Establishment of a risk score model for bladder urothelial carcinoma based on energy metabolism-related genes and their relationships with immune infiltration.

Bladder urothelial carcinoma (BLCA) is a common malignant tumor of the human urinary system, and a large proportion of BLCA patients have a poor prognosis. Therefore, there is an urgent need to find more efficient and sensitive biomarkers for the prognosis of BLCA patients in clinical practice. RNA sequencing (RNA-seq) data and clinical information were obtained from The Cancer Genome Atlas, and 584 energy metabolism-related genes (EMRGs) were obtained from the Reactome pathway database. Cox regression analysis and least absolute shrinkage and selection operator analysis were applied to assess prognostic genes and build a risk score model. The estimate and cibersort algorithms were used to explore the immune microenvironment, immune infiltration, and checkpoints in BLCA patients. Furthermore, we used the Human Protein Atlas database and our single-cell RNA-seq datasets of BLCA patients to verify the expression of 13 EMRGs at the protein and single-cell levels. We constructed a risk score model; the area under the curve of the model at 5 years was 0.792. The risk score was significantly correlated with the immune markers M0 macrophages, M2 macrophages, CD8 T cells, follicular helper T cells, regulatory T cells, and dendritic activating cells. Furthermore, eight immune checkpoint genes were significantly upregulated in the high-risk group. The risk score model can accurately predict the prognosis of BLCA patients and has clinical application value. In addition, according to the differences in immune infiltration and checkpoints, BLCA patients with the most significant benefit can be selected for immune checkpoint inhibitor therapy.

Zinc homeostasis may reverse the synergistic neurotoxicity of heavy metal mixtures in Caenorhabditis elegans.

Heavy metal mixtures can cause nerve damage. However, the combined effects of metal mixtures are extremely complex and rarely studied. Zinc (Zn) homeostasis plays an integral role in neural function, but the role of Zn homeostasis in the toxicity of metal mixtures is not well understood. Here, we investigated the combined effects of manganese (Mn), lead (Pb) and arsenic (As) on nerves and the effect of Zn homeostasis on metal toxicity. Caenorhabditis elegans (Maupas, 1900) were exposed to single and multiple metals for 8 days, their movement, behavior, neurons and metal concentration were detected to evaluate the combined effect of metal mixtures. After nematodes were co-treated with metal mixtures and Zn, the nerve function, Zn concentration and redox balance were detected to evaluate the effect of Zn homeostasis on metal toxicity. The results showed that Mn + Pb and Pb + As mixtures induced synergistic toxicity for nematode nerves, which damaged movement, behavior and neurons, and decreased Zn concentration. While Zn supplementation recovered Zn homeostasis and promoted redox balance on nematodes, and then improved the nerve function. Our study demonstrated the combined effects of metal mixtures and the neuroprotective effect of Zn homeostasis. Therefore, assessment of metal mixtures toxicity should consider their interaction and the impacts of essential metals homeostasis.

Relationship of multiple metals mixture and osteoporosis in older Chinese women: An aging and longevity study.

Osteoporosis has become a major health problem in older women. Previous studies have linked individual metals exposure with osteoporosis, but combined effects remain inconclusive. We aimed to explore the individual and combined association between multiple metals mixture and osteoporosis risk in older Chinese women. A total of 2297 older women (aged ≥60) from the Hongshuihe region of Guangxi, southern China included. We measured 22 blood metal levels through inductively coupled plasma mass spectrometry. And osteoporosis was defined as a T score ≤ -2.5. The least absolute shrinkage and selection operator (LASSO) penalized regression, and Bayesian kernel machine regression (BKMR) models were performed to explore the association between blood metals and osteoporosis risk. Of 2297 older women, there were 829 osteoporosis and 1468 non-osteoporosis participants. The median age was 71 and 68 years old in the osteoporosis and the non-osteoporosis group, respectively. In the single-metal model, rubidium and vanadium were negatively associated with osteoporosis (P for trend = 0.02 and 0.002, respectively), and lead presented the reverse trend (P for trend = 0.01). The LASSO penalized regression model selected nine metals (calcium, cadmium, cobalt, lead, magnesium, rubidium, strontium, vanadium and zinc), which were included in the subsequent analysis. And the multiple-metal model presented a consistent trend with the single-metal model using the selected metals. Furthermore, we performed BKMR to explore the combined effect, and found an overall negative effect between metals mixture and osteoporosis risk when all the metals were fixed at 50th, and rubidium and vanadium were the main contributors. In addition, blood Rb and V were significantly negatively related to OP risk with other metals at different levels (25th, 50th and 75th percentiles). The study suggests metal mixture exposure and osteoporosis risk in older Chinese women, and further studies need to be conducted.

Long noncoding RNA as a potential diagnostic tool for prostate cancer: a systematic review and meta-analysis.

PURPOSE: To identify consistently expressed lncRNAs and suitable lncRNAs with high sensitivity and specificity from multiple independent studies as potential biomarkers for PCa diagnostics. METHODS: We searched multiple electronic databases including PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, CQVIP, Wanfang, and CBMdisc for studies published up to July 2022. The quality of the included studies was assessed by two independent reviewers based on the QUADAS-2 tool using Review Manager 5.3. A vote-counting method was used based on the ranking of potential molecular biomarkers. The top-ranked lncRNAs were further assessed for diagnostic value using Meta-disc version 1.4 software. RESULTS: Among the 26 included studies, 2 circulating lncRNAs (PCA3 and MALAT-1) were reported 3 or more times in PCa patients versus non-PCa patients. In further analysis, the areas under the curve of the summary receiver operating characteristic curves for PCA3 and MALAT-1 distinguishing PCa patients were 0.775 and 0.771, respectively. CONCLUSIONS: Based on the current evidence, PCA3 and MALAT-1 are reliable lncRNAs for the diagnosis of PCa.

Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk.

Importance: Genetic and lifestyle factors are related to thyroid cancer (TC). Whether a healthy lifestyle is associated with TC and could attenuate the influence of genetic variants in TC remains equivocal. Objectives: To examine the associations between genetics and healthy lifestyle with incident TC and whether adherence to a healthy lifestyle modifies the association between genetic variants and TC. Design, Setting, and Participants: A prospective cohort study using UK Biobank data recruited 502 505 participants aged 40 to 69 years between March 13, 2006, and October 1, 2010. A total of 307 803 participants of European descent were recruited at baseline, and 264 956 participants were available for the present study. Data analysis was conducted from November 1, 2021, to April 22, 2022. Exposures: Lifestyle behaviors were determined by diet index, physical activity, weight, smoking, and alcohol consumption. Lifestyle was categorized as unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5). The polygenic risk score (PRS) was derived from a meta-genome-wide association study using 3 cohorts and categorized as low, intermediate, and high. Main Outcomes and Measures: Thyroid cancer was defined using the International Classification of Diseases, Ninth Revision (code 193), International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (code C73), and self-report (code 1065). Results: Of 264 956 participants, 137 665 were women (52%). The median age was 57 (IQR, 49-62) years. During a median follow-up of 11.1 (IQR, 10.33-11.75) years (2 885 046 person-years), 423 incident TCs were ascertained (14.66 per 100 000 person-years). Higher PRSs were associated with TC (hazard ratio [HR], 2.25; 95% CI, 1.91-2.64; P = 8.65 × 10-23). An unfavorable lifestyle was also associated with a higher risk of TC (HR, 1.93; 95% CI, 1.50-2.49; P < .001). When stratified by PRS, unfavorable lifestyle was associated with TC in the higher PRS group (favorable vs unfavorable HR, 0.52; 95% CI, 0.37-0.73; P < .001). Furthermore, participants with both a high PRS and unfavorable lifestyle had the highest risk of TC (HR, 4.89; 95% CI, 3.03-7.91; P < .001). Conclusions and Relevance: In this prospective cohort study, genetic and lifestyle factors were independently associated with incident TC, which suggests that a healthier lifestyle may attenuate the deleterious influence of genetics on the risk of TC in individuals of European descent.

Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.

BACKGROUND: Exposure to heavy metals has been reported to be associated with multiple diseases. However, direct associations and potential mechanisms of heavy metals with physical disability remain unclear. OBJECTIVES: We aimed to quantify associations of heavy metals with physical disability and further explore the potential mechanisms of DNA methylation on the genome scale. METHODS: A cross-sectional study of 4,391 older adults was conducted and activities of daily living (ADL) disability were identified using a 14-item scale questionnaire including basic and instrumental activities to assess the presence of disability (yes or no) rated on a scale of dependence. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated to quantify associations between heavy metals and ADL disability prevalence using multivariate logistic regression and Bayesian kernel machine regression (BKMR) models. Whole blood-derived DNA methylation was measured using the HumanMethylationEPIC BeadChip array. An ADL disability-related epigenome-wide DNA methylation association study (EWAS) was performed among 212 sex-matched ADL disability cases and controls, and mediation analysis was further applied to explore potential mediators of DNA methylation. RESULTS: Each 1-standard deviation (SD) higher difference in log10-transformed manganese, copper, arsenic, and cadmium level was significantly associated with a 14% (95% CI: 1.05, 1.24), 16% (95% CI:1.07, 1.26), 22% (95% CI:1.13, 1.33), and 15% (95% CI:1.06, 1.26) higher odds of ADL disability, which remained significant in the multiple-metal and BKMR models. A total of 85 differential DNA methylation sites were identified to be associated with ADL disability prevalence, among which methylation level at cg220000984 and cg23012519 (annotated to IRGM and PKP3) mediated 31.0% and 31.2% of manganese-associated ADL disability prevalence, cg06723863 (annotated to ESRP2) mediated 32.4% of copper-associated ADL disability prevalence, cg24433124 (nearest to IER3) mediated 15.8% of arsenic-associated ADL disability prevalence, and cg07905190 and cg17485717 (annotated to FREM1 and TCP11L1) mediated 21.5% and 30.5% of cadmium-associated ADL disability prevalence (all p<0.05). DISCUSSION: Our findings suggested that heavy metals contributed to higher prevalence of ADL disability and that locus-specific DNA methylation are partial mediators, providing potential biomarkers for further cellular mechanism studies. https://doi.org/10.1289/EHP10602.

Circulating exosomal mRNA signatures for the early diagnosis of clear cell renal cell carcinoma.

BACKGROUND: There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. METHODS: Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. RESULTS: Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). CONCLUSIONS: We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

Gender-specific effects of prenatal mixed exposure to serum phthalates on neurodevelopment of children aged 2-3 years:the Guangxi Birth Cohort Study.

Phthalates have been shown to have adverse effects on neurodevelopment, which may be gender-specific. However, the association between prenatal mixed exposure to phthalates and children's neurodevelopment remains inconsistent. We measured 15 prenatal serum phthalate levels and evaluated children's neurodevelopmental indicators using Gesell Developmental Schedule (GDS) (n = 750). Generalized linear regression was fitted to examine the association. Among boys, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) had adverse effects on gross motor [odds ratio (OR): 7.38, 95% confidence interval (CI):1.42, 38.46]. For gross motor in boys, joint effect was discovered between mono-2-ethylhexyl phthalate (MEHP) and MEHHP. Moreover, synergistic effects were found for MEHP with vanadium and cadmium, and antagonistic effects for MEHP with magnesium, calcium, titanium, iron, copper, selenium, rubidium, and strontium. We did not find statistically significant relationships in girls. In the 1st trimester, adverse effects were identified between mono-2-ethyl-5-oxoyhexyl phthalate (MEOHP) and adaptation (P = 0.024), and monomethyl phthalate (MMP) with social area (P = 0.017). In the 2nd trimester, MEHHP had adverse effects on social area (P = 0.035). In summary, we found boys may be more vulnerable to the neurotoxicity than girls in gross motor, and we also discovered the detrimental effects of phthalates on children's neurodevelopment in the 1st and 2nd trimesters. Therefore, the supplementation of appropriate elements in the 1st and 2nd trimesters may help reduce the adverse effects of phthalates on children's neurodevelopment, especially among boys.

Genome-wide association and Mendelian randomization study of blood copper levels and 213 deep phenotypes in humans.

Metal elements are present in the human body, and their levels in the blood have important impacts on health. In this study, 2488 Chinese individuals were included in a genome-wide association study of 21 serum metal levels, with approximately 179,000 East Asian individuals in a bidirectional two-sample Mendelian randomization (MR) analysis, and 628,000 Europeans in a two-sample MR analysis. We identified two single nucleotide polymorphisms (SNPs) rs35691438 and rs671 that were significantly associated with serum copper levels (SCLs). The bidirectional two-sample MR analysis in the East Asian population showed that gamma-glutamyl transpeptidase levels have a causal effect on SCLs. SCLs have causal effects on six outcomes, namely risks of esophageal varix, glaucoma, sleep apnea syndrome, and systemic lupus erythematosus, white blood cell count, and usage of drugs affecting bone structure and mineralization. The two-sample MR analyses in the European population showed causal effects of erythrocyte copper levels on risks of carpal tunnel syndrome and compression fracture. Our results provide original insights into the causal relationship between blood metal levels and multiple human phenotypes.

Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.

BACKGROUND & AIMS: Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms. METHODS: We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network. RESULTS: Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level. CONCLUSIONS: Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.

Associations Between Blood Pressure and Accelerated DNA Methylation Aging.

Background Individuals of the same chronological age may exhibit diverse susceptibilities to death. However, few studies have investigated the associations between blood pressure and the accelerated aging. Methods and Results A cross-sectional study was conducted in 288 adults aged ≥50 years. We assessed the DNA methylation-based measures of biological age using CpG sites on the Illumina HumanMethylationEPIC BeadChip. Epigenetic age acceleration metrics were derived by regressing residuals (ΔAge) and ratios (aging rate) of DNA methylation age on chronological age. Dose-response relationships between blood pressure and epigenetic age acceleration were quantified using multiple linear regression and restricted cubic regression models. We found that each 10-mm Hg increase in systolic blood pressure was associated with 0.608 (95% CI, 0.231-0.984) years increase in ΔAge and 0.007 (95% CI, 0.002-0.012) increase in aging rate; meanwhile, for pulse pressure, the increase was 1.12 (95% CI, 0.625-1.61) years for ΔAge and 0.013 (95% CI, 0.007-0.020) for aging rate. Subgroup analysis showed that the significant associations of systolic blood pressure and pulse pressure with epigenetic age acceleration appeared to be limited to women, although interactions between blood pressure and sex were not significant (P values for interaction >0.05). The combination of women and hypertension was associated with a much higher increase in ΔAge (ß [95% CI], 4.05 [1.07-7.02]) and aging rate (ß [95% CI], 0.047 [0.008-0.087]), compared with male participants without hypertension. Conclusions Our findings suggested that high systolic blood pressure and pulse pressure were associated with the epigenetic age acceleration, providing important clues for relationships between blood pressure and epigenetic aging.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study.

Exposures to copper have become a health concern. We aim to explore the broad clinical effects of blood copper concentrations. A total of 376,346 Caucasian subjects were enrolled. We performed a Mendelian randomization and phenome-wide association study (MR-PheWAS) to evaluate the causal association between copper and a wide range of outcomes in UK Biobank, and we constructed a protein-protein interaction network. We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male. MR analysis implicated a causal role of blood copper in five diseases (overall population), including prostate cancer (OR = 0.87, 95% CI 0.77-0.98), malignant and unknown neoplasms of the brain and nervous system (OR = 0.58, 95% CI 0.38-0.89), and hypertension (OR = 0.94, 95% CI 0.90-0.98), essential hypertension (OR = 0.94, 95% CI 0.90-0.98) and cancer of brain and nervous system (OR = 0.63, 95% CI 0.41-0.98). For male, except for dysphagia being newly associated with blood copper (OR = 1.39, 95% CI 1.18-1.63), other MR results were consistent with the overall population. In addition, the PPI network showed possible relationship between blood copper and four outcomes, namely brain cancer, prostate cancer, hypertension, and dysphagia. Blood copper may have causal association with prostate cancer, malignant and unknown neoplasms of the brain and nervous system, hypertension, and dysphagia. Considering that copper is modifiable, exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00052-3.

MR-PheWAS for the causal effects of serum magnesium on multiple disease outcomes in Caucasian descent.

Magnesium is integral to many physiological processes, whereas variations in its levels, even within the normal range, can have critical implications for health. To explore the broad clinical effects of varying serum magnesium levels, we performed a two-sample Mendelian randomization and phenome-wide association study (MR-PheWAS) in the UK Biobank cohort. In total, MR-PheWAS analysis implicated a causal role of serum magnesium levels in five disease groups and six disease outcomes. In addition, our study indicated the gender-specific effects of nine disease groups/outcomes in MR estimated effects. The protein-protein interaction network demonstrated an interaction between the serum magnesium-associated gene DCDC1 and the cataract- associated gene PAX6. The present study verified several previously reported disease outcomes and identified novel potential disease outcomes for serum magnesium levels. The DCDC1 gene and the PAX6 gene may be the new targets for promoting the treatments of cataracts using magnesium intervention.

The impacts of different anticoagulants and long-term frozen storage on multiple metal concentrations in peripheral blood: a comparative study.

It is important but remains unclear whether ethylenediaminetetraacetic acid (EDTA) and sodium heparin anticoagulants have different impacts on the levels of various metals in peripheral blood after long-term frozen storage. The concentrations of 22 metals (Al, As, Ba, Ca, Cd, Cr, Co, Cu, Mn, Mg, Mo, Ni, Fe, Pb, Rb, Se, Sn, Sb, Sr, Ti, V, Zn) in whole blood, blood cells and plasma from 22 healthy participants were determined twice, 18 months apart, using inductively coupled plasma mass spectrometry (ICP-MS). The mean percentage error (MPE) and intraclass correlation coefficient (ICC) were calculated to evaluate the impact of the anticoagulants and long-term frozen storage on metal concentrations, respectively. The concentrations of Sb and Ba in whole blood, blood cells and plasma were significantly altered by EDTA and sodium heparin at two measurement timepoints (P < 0.05 and MPE > 80%). In EDTA tubes, the Ti and Ni concentrations in blood cells were changed significantly; and in heparin tubes, the concentrations of Ni and Mo in blood cells and Sb in plasma were also altered (P < 0.05 and MPE > 80%). The ICCs of 11 metals in whole blood, 15 metals in blood cells and 16 metals in plasma remained unchanged in EDTA tubes, and 16 metals in whole blood, 15 metals in blood cells and 17 metals in plasma remained unchanged in heparin tubes (ICC > 0.40). Our study suggested the use of EDTA tubes to determine Sb concentrations in peripheral blood and heparin tubes to determine Ba concentrations. Additionally, heparin tubes may be more suited for determining multiple metal concentrations in whole blood, whereas for blood cells and plasma either EDTA or heparin tubes could be used.

Mediated relationships between multiple metals exposure and fasting blood glucose by reproductive hormones in Chinese men.

Previous studies have reported metals exposure contribute to the change of fasting blood glucose (FBG) level. However, the roles of reproductive hormones in their associations have not been fully elucidated. The aim of the study is to investigate the associations of multiple serum metals with reproductive hormones, and to further explore potential roles of reproductive hormones in relationships between metals exposure and FBG level. A total of 1911 Chinese Han men were analyzed by a cross-sectional study. We measured serum levels of 22 metals by inductively coupled plasma mass spectrometer (ICP-MS). FBG, total testosterone (TT), estradiol (E2), follicle stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels were determined. Least absolute shrinkage and selection operator (LASSO) regression models were conducted to select important metals, and restricted cubic spline models were then used to estimate dose-response relationships between selected metals and reproductive hormones. We also conducted mediation analyses to evaluate whether reproductive hormones played mediating roles in the associations between metals and FBG. We found significant inverse dose-dependent trends of copper, tin and zinc with E2; zinc with SHBG; copper and nickel with TT, while significant positive dose-dependent trend of iron with E2, respectively. Moreover, approximately inverted U-shaped associations existed between lead and SHBG, iron and TT. In addition, E2, SHBG and TT were negatively associated with FBG level. In mediation analyses, the association of copper with FBG was mediated by E2 and TT, with a mediation ratio of 10.4% and 22.1%, respectively. Furthermore, E2 and SHBG mediated the relationship of zinc with FBG, with a mediation ratio of 7.8% and 14.5%, respectively. E2 mediated 11.5% of positive relationship between tin with FBG. Our study suggested that the associations of metals exposure with FBG may be mediated by reproductive hormones.

Sex-specific associations of plasma metals and metal mixtures with glucose metabolism: An occupational population-based study in China.

Studies with multi-pollutant approach on the relationships between multiple metals and fasting plasma glucose (FPG) are limited. Few studies are available on the potential sex-specific associations between metal exposures and glucose metabolism. We explored the associations between 22 plasma metals and FPG level among the 769 participants from the manganese-exposed workers healthy cohort in China. We applied a sparse partial least squares (sPLS) regression followed by ordinary least-squares regression to evaluate multi-pollutant association. Bayesian kernel machine regression (BKMR) model was used to deal with metal mixtures and evaluate their joint effects on FPG level. In the sPLS model, negative associations on FPG levels were observed for plasma iron (belta = -0.066), cobalt (belta = -0.075), barium (belta = -0.109), and positive associations for strontium (belta = 0.082), and selenium (belta = 0.057) in men, which overlapped with the results among the overall participants. Among women, plasma copper (belta = 0.112) and antimony (belta = 0.137) were positively associated with elevated FPG level. Plasma magnesium was negatively associated with FPG level in both sexes (belta = -0.071 in men and belta = -0.144 in women). The results of overlapped for plasma magnesium was selected as the significant contributor to decreasing FPG level in the multi-pollutant, single-metal, and multi-metal models. BKMR model showed a significantly negative over-all effect of six metal mixtures (magnesium, iron, cobalt, selenium, strontium and barium) on FPG level among the overall participants from all the metals fixed at 50th percentile. In summary, our findings underline the probable role of metals in glucose homeostasis with potential sex-dependent heterogeneities, and suggest more researches are needed to explore the sex-specific associations of metal exposures with risk of diabetes.

Advances in the Detection of Pancreatic Cancer Through Liquid Biopsy.

Pancreatic cancer refers to the development of malignant tumors in the pancreas: it is associated with high mortality rates and mostly goes undetected in its early stages for lack of symptoms. Currently, surgical treatment is the only effective way to improve the survival of pancreatic cancer patients. Therefore, it is crucial to diagnose the disease as early as possible in order to improve the survival rate of patients with pancreatic cancer. Liquid biopsy is a unique in vitro diagnostic technique offering the advantage of earlier detection of tumors. Although liquid biopsies have shown promise for screening for certain cancers, whether they are effective for early diagnosis of pancreatic cancer is unclear. Therefore, we reviewed relevant literature indexed in PubMed and collated updates and information on advances in the field of liquid biopsy with respect to the early diagnosis of pancreatic cancer.

Causal Relationship Between Complement C3, C4, and Nonalcoholic Fatty Liver Disease: Bidirectional Mendelian Randomization Analysis.

The complement system is activated during the development of nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the causal relationship between serum C3 and C4 levels and NAFLD. After exclusion criteria, a total of 1600 Chinese Han men from the Fangchenggang Area Male Health and Examination Survey cohort were enrolled in cross-sectional analysis, while 572 participants were included in the longitudinal analysis (average follow-up of 4 years). We performed a bidirectional Mendelian randomization (MR) analysis using two C3-related, eight C4-related and three NAFLD-related gene loci as instrumental variables to evaluate the causal associations between C3, C4, and NAFLD risk in cross-sectional analysis. Per SD increase in C3 levels was significantly associated with higher risk of NAFLD (OR = 1.65, 95% CI 1.40, 1.94) in cross-sectional analysis while C4 was not (OR = 1.04, 95% CI 0.89, 1.21). Longitudinal analysis produced similar results (HRC3 = 1.20, 95% CI 1.02, 1.42; HRC4 = 1.10, 95% CI 0.94, 1.28). In MR analysis, there were no causal relationships for genetically determined C3 levels and NAFLD risk using unweighted or weighted GRS_C3 (ßE_unweighted = -0.019, 95% CI -0.019, -0.019, p = 0.202; ßE_weighted = -0.019, 95% CI -0.019, -0.019, p = 0.322). Conversely, serum C3 levels were significantly effected by the genetically determined NAFLD (ßE_unweighted = 0.020, 95% CI 0.020, 0.020, p = 0.004; ßE_weighted = 0.021, 95% CI 0.020, 0.021, p = 0.004). Neither the direction from C4 to NAFLD nor the one from NAFLD to C4 showed significant association. Our results support that the change in serum C3 levels but not C4 levels might be caused by NAFLD in Chinese Han men. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-021-00023-0.

Associations Between Serum Multiple Metals Exposures and Metabolic Syndrome: a Longitudinal Cohort Study.

Although many studies have confirmed metabolic syndrome (MetS) is correlated with metal exposures, few studies have elucidated the associations of multiple metals with MetS risk. We aim to explore the relationship between serum 22 metals and MetS. We determined serum 22 metals using ICP-MS and used LASSO regression to select metals independently related with MetS to construct multiple-metals model. We further explored the dose-response relationship between positive metals and MetS by the restricted cubic spline regression. After screening by LASSO regression, serum 11 metals were selected to construct multiple-metals model in cross-sectional analysis, while 5 metals in longitudinal analysis. In the 11-metal model, only tin and zinc were associated with MetS in cross-sectional analysis (ORtin = 2.22, 95% CI:1.43, 3.45; ORzinc = 2.17, 95% CI: 1.42, 3.32; both Ptrend < 0.05). Besides, the same results were found in the 5-metal model in longitudinal analysis (HRtin = 1.66, 95% CI: 0.87, 3.17; HRzinc = 1.83, 95% CI: 1.07, 3.14; both Ptrend < 0.05). Moreover, there were positive linear relationships between serum tin and zinc concentrations and the increasing risk of MetS (both Poverall < 0.05, Pnon-linearity > 0.05). Furthermore, the interaction between high tin and high zinc was also associated with increasing MetS risk (Pinteraction < 0.05). We found that serum tin and zinc were independently and interactively associated with MetS in the southern Chinese men. Our results suggested that high tin and zinc may be the risk factors of MetS.

Associations of prenatal exposure to multiple metals with testicular volume and anogenital distance in infant boys: A longitudinal cohort study.

BACKGROUND: Human are widely exposed to multiple metals, some of which have suspected reproductive toxicity, but no human studies have investigated the developmental effects of prenatal metal exposure. OBJECTIVES: We aimed to evaluate the associations between prenatal multiple metal exposure and reproductive development in boys at 2-3 years using multi-pollutant approach. METHODS: This prospective study used data of 564 mother-child pairs recruited from the Guangxi Birth Cohort Study. Twenty serum metal concentrations were measured. Least absolute shrinkage and selection operator (LASSO) penalized regression was used to identify independent associations between prenatal multiple metal exposure and testicular volume (TV), and anogenital distance (AGD). Adjusted estimates were then obtained using multiple linear regression analysis, and the regression tree method was used to explore the interactions. RESULTS: Boys in the highest quartile of prenatal lead exposure had a 0.064 mL (95% CI: -0.124, -0.004) smaller ln-transformed TV, 0.060 cm (95% CI: -0.110, -0.011) shorter ln-transformed anopenile distance (AGDap), and 0.115 cm (95% CI: -0.190, -0.039) shorter ln-transformed anoscrotal distance (AGDas) than boys in the lowest quartile (all Ptrend < 0.05). Chromium was inversely with ln-transformed AGDap (ß = -0.078, 95% CI: -0.127, -0.030) and ln-transformed AGDas (ß = -0.113, 95% CI: -0.188, -0.038), while stibium was positivity associated with ln-transformed AGDap (ß = 0.091, 95% CI: 0.046, 0.136) and strontium was positivity associated with ln-transformed AGDas (ß = 0.120, 95% CI: 0.051, 0.189) (all Ptrend < 0.05). And the critical window of vulnerability may be the late pregnancy (the second and third trimester). Moreover, we detected interaction effects between lead, chromium and stibium on AGDap; lead, chromium and strontium on AGDas. CONCLUSIONS: The results suggest that prenatal exposure to lead, chromium, stibium and strontium may affect TV and/or AGD in infant boys. Potential mechanisms for the complex metal interactive effects during vulnerable periods are worthy of further investigation.