Correlation between urinary rare earth elements and liver function in a Zhuang population aged 35-74 years in Nanning.

BACKGROUND: Animal studies have shown that exposure to REEs can cause severe liver damage, but evidence from population studies is still lacking. Therefore, we investigated the relationship between REEs concentrations in urine and liver function in the population. METHODS: We conducted a cross-sectional study on 1024 participants in Nanning, China. An inductively coupled plasma mass spectrometer (ICP-MS) was used to detect the concentrations of 12 REEs in urine. The relationship between individual exposure to individual REE and liver function was analyzed by multiple linear regression. Finally, the effects of co-exposure to 5 REEs on liver function were assessed by a weighted sum of quartiles (WQS) regression model and a Bayesian kernel machine regression (BKMR) model. RESULTS: The detection rate of 5 REEs, lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), and dysprosium (Dy), is greater than 60%. After multiple factor correction, La, Ce, Pr, Nd, and Dy were positively correlated with serum ALP, Ce, Pr, and Nd were positively correlated with serum AST, while Ce was negatively correlated with serum TBIL and DBIL. Both WQS and BKMR results indicate that the co-exposure of the 5 REEs is positively correlated with serum ALP and AST, while negatively correlated with serum DBIL. There were potential interactions between La and Ce, La and Dy in the association of co-exposure of the 5 REEs with serum ALP. CONCLUSIONS: The co-exposure of the 5 REEs was positively correlated with serum ALP and AST, and negatively correlated with serum DBIL.

Associations between co-exposure to multiple metals and renal function: a cross-sectional study in Guangxi, China.

The association between co-exposure to multiple metals and renal function is poorly understood. We aimed to evaluate the individual and joint effects of metal exposure on renal function in this study. We performed a cross-sectional study including 5828 participants in Guangxi, China, in 2019. Urine concentrations of 17 metals were detected by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression model and restricted cubic spline (RCS) were applied to investigate the association of individual metal exposure with renal dysfunction. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the co-exposure effects of the metals. Participants with the highest quartile of urinary Cu were at 1.84-fold (95% confidence interval (CI): 1.20-2.87) increased risk of renal dysfunction compared with the lowest quartile. The highest quartiles of urinary Sr, Cs, V, Ba, and Se were associated with 0.27-fold (95% CI: 0.17-0.43), 0.33 (95% CI: 0.19-0.53), 0.41 (95% CI: 0.25-0.65), 0.58 (95% CI: 0.36-0.90), and 0.33 (95% CI: 0.19-0.56) decreased risk of renal dysfunction compared with their lowest quartile, respectively. Furthermore, urinary Ba and Cu were non-linearly correlated with renal dysfunction. The WQS analysis showed that mixed metal exposure was inversely associated with renal dysfunction (OR = 0.47, 95% CI: 0.35-0.62), and Sr accounted for the largest weight (52.2%), followed by Cs (32.3%) in the association. Moreover, we observed a potential interaction between Cu, Cs, and Ba for renal dysfunction in BKMR model. Exposure to Se, Sr, Cs, V, and Ba is associated with decreased risk of renal dysfunction, whereas an increased risk is associated with Cu exposure. Co-exposure to these metals is negatively associated with renal dysfunction, and Sr and Cs are the main contributors to the associations.

The mediating role of coagulation function on the association of prenatal exposure to aflatoxin B1 and postpartum hemorrhage in Guangxi, China.

Pregnant women are vulnerable to certain environmental agents, one of which is aflatoxin. As one of the most popular aflatoxins, Aflatoxin B1 (AFB1) has recently garnered increased attention concerning its potential association between exposure and adverse pregnancy outcomes. The aims of the study were to examine the associations between prenatal exposure to AFB1 and postpartum hemorrhage (PPH), and whether coagulation function has a mediating effect on their relationship. A total of 379 mother-infant pairs were included in the present study. Prenatal serum AFB1 albumin (AFB1-Alb) adduct levels in peripheral venous blood were detected by using an ELISA kit. Multiple linear and logistics regression models were applied to analyze the relationship between AFB1-Alb levels and PPH. We found mothers with high levels of AFB1-Alb adduct levels had significantly increased postpartum blood loss (partial regression coefficient (ß) = 50.71, 95% confidence interval (CI) 3.48, 97.95). Mothers with high levels of AFB1-Alb adduct levels also had significantly increased risk of PPH (odds ratio (OR) = 4.81, 95% CI 1.01, 22.98). Moreover, concentrations of AFB1-Alb were positively associated with activated partial thromboplastin time (APTT) while negatively associated with fibrinogen (FIB). One-unit increase in APTT was correlated with a 6.62-ml (95% CI 3.04, 10.20) increase in postpartum blood loss. Mediation analysis suggested that the maternal blood APTT levels had a positive mediating effect in the association between AFB1-Alb adduct levels and postpartum blood loss (ß = 0.32, 95% CI 0.04, 0.68). These results indicated that prenatal exposure to AFB1 was associated with increased postpartum blood loss, possibly by interfering with maternal APTT levels.

Associations between Serum Aflatoxin-B1 and Anemia in Pregnant Women: Evidence from Guangxi Zhuang Birth Cohort in China.

Aflatoxin B1 (AFB1) is a common toxic mycotoxin and is detectable in pregnant women. Animal studies have revealed that AFB1 caused the lysis of erythrocytes and a decrease in hemoglobin. We conducted a prospective cohort study in Guangxi, China, in order to evaluate the association between AFB1 exposure and anemia in pregnant women during the entire pregnancy. A total of 616 pregnant women from the Guangxi Zhuang Birth Cohort were included in the study. Serum AFB1-albumin (AFB1-ALB) adduct levels were measured. The effect of AFB1-ALB adducts on hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were analyzed by using multivariable linear regression. The risks of anemia from AFB1-ALB adduct exposure were assessed by multivariable logistic regression. We found that the AFB1-ALB adduct was significantly associated with a decrease in Hb (ß = -4.99, 95% CI: -8.42, -1.30), MCV (ß = -4.58, 95% CI: -7.23, -1.94), MCH (ß = -1.86, 95% CI: -2.87, -0.85), and MCHC (ß = -5.23, 95% CI: -8.28, -2.17) in the first trimester with the third tertile of AFB1-ALB adducts when compared with the first tertile. Furthermore, the third tertile of the AFB1-ALB adduct significantly increased the risk of anemia by 2.90 times than compared to the first tertile in the first trimester (OR = 3.90, 95% CI: 1.67, 9.14). A significant positive does-response relationship existed between AFB1-ALB adduct levels and anemia risk (Ptrend = 0.001). When dividing anemia types, we only found that the third tertile of AFB1-ALB adduct increased the risk of microcytic hypochromic anemia (MHA) in the first trimester (OR = 14.37, 95% CI: 3.08, 67.02) and second trimester (OR = 4.75, 95% CI: 1.96, 11.51). These findings demonstrate the correlation between maternal AFB1 exposure during early pregnancy and risk of anemia, especially MHA, and during different trimesters in Southern China. More efforts should be made to diminish AFB1 exposure for pregnant women.

Predicting cancer-specific mortality in patients with parotid gland carcinoma by competing risk nomogram.

BACKGROUND: The aim of the present study was to establish a competing risk nomogram to predict parotid gland cancer-specific mortality (PGC-SM). METHODS: Seven thousand nine hundred and sixty-two patients extracted from SEER database were randomly categorized into training and validation sets. The competing risk model was used to identify factors associated with PGC-SM. The nomogram was evaluated via concordance indexes (C-indexes), calibration plots, and decision curve analysis (DCA). RESULTS: Male, elderly, white, widowed, larger tumor, no surgery, advanced tumor grade, lymph node (LN) metastasis, adenocarcinoma (ADC), and higher TNM stage were associated with higher incidence of PGC-SM. Calibration plots showed that the nomogram was well calibrated. C-indexes for nomogram were 0.84 (95% CI: 0.81-0.86) and 0.84 (95% CI: 0.82-0.86) in training and validation sets, respectively. DCA demonstrated the clinical usefulness of nomogram. CONCLUSIONS: The competing risk nomogram shows high performance in predicting PGC-SM, which might enable clinicians formulate suitable treatment protocols for patients with parotid gland carcinoma (PGC).

Big Data-Based Identification of Multi-Gene Prognostic Signatures in Liver Cancer.

Simultaneous identification of multiple single genes and multi-gene prognostic signatures with higher efficacy in liver cancer has rarely been reported. Here, 1,173 genes potentially related to the liver cancer prognosis were mined with Coremine, and the gene expression and survival data in 370 samples for overall survival (OS) and 319 samples for disease-free survival (DFS) were retrieved from The Cancer Genome Atlas. Numerous survival analyses results revealed that 39 genes and 28 genes significantly associated with DFS and OS in liver cancer, including 18 and 12 novel genes that have not been systematically reported in relation to the liver cancer prognosis, respectively. Next, totally 9,139 three-gene combinations (including 816 constructed by 18 novel genes) for predicting DFS and 3,276 three-gene combinations (including 220 constructed by 12 novel genes) for predicting OS were constructed based on the above genes, and the top 15 of these four parts three-gene combinations were selected and shown. Moreover, a huge difference between high and low expression group of these three-gene combination was detected, with median survival difference of DFS up to 65.01 months, and of OS up to 83.57 months. The high or low expression group of these three-gene combinations can predict the longest prognosis of DFS and OS is 71.91 months and 102.66 months, and the shortest is 6.24 months and 13.96 months. Quantitative real-time polymerase chain reaction and immunohistochemistry reconfirmed that three genes F2, GOT2, and TRPV1 contained in one of the above combinations, are significantly dysregulated in liver cancer tissues, low expression of F2, GOT2, and TRPV1 is associated with poor prognosis in liver cancer. Overall, we discovered a few novel single genes and multi-gene combinations biomarkers that are closely related to the long-term prognosis of liver cancer, and they can be potential therapeutic targets for liver cancer.

MiR-124 sensitizes cisplatin-induced cytotoxicity against CD133+ hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway.

Drug resistance is still a major obstacle for efficient treatment of hepatocellular carcinoma (HCC) during the cisplatin-based chemotherapy. Recent studies have demonstrated that CD133 positive population of cancer cells are responsible for multiple drug resistance. We are supposed to take strategies to sensitize CD133+ HCC cells to cisplatin treatment. In the present study, CD133+ HCC cells showed significant cisplatin-resistance compared to the CD133- HCC cells. Downregulation of miR-124 was observed in CD133+ HCC cells. However, enforced expression of miR-124 can increase the sensitivity of CD133+ HCC cells to cisplatin treatment in vitro and in vivo. Mechanically, overexpression of miR-124 was found to inhibit the expression of SIRT1 and thus promoted the generation of ROS and phosphorylation of JNK. As the results, overexpression of miR-124 expanded the apoptosis in cisplatin-treated CD133+ HCC cells. We then demonstrated that overexpression of miR-124 sensitized cisplatin-induced cytotoxicity against CD133+ hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway.

CCL26 Participates in the PRL-3-Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration.

Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAM) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer invasion and metastasis by inducing TAM infiltration remains unclear. In the current study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and colorectal cancer invasion and the underlying mechanism in colorectal cancer cells by overexpressing or silencing PRL-3. We found that PRL-3 upregulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. In addition, IHC analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV colorectal cancer tissues and were associated with a worse prognosis in colorectal cancer patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were cocultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca2+of TAMs to increase the expression of IL6 and IL8. In addition, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV colorectal cancer tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes colorectal cancer invasion and metastasis by upregulating CCL26 to induce TAM infiltration. Mol Cancer Ther; 17(1); 276-89. ©2017 AACR.

PRL-3 improves colorectal cancer cell proliferation and invasion through IL-8 mediated glycolysis metabolism.

Phosphatase of regenerating liver-3 (PRL-3) has been found to be overexpressed in liver metastases of colorectal cancer and rarely expressed in primary tumors, which plays an important role in the metastasis of colorectal cancer cells. Metabolism reprogramming has been found to be a hallmark of cancer cells, and aerobic glycolysis is a metabolic adaption for cancer cells and promotes cell proliferation. However, the association between PRL-3 and glycolysis in colorectal cancer cells is not well understood. In the present study, we explored the association between PRL-3 and glycolysis. We found that PRL-3 improved colorectal cancer cell glucose assumption, lactate production and reduced intracellular ROS levels. Besides, PRL-3 improved the expression of Glut1, HK2, PKM2 and LDHA, which are important glycolysis related molecules and enzymes. Moreover, we explored IL-8 mediated enhancement of glycolysis by PRL-3. More importantly, the proliferation and invasion of colorectal cancer cells were enhanced significantly by PRL-3 through improving glycolysis. Taken together, these results implicated the important role of PRL-3 in glycolysis metabolism through improving IL-8 secretion in colorectal cancer cells, and PRL-3 mediated glycolysis contributed to the promotion of cancer metastasis.

Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner.

BACKGROUND: Tumor-associated macrophages (TAMs) are known to promote cancer progression and metastasis through the release of a variety of cytokines. Phosphatase of regenerating liver (PRL-3) has been considered as a marker of colorectal cancer (CRC) liver metastasis. Our previous research suggests that PRL-3 can enhance the metastasis of CRC through the up-regulation of intermediate-conductance Ca2+-activated K+ (KCNN4) channel, which is dependent on the autocrine secretion of tumor necrosis factor-alpha (TNF-α). However, whether TAMs participate in the progression and metastasis of CRC induced by PRL-3 remains unknown. METHODS: We used flow cytometry, coculture, western blotting, invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, and immunofluorescence staining to determine the effect of TAMs on the ability of PRL-3 to promote invasiveness of CRC cells. RESULTS: In this study, we found that TAMs facilitated the metastasis of CRC induced by PRL-3. When TAMs were cocultured with CRC cells, the expression of KCNN4 was increased in TAMs and the invasion of CRC cells was enhanced. Furthermore, cytokines that were secreted by TAMs, such as IL-6 and IL-8, were also significantly increased. This response was attenuated by treating TAMs with the KCNN4 channel-specific inhibitor, 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34), which suggested that KCNN4 channels may be involved in inducing the secretion of IL-6 and IL-8 by TAMs and improving CRC cell invasiveness. Moreover, the expression of KCNN4 channels in TAMs was regulated through the NF-κB signal pathway, which is activated by TNF-α from CRC cells. Immunofluorescence analysis of colorectal specimens indicated that IL-6 and IL-8 double positive cells in the stroma showed positive staining for the TAM marker CD68, suggesting that TAMs produce IL-6 and IL-8. Increased numbers of these cells correlated with higher clinical stage. CONCLUSIONS: Our findings suggested that TAMs participate in the metastasis of CRC induced by PRL-3 through the TNF-α mediated secretion of IL-6 and IL-8 in a paracrine manner.

Prognostic significance of neuroendocrine differentiation in colorectal adenocarcinoma after radical operation: a meta-analysis.

BACKGROUND: The phenomenon of neuroendocrine differentiation has been observed in colorectal adenocarcinoma. However, the ability of neuroendocrine differentiation to predict the outcome of colorectal adenocarcinoma remains controversial. METHODS: We conducted an extensive search of research studies related to neuroendocrine differentiation using scientific databases, including the PubMed, Embase, OVID, BIOSIS Previews, and Cochrane Central Register of Controlled Trials (up to July, 2013), according to the established search terms. RevMan version 5.2 statistical program was used to analyze the data. An odds ratio (OR) with a 95% confidence interval (CI) was used for the dichotomous data. RESULTS: Eleven studies with a total of 1,587 patients were included. Patients with neuroendocrine differentiation who underwent a radical operation had a lower 5-year survival rate (pooled OR 0.60, 95% CI 0.37-0.97) compared with those without neuroendocrine differentiation, with evidence of moderate heterogeneity (I (2) = 37%, p = 0.10). A sensitivity analysis and meta-regression showed that the different classification criteria of neuroendocrine differentiation used in these studies were the main source of heterogeneity. When the strong positive rates of neuroendocrine differentiation indicators between the higher (stage III + IV) and the lower (stage I + II) clinical stages were compared, the pooled OR was 1.84 (703 patients; 95% CI 0.98-3.43) without evidence of heterogeneity (I (2) = 0 %, p = 0.89). However, comparisons between consecutive stages showed different ORs: stage II vs. I (203 patients; OR = 0.52, 95% CI 0.17-1.56), stage III vs. II (569 patients; OR = 2.27, 95% CI 1.03-4.98), and stage IV vs. III (375 patients; OR = 1.81, 95% CI 1.00-3.29). CONCLUSION: The patients with strong positive indicators of neuroendocrine differentiation had a lower 5-year survival rate. The ability to detect neuroendocrine indicators using conventional methods could improve the prognosis judgment of colorectal adenocarcinoma.