occurred among patients with AIDS-KS, which deserves further attention to improve the prognosis of these patients.

Global epidemiology of early-onset liver cancer attributable to specific aetiologies and risk factors from 2010 to 2019.

Background: Considering its emergence as a public health concern worldwide, with potential spatial-temporal heterogeneities, we aimed to determine the global burden of early-onset liver cancer attributable to aetiologies and concomitant risk factors. Methods: We used data from the Global Burden of Diseases Study 2019 to determine age-standardised disability-adjusted life-year (DALY) rates for early-onset liver cancer by aetiologies and the population DALYs attributable to concomitant risk factors between 2010 and 2019. We also calculated estimated annual percentage changes (EAPCs) to measure temporal trends. Results: There were 2.9 million DALYs related to early-onset liver cancer globally in 2019. East Asia contributed over half of DALYs, which increased annually by 1.23% (95% confidence interval (CI) = 0.71, 1.76) between 2010 and 2019. Non-alcoholic steatohepatitis was the only growing aetiology. The proportion of DALYs attributed to metabolic risks increased by 22.50% (95% CI = 14.33, 38.13), while behavioral risks remained stable. Obesity surpassed smoking as the most prevalent nondeterministic aetiological risk factor from 2010 to 2019, while the population DALY attributable to hepatitis B combined with obesity increased by 29.93% (95% CI = 8.49, 60.77) in the same period, making it the principal joint contributor. Conclusions: Early-onset liver cancer poses considerable disability and continues to increase in many regions, especially in East Asia. Metabolic risk factors, particularly when hepatitis B and obesity coexist, are the fastest-growing contributors to this type of cancer. More targeted interventions are imperative to curb the growing burden of early-onset liver cancer due to metabolic risks.

Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: a systematic literature review and meta-analysis of 3740 studies and 231 million people.

OBJECTIVE: China concentrates a large part of the global burden of HBV infection, playing a pivotal role in achieving the WHO 2030 global hepatitis elimination target. METHODS: We searched for studies reporting HBV surface antigen (HBsAg) seroprevalence in five databases until January 2023. Eligible data were pooled using a generalised linear mixed model with random effects to obtain summary HBsAg seroprevalence. Linear regression was used to estimate annual percentage change (APC) and HBsAg prevalence in 2021. RESULTS: 3740 studies, including 231 million subjects, were meta-analysed. HBsAg seroprevalence for the general population decreased from 9.6% (95% CI 8.4 to 10.9%) in 1973-1984 to 3.0% (95% CI 2.1 to 3.9%) in 2021 (APC=-3.77; p<0.0001). Decreases were more pronounced in children <5 years (APC=-7.72; p<0.0001) and 5-18 years (-7.58; p<0.0001), than in people aged 19-59 years (-2.44; p<0.0001), whereas HBsAg seroprevalence increased in persons ≥60 years (2.84; p=0.0007). Significant decreases were observed in all six major Chinese regions, in both men (APC=-3.90; p<0.0001) and women (-1.82; p<0.0001) and in high-risk populations. An estimated 43.3 million (95% uncertainty interval 30.7-55.9) persons remained infected with HBV in China in 2021 (3.0%), with notable heterogeneity by region (<1.5% in North China to>6% in Taiwan and Hong Kong) and age (0.3%, 1.0%, 4.7% and 5.6% for <5 years, 5-18 years, 19-59 years and ≥60 years, respectively). CONCLUSIONS: China has experienced remarkable decreases in HBV infection over the last four decades, but variations in HBsAg prevalence persist in subpopulations. Ongoing prevention of HBV transmission is needed to meet HBV elimination targets by 2030. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021284217).

Associations of healthy lifestyle and three latent socioeconomic status patterns with physical multimorbidity among middle-aged and older adults in China.

BACKGROUND: Multimorbidity is an emerging global public health concern. However, complex associations of healthy lifestyle and socioeconomic status (SES) with multimorbidity have not been identified. METHODS: This population-based prospective cohort study used data from four waves of the China Health and Retirement Longitudinal Study (CHARLS) to explore these relationships. Physical multimorbidity was measured using 12 non-communicable diseases. Latent class analysis (LCA) was conducted to determine the optimal SES patterns based on annual per-capita household expenditure, occupation, education level, and health insurance. The healthy lifestyle score (0-5) was constructed comprising information on smoking, drinking, physical activity, sleep, and body shape. RESULTS: Of 17,708 participants in the CHARLS, 7776 were eligible for inclusion in our analysis (13.3% with high SES, 26.1% with medium SES, and 60.6% with low SES). Compared with high SES participants, those with low SES had higher risks of incident physical multimorbidity (OR 1.22, 95% CI 1.05, 1.42), which was competitively mediated by lifestyle (mediation proportion, -10.17%, 95% CI -19.12%, -1.23%). Significant interactions were observed between lifestyle factors and SES in patients with incident diabetes. Participants with low SES and no or one healthy lifestyle factor had a higher risk of incident physical multimorbidity than those with high SES and four to five healthy lifestyle factors (OR 2.19, 95% CI 1.57, 3.04). CONCLUSION: Healthy lifestyles competitively mediate a fractional proportion of socioeconomic inequity in incident physical multimorbidity. Furthermore, healthy lifestyles were associated with lower multimorbidity risk in the SES subgroups, supporting the important role of lifestyle in reducing physical multimorbidity burden.

Candidate biomarkers and persistent transcriptional responses after low and high dose ionizing radiation at high dose rate.

PURPOSE: Development of an integrated time and dose model to explore the dynamics of gene expression alterations and identify biomarkers for biodosimetry following low- and high-dose irradiations at high dose rate. MATERIAL AND METHODS: We utilized multiple transcriptome datasets (GSE8917, GSE43151, and GSE23515) from Gene Expression Omnibus (GEO) for identifying candidate biological dosimeters. A linear mixed-effects model with random intercept was used to explore the dose-time dynamics of transcriptional responses and to functionally characterize the time- and dose-dependent changes in gene expression. RESULTS: We identified genes that are correlated with dose and time and discovered two clusters of genes that are either positively or negatively correlated with both dose and time based on the parameters of the model. Genes in these two clusters may have persistent transcriptional alterations. Twelve potential transcriptional markers for dosimetry-ARHGEF3, BAX, BBC3, CCDC109B, DCP1B, DDB2, F11R, GADD45A, GSS, PLK3, TNFRSF10B, and XPC were identified. Of these genes, BAX, GSS, and TNFRSF10B are positively associated with both dose and time course, have a persistent transcriptional response, and might be better biological dosimeters. CONCLUSIONS: With the proposed approach, we may identify candidate biomarkers that change monotonically in relation to dose, have a persistent transcriptional response, and are reliable over a wide dose range.

Global Burden, Risk Factor Analysis, and Prediction Study of Ischemic Stroke, 1990-2030.

BACKGROUND AND OBJECTIVES: Ischemic stroke (IS), 1 of the 2 main subtypes of stroke, occurs because of brain ischemia caused by thrombosis of a cerebral blood vessel. IS is one of the most important neurovascular causes of death and disability. It is affected by many risk factors, such as smoking and a high body mass index (BMI), which are also critical in the preventive control of other cardiovascular and cerebrovascular diseases. However, there are still few systematic analyses of the current and predicted disease burden and the attributable risk factors of IS. METHODS: Based on the Global Burden of Disease 2019 database, we used age-standardized mortality rate and disability-adjusted life year to systematically present the geographical distribution and trends of IS disease burden worldwide from 1990 to 2019 by calculating the estimated annual percentage change and to analyze and predict the death number of IS accounted by 7 major risk factors for 2020-2030. RESULTS: Between 1990 and 2019, the global number of IS deaths increased from 2.04 million to 3.29 million and is expected to increase further to 4.90 million by 2030. The downward trend was more pronounced in women, young people, and high sociodemographic index (SDI) regions. At the same time, a study of attributable risk factors of IS found that 2 behavioral factors, smoking and diet in high sodium, and 5 metabolic factors, including high systolic blood pressure, high low-density lipoprotein cholesterol, kidney dysfunction, high fasting plasma glucose, and a high BMI, are major contributors to the increased disease burden of IS now and in the future. DISCUSSION: Our study provides the first comprehensive summary for the past 30 years and the prediction of the global burden of IS and its attributable risk factors until 2030, providing detailed statistics for decision-making on the prevention and control of IS globally. An inadequate control of the 7 risk factors would lead to an increased disease burden of IS in young people, especially in low SDI regions. Our study identifies high-risk populations and helps public health professionals develop targeted preventive strategies to reduce the global disease burden of IS.

IGF2BP1 regulates the cargo of extracellular vesicles and promotes neuroblastoma metastasis.

Neuroblastoma is a highly metastatic cancer, and thus is one of the leading causes of cancer-related mortalities in pediatric patients. More than 50% of NB cases exhibit 17q21-ter partial chromosomal gain, which is independently associated with poor survival, suggesting the clinical importance of genes at this locus in NB. IGF2BP1 is one such proto-oncogene located at 17q locus, and was found to be upregulated in patients with metastatic NBs. Here, utilizing multiple immunocompetent mouse models, along with our newly developed highly metastatic NB cell line, we demonstrate the role of IGF2BP1 in promoting NB metastasis. Importantly, we show the significance of small extracellular vesicles (EVs) in NB progression, and determine the pro-metastatic function of IGF2BP1 by regulating the NB-EV-protein cargo. Through unbiased proteomic analysis of EVs, we discovered two novel targets (SEMA3A and SHMT2) of IGF2BP1, and reveal the mechanism of IGF2BP1 in NB metastasis. We demonstrate that IGF2BP1 directly binds and governs the expression of SEMA3A/SHMT2 in NB cells, thereby modulating their protein levels in NB-EVs. IGF2BP1-affected levels of SEMA3A and SHMT2 in the EVs, regulate the formation of pro-metastatic microenvironment at potential metastatic organs. Finally, higher levels of SEMA3A/SHMT2 proteins in the EVs derived from NB-PDX models indicate the clinical significance of the two proteins and IGF2BP1-SEMA3A/SHMT2 axis in NB metastasis.