Associations between Polyfluoroalkyl Substances Exposure and Breast Cancer: A Meta-Analysis.

Polyfluoroalkyl substances (PFASs) are persistent pollutants that may cause breast cancer. However, associations between exposure to PFASs and the risk of breast cancer are controversial. We retrieved studies on the association between PFASs­perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS)­and breast cancer risk in women from PubMed, Embase, and the Web of Science. The pooled odds ratios (ORs) or relative risks (RRs) and their 95% confidence intervals (CIs) were extracted or calculated from provided data. Moreover, subgroup and metaregression analyses were performed to distinguish the potential sources of heterogeneity between studies. Lastly, eight original studies were included in the meta-analysis. PFOA and PFHxS were positively correlated with breast cancer risk, and the pooled ORs (and 95% CIs) were 1.32 (1.19 and 1.46) and 1.79 (1.51 and 2.11), respectively. PFNA was negatively correlated with breast cancer risk and the pooled OR (and 95% CIs) was 0.76 (0.6 and 0.96), and PFOS was shown to have no correlation with breast cancer risk and the pooled OR (and 95% CIs) was 1.01 (0.87 and 1.17). All results were merged in a random-effects model with significant heterogeneities (I2 > 90%, p < 0.001). The results demonstrated that PFASs might be potential risk factors for breast cancer, and the compounds in low exposure levels could have a more harmful impact on human health.

The Association of Bisphenol A and Phthalates with Risk of Breast Cancer: A Meta-Analysis.

BACKGROUND: Breast cancer is the most common cancer and the second leading cause of cancer-related death amongst American women. Endocrine-disrupting chemicals (EDCs), especially bisphenol A (BPA) and phthalates, have adverse effects on human health. However, the association of BPA and phthalates with breast cancer remains conflicting. This study aims to investigate the association of BPA and phthalates with breast cancer. METHODS: Correlative studies were identified by systematically searching three electronic databases, namely, PubMed, Web of Sciences, and Embase, up to November 2020. All data were analyzed using Stata 15.0. RESULTS: A total of nine studies, consisting of 7820 breast cancer cases and controls, were included. The urinary phthalate metabolite mono-benzyl phthalate (MBzP) and mono-2-isobutyl phthalate (MiBP) were negatively associated with breast cancer (OR = 0.73, 95% CI: 0.60-0.90; OR = 0.75, 95% CI: 0.58-0.98, respectively). However, the overall ORs for BPA, mono-ethyl phthalate (MEP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(3-carboxypropyl) phthalate (MCPP), and mono-butyl phthalate (MBP) were 0.85 (95% CI: 0.69-1.05), 0.96 (95% CI: 0.62-1.48), 1.12 (95% CI: 0.88-1.42), 1.13 (95% CI: 0.74-1.73), 1.01 (95% CI: 0.74-1.40), 0.74 (95% CI: 0.48-1.14), and 0.80 (95% CI: 0.55-1.15), respectively, suggesting no significant association. The sensitivity analysis indicated that the results were relatively stable. CONCLUSION: Phthalate metabolites MBzP and MiBP were passively associated with breast cancer, whereas no associations were found between BPA, MEP, MEHHP, MEHP, MEOHP, MCPP, and MBP and breast cancer. More high-quality case-control studies or persuasive cohort studies are urgently needed to draw the best conclusions.

Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology.

Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.

Analysis of Heavy Metal Contamination of Agricultural Soils and Related Effect on Population Health-A Case Study for East River Basin in China.

To understand the heavy metal pollution in agricultural soils along the East River basin and assess the pollution related health effect to local residents, interviews and archived data were obtained to identify the study sites affected by polluted tailing. Soil samples were collected and tested for heavy metal content and the Comprehensive Pollution Index (CPI). The degree of pollution of agricultural soils in the area was assessed using GIS-based Spatial distribution map of heavy metals and the trend of soil heavy metal risk. Two villages (Matian and Zhudui) near the East River were included in this study for health effect assessment. A total of 193 residents aged 15 or above from each village were tested for the present status of chronic diseases. Convenient sampling method was used to collect blood samples from 78 residents for heavy metal concentration. The contents of Pb, Cd, As, Zn, and Cu in the agricultural soils were all over the standards with a moderate to severe CPI. Among these metals, Cd was the highest followed by Pb, and Cu was the lowest. The contents of Pb, Cd, As, and Zn tend to be higher in soils closer to the river. The prevalence of chronic diseases was over 30%, which is significantly higher than the report from the national central region (23.15%). The average blood lead level (BLL) among children under 14 years is 7.42 µg/dL. Although the adults in Matian village had a significantly higher BLL (χ2 = 8.70, p = 0.03) as compared to Zhudui village, there was no significant difference for the prevalence of chronic diseases between the two villages (χ2 = 3.23, p = 0.09). The mean BLL of children and the proportion of children with BLL ≥ 10 µg/dL in this study are equivalent to the national average. The higher BLL concentration and prevalence of chronic diseases in adults might be due to their long-term exposure to heavy metal contamination environment and higher background level of heavy metals. Findings from this study will form the baseline information for local government to the development of effective approaches to control the heavy metal contamination and reduce the pollution related adverse health effect on local residents.

Effect of metformin on the risk of prostate cancer in patients with type 2 diabetes by considering different confounding factors: a meta-analysis of observational studies.

Preclinical studies have suggested the antitumorigenic properties of metformin on prostate cancer; results from epidemiological studies remain contradictory. We aim to investigate the evidence of metformin and the risk of prostate cancer. PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies. Meta-analyses were carried out using the most fully adjusted hazard ratios and the corresponding 95% confidence intervals. Eighteen cohort studies and six case-control studies representing 2 009 504 male patients with type 2 diabetes mellitus were identified. The pooled HR of prostate cancer for metformin therapy was 0.97 (0.84-1.12) in case-control studies and 0.94 (0.79-1.12) in cohort studies, respectively. In cohort studies, we found that there was a modest association in studies with samples from Europe, but not in studies with samples from North America, Asia, and Oceania. In addition, metformin showed a slightly protective effect compared with sulfonylurea, but not insulin and other comparators. Meta-regression analyses found that obesity and prostate-specific antigen adjustment in statistical models may be the sources of heterogeneity. However, there were no significant differences in subgroups stratified by time-related biases, analytical approaches, types of risk estimates, study quality, publication year, and whether adjusted for smoking, alcohol abuse, hemoglobin A1c, diabetes duration, and other confounding factors. Our study showed that metformin therapy was not associated with the risk of prostate cancer in patients with type 2 diabetes mellitus. However, exploratory analyses suggest that metformin use may be protective in a certain subgroup of patients.

Association between Phthalate Metabolites and Risk of Endometriosis: A Meta-Analysis.

Objective: The association between phthalates and endometriosis risk is inconclusive. This meta-analysis aims to evaluate the association between five different phthalate metabolites and endometriosis, based on current evidence. Methods: The literature included PubMed, WOS (web of science), and EMBASE, published until 3 March 2019. We selected the related literature and evaluated the relationship between phthalates exposure and endometriosis risk. All statistical analyses were conducted with STATA version 12.0. Results: Data from eight studies were used in this review. The results of this analysis showed that mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) exposure was potentially associated with endometriosis (OR = 1.246, 95% CI = 1.003-1.549). We have not found positive results in mono(2-ethylhexyl) phthalate (MEHP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) analyses (MEHP: OR = 1.089, 95% CI = 0.858-1.383; MEP: OR = 1.073, 95% CI = 0.899-1.282; MBzP: OR = 0.976, 95% CI = 0.810-1.176; MEOHP: OR = 1.282, 95% CI = 0.874-1.881). In subgroup analyses for regions, the associations were significant between MEHHP and endometriosis in Asia (OR = 1.786, 95% CI = 1.005-3.172, I² = 0%), but not in USA (OR = 1.170, 95% CI = 0.949-1.442, I² = 45.6%). Conclusions: Our findings suggested a potential statistical association between MEHHP exposure and endometriosis, particularly, the exposure of MEHHP might be a potential risk for women with endometriosis in Asia. However, positive associations between the other four Phthalate acid esters (PAEs) and endometriosis was not found. Given the weak strength of the results, well-designed cohort studies, with large sample sizes, should be performed in future.

SAM targeting methylation by the methyl donor, a novel therapeutic strategy for antagonize PFOS transgenerational fertilitty toxicity.

DNA methylation have been suggested as possible mediators of long-term health effects of environmental stressors. This study aimed to evaluate the potential therapy of methylation of S-adenosyl-l-methionine (SAM) on PFOS induced trangeneral reproductive toxicity. In this study, postnatal 5d Sprague Dawley rats were randomly divided into four groups: control, PFOS, PFOS + SAM, and PFOS + Decitabine (DAC). The F0 rats were exposed to 5 mg/kg PFOS and SAM or DAC until PND60. The development of the offsprings were monitored without PFOS exposure. The fertility in F0, F1 rats, and change in F1 testes were observed. The results were as follows. The significant increase in F0 pregnancy rate, and survival rate in F1 offspring in PFOS + SAM relative to PFOS group were observed. Changes of birth weights and physical development in F1 offspring with SAM were approached as a corresponding variation of the control after the deparation period. No pregnant in F1 maternal rats in the PFOS and DAC groups were found, but pregnant in the SAM group. Significantly decrease in the percentage of abnormal seminiferous tubules and increase in expression of promyelocytic leukemia zinc finger (PLZF+) spermatogonial stem cells in F1 testis compared with the PFOS group. Taken together, Methyl donor SAM improve PLZF + spermatogonia stem cell proliferation, attenuate damage in testicular tissue structure, which subsequently improve the transgenerational growth retard and infertility induced by PFOS chronic stress.

No Effect of Metformin on Ovarian Cancer Survival: A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: A number of observational studies examined the association between metformin therapy and ovarian cancer survival outcomes, but the results are inconsistent. OBJECTIVE: The study aimed to investigate the effect of metformin on survival for ovarian cancer patients. METHOD: PubMed, Embase and Web of Science databases were searched for relevant studies from the inception to June 11, 2019. The strength of the relationship was assessed using summary of hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Statistical analyses were carried out using the random-effects model. RESULTS: Totally, 6 retrospective cohort studies involving 2,638 ovarian cancer patients were included. Metformin was not associated with improved overall survival (HR=0.78, 95% CI 0.54-1.12, P=0.175, I2= 61.6%) and disease- free survival (HR=0.49, 95% CI 0.20-1.17, P=0.106, I2=82.1%) in ovarian cancer patients compared to nonmetformin users. CONCLUSION: The current study provides preliminary evidence that metformin may not be associated with a survival benefit for ovarian cancer patients. More studies with rigorous designs are needed.

Secular trends in incidence and mortality of bladder cancer in China, 1990-2017: A joinpoint and age-period-cohort analysis.

BACKGROUND: Bladder cancer is closely related to occupational carcinogens, and China is undergoing a rapid industrialization. However, trend of bladder cancer incidence and mortality remains unknown in China. METHODS: Incidence and mortality rates of bladder cancer (1990-2017) were collected for each 5-year age group stratified by gender (males/females) from the Global Burden of Disease (GBD) 2017 study. The average annual percentage change (AAPC) of rates were analyzed by joinpoint regression analysis; age, period and cohort effects on incidence and mortality were simultaneously estimated by age-period-cohort model. RESULTS: Through 1990-2017, age-standardized incidence rates significantly rose in men (AAPC = 0.72%, 95% CI: 0.5%, 0.9%) while decreased in women (-1.25%: -1.6%, -0.9%); age-standardized mortality rates decreased in both men (-1.09%: -1.2%, -0.9%) and women (-2.48%: -2.8%, -2.2%). The joinpoint regression analysis showed the mortality almost decreased in all age groups; while the incidence increased in men for older age groups (from 45 to 49 to 80-84). Moreover, age effect showed the incidence and mortality increased with age; the incidence and mortality increased with time period, while in women period effect stop decreasing and began to increase since 2007; cohort effect showed them decreased with birth cohorts. CONCLUSIONS: The incidence of bladder cancer is increasing in men but mortality decreases in both sexes. Both the incidence and mortality in men substantially increase with age and period, while the rates in women increased with period since 2007. The period effect may indicate the increased risks to bladder cancer in Chinese men. Etiological studies are needed to identify the factors driving these trends of bladder cancer.

ARID5B gene polymorphisms and the risk of childhood acute lymphoblastic leukemia: a meta-analysis.

Genome-wide association studies have implicated several single-nucleotide polymorphisms (SNPs) in the AT-rich interactive domain 5B (ARID5B) gene in children with ALL; however, whether ARID5B variants (rs10821936, rs10994982, rs7089424) are associated with childhood ALL remains controversial. We performed this study to obtain more conclusive results. Eligible studies were searched in PubMed, Web of Science, and EMBASE. Odds ratios and 95% confidence intervals were calculated. A total of 26 studies were included. Analyses stratified by ethnicity revealed that three polymorphisms are significantly associated with the odds of childhood ALL in Caucasians, and rs10994982 and rs7089424 with the odds of childhood ALL in Asian populations. Furthermore, subtype analyses provided strong evidence that the three polymorphisms are highly associated with the risk of B-cell ALL. Our findings indicate that the ARID5B variants (rs10821936, rs10994982, rs7089424) are significantly associated with the risk of childhood ALL.

Metformin and pancreatic cancer survival: Real effect or immortal time bias?

High heterogeneity has been reported among cohort studies investigating the association between metformin and pancreatic cancer survival. Immortal time bias may be one importance source of heterogeneity, as it is widely present in previous cohort studies and may severely impair the validity. Our study aimed to examine whether metformin therapy improves pancreatic cancer survival, and to assess the impact of immortal time bias on the effect estimation of metformin in cohort studies. PubMed, EMbase and SciVerse Scopus were searched. Pooled relative risks (RRs) were derived using a random-effects model. Pooled RR from the six studies without immortal time bias showed no association between metformin and mortality in pancreatic cancer patients (RR 0.93, 95% CI 0.82, 1.05; p = 0.22 and I2 = 75%). In contrast, pooled RR from the nine studies with immortal time bias showed a reduction of 24% in mortality associated with metformin (RR 0.76, 95% CI 0.69, 0.84; p < 0.001 and I2 = 1%). From a meta-regression model, existence of immortal time bias was associated with a reduction of 18% in the effect estimate of metformin on pancreatic cancer survival (ratio of RR 0.82, 95% CI 0.70, 0.96; p = 0.02). In conclusions, cumulative evidence from cohort studies does not support a beneficial effect of metformin on pancreatic cancer survival. The association between metformin and pancreatic cancer survival has been greatly exaggerated in previous cohort studies due to the wide existence of immortal time bias. More rigorous designs and statistical methods are needed to account for immortal time bias.

Trends in the Incidence and Mortality of Diabetes in China from 1990 to 2017: A Joinpoint and Age-Period-Cohort Analysis.

Background: The prevalence of diabetes mellitus is rapidly increasing in China, but the secular trends in incidence and mortality remain unknown. This study aims to examine time trends from 1990 to 2017 and the net age, period, and cohort effects on diabetes incidence and mortality. Methods: Incidence and mortality rates of diabetes (1990⁻2017) were collected for each 5-year age group (from 5⁻9 to 80⁻84 age group) stratified by gender from the Global Burden of Disease 2017 Study. The average annual percentage changes in incidence and mortality were analyzed by joinpoint regression analysis; the net age, period, and cohort effects on the incidence and mortality were estimated by age-period-cohort analysis. Results: The joinpoint regression analysis showed that age-standardized incidence significantly rose by 0.92% (95% CI: 0.6%, 1.3%) in men and 0.69% in women (95% CI: 0.3%, 1.0%) from 1990 to 2017; age-standardized mortality rates rose by 0.78% (95% CI: 0.6%, 1.0%) in men and decreased by 0.12% (95% CI: -0.4%, 0.1%) in women. For age-specific rates, incidence increased in most age groups, with exception of 30⁻34, 60⁻64, 65⁻69 and 70⁻74 age groups in men and 25⁻29, 30⁻34, 35⁻39 and 70⁻74 age groups in women; mortality in men decreased in the younger age groups (from 20⁻24 to 45⁻49 age group) while increased in the older age groups (from 50⁻54 to 80⁻84 age group), and mortality in women decreased for all age groups with exception of the age group 75⁻79 and 80⁻84. The age effect on incidence showed no obvious changes with advancing age while mortality significantly increased with advancing age; period effect showed that both incidence and mortality increased with advancing time period while the period trend on incidence began to decrease since 2007; cohort effect on incidence and mortality decreased from earlier birth cohorts to more recent birth cohorts while incidence showed no material changes from 1982⁻1986 to 2012⁻2016 birth cohort. Conclusions: Mortality decreased in younger age groups but increased in older age groups. Incidence increased in most age groups. The net age or period effect showed an unfavorable trend while the net cohort effect presented a favorable trend. Aging likely drives a continued increase in the mortality of diabetes. Timely population-level interventions aiming for obesity prevention, healthy diet and regular physical activity should be conducted, especially for men and earlier birth cohorts at high risk of diabetes.

The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials.

Observational studies show a beneficial effect of adjuvant metformin therapy on breast cancer survivals, but data from randomized clinical trials are lacking. This study systematically evaluated the evidence from randomized clinical trials currently available. Ten studies were retrieved, comprising 1520 breast cancer patients. Metformin therapy reduced the levels of insulin and HOMA-IR, sex hormones and sex hormone-binding globulin, Ki67, caspase-3, p-Akt, obesity, hs-CRP, blood glucose and lipid profile. Two studies reported conflicting results on survival outcomes. The overall survival was nonsignificantly better in the metformin arm than the control arm (pooled rate ratio 0.89, 95% confidence interval 0.68-1.18, P = 0.43). The progression-free survival was not different between the arms (pooled rate ratio 0.96, 95% confidence interval 0.86-1.06, P = 0.39). These findings provide in vivo evidence in human, supporting an antitumor effect of metformin on breast cancer. Further clinical trials with larger sample size are warranted.

Does diabetes decrease the risk of glioma? A systematic review and meta-analysis of observational studies.

PURPOSE: Increasing epidemiologic evidence suggests that diabetes mellitus (DM) may be associated with a decreased risk of glioma. This systematic review assessed whether DM was associated with glioma risk. METHODS: Electronic searches were performed in PubMed, Web of Science, EMBASE, and Cochrane Library databases up to August 30, 2018. A random-effects model was performed to calculate summary effect size with corresponding 95% confidence intervals (CIs). RESULTS: In total, 10 studies (eight case-control studies and two cohort studies) matched the inclusion criteria. Meta-analyses of case-control studies showed that DM decreased the risk of glioma by 23% (odds ratio: 0.77, 95% CI: 0.61-0.96; P = .02, I2 = 82.0%). However, no such effect was observed in cohort studies (relative risk: 0.71, 95% CI: 0.10-4.80; P = .72, I2 = 61.6%). In the subgroup analyses, DM was associated with a decreased risk of glioma in Caucasians but not in Asians; the inverse association was slightly higher in males than in females. CONCLUSIONS: Our results indicate that DM decreases the risk of glioma, but the inverse association may vary in subgroups. The present conclusions should be confirmed with further studies.