PurposeTumor associated macrophages (TAMs) are important prognostic factors and have been proved to be associated with the invasion and migration of various cancer. However, the relationship between TAMs and breast cancer outcomes remains unclear.Experimental DesignSixteen studies with a total of 4,541 breast cancer patients were included in this meta-analysis. Correlation of TAMs with overall survival (OS), disease-free survival(DFS), relapse-free survival (RFS), breast cancer special survival (BCSS) and clinicopathological features were analyzed. Survival data and clinicopathological value were integrated by analyzing hazard ratio(HR) and odds ratio(OR) separately and using Fixed-effect or Random-effect model according to heterogeneity. All statistical tests were two-sided.ResultsOS and DFS were correlated with high density of TAMs with HR= 1.504(1.200, 1.884)/ 2.228(1.716, 2.892) respectively. And subgroup analysis of location and biomarker in OS and DFS group showed prognosis was associated with TAMs distribution and biomarker selection. Besides, TAMs high infiltration was significantly related to age, size, histologic grade, ER/PR status, basal phenotype and vascular invasion.ConclusionHigh density of TAMs was associated with poor survival rates of breast cancer. TAMs in stroma are associated with worse outcome than that in nest and using CD68 as a biomarker for TAMs to evaluate the risk is better than CD163 or CD206 alone. Moreover, high infiltration of TAMs was significantly associated with negative hormone receptor status and malignant phenotype. TAMs infiltration can serve as a novel prognostic factor in breast cancer patients.

Hypoxic preconditioning (HPC) exerts a protective effect against hypoxic/ischemic brain injury, and one mechanism explaining this effect may involve the upregulation of hypoxia-inducible factor-1 (HIF-1). Autophagy, an endogenous protective mechanism against hypoxic/ischemic injury, is correlated with the activation of the HIF-1α/Beclin1 signaling pathway. Based on previous studies, we hypothesize that the protective role of HPC may involve autophagy occurring via activation of the HIF-1α/Beclin1 signaling pathway. To test this hypothesis, we evaluated the effects of HPC on oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis and autophagy in SH-SY5Y cells. HPC significantly attenuated OGD/R-induced apoptosis, and this effect was suppressed by the autophagy inhibitor 3-methyladenine and mimicked by the autophagy agonist rapamycin. In control SH-SY5Y cells, HPC upregulated the expression of HIF-1α and downstream molecules such as BNIP3 and Beclin1. Additionally, HPC increased the LC3-II/LC3-I ratio and decreased p62 levels. The increase in the LC3-II/LC3-I ratio was inhibited by the HIF-1α inhibitor YC-1 or by Beclin1-short hairpin RNA (shRNA). In OGD/R-treated SH-SY5Y cells, HPC also upregulated the expression levels of HIF-1α, BNIP3, and Beclin1, as well as the LC3-II/LC3-I ratio. Furthermore, YC-1 or Beclin1-shRNA attenuated the HPC-mediated cell viability in OGD/R-treated cells. Taken together, our results demonstrate that HPC protects SH-SY5Y cells against OGD/R via HIF-1α/Beclin1-regulated autophagy.

Short-chain chlorinated paraffins (SCCPs) have attracted considerable attention for their characteristic of persistent organic pollutants. However, very limited information is available for their toxic effects at environmentally relevant doses, limiting the evaluation of their health risks. In this study, cell viability assay and targeted metabolomic approach was used to evaluate the environmental dose (<100 μg/L) effect of SCCPs on HepG2 cells. Cell viability was found to be decreased with increases in exposure dose of SCCPs. Exposure for 48 h to C10-CPs resulted in a significant reduction in cell viability compared with 24 h, even at 1 μg/L. SCCPs exposure altered the intracellular redox status and caused significant metabolic disruptions. As a kind of peroxisome proliferator, SCCPs specifically stimulated the β-oxidation of unsaturated fatty acids and long-chain fatty acids. Meanwhile, SCCPs exposure disturbed glycolysis and amino acid metabolism, and led to the up-regulation of glutamate metabolism and urea cycle. The toxic effects of SCCPs might mainly involve the perturbation of energy production, protein biosynthesis, fatty acid metabolism, and ammonia recycling.

Backgroundc-Met has been shown to promote organ development and cancer progression in many cancers. However, clinicopathological and prognostic value of c-Met in breast cancer remains elusive.MethodsPubMed and EMBASE databases were searched for eligible studies. Correlation of c-Met overexpression with survival data and clinicopathological features was analyzed by using hazard ratio (HR) or odds ratio (OR) and fixed-effect or random-effect model according to heterogeneity. All statistical tests were two-sided.Results32 studies with 8281 patients were analyzed in total. The c-Met overexpression was related to poor OS (overall survival) (HR=1.65 (1.328, 2.051)) of 18 studies with 4751 patients and poor RFS/DFS (relapse/disease free survival) (HR=1.53 (1.20, 1.95)) of 12 studies with 3598 patients. Subgroup analysis according to data source/methods/ethnicity showed c-Met overexpression was related to worse OS and RFS/DFS in Given by author group, all methods group and non-Asian group respectively. Besides, c-Met overexpression was associated with large tumor size, high histologic grade and metastasis.ConclusionsOur results showed that c-Met overexpression was connected with poor survival rates and malignant activities of cancer, including proliferation, migration and invasion, which highlighted the potential of c-Met as significant candidate biomarker to identify patients with breast cancer at high risk of tumor death.

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The toxic effects of hexabromocyclododecane (HBCD) are complex, and the underlying toxicological mechanisms are still not completely understood. In this study, a pseudotargeted metabolomic approach based on the UHPLC/Q-Trap MS system was developed to assess the HBCD-intervention-related metabolic alteration in HepG2 cells. In addition, some physiologic indicators and relevant enzyme activities were measured. HBCD exposure obviously impaired metabolic homeostasis and induced oxidative stress, even at an environmentally relevant dose (0.05 mg/L). Metabolic profiling and multivariate analysis indicated that the main metabolic pathways perturbed by HBCD included amino acid metabolism, protein biosynthesis, fatty acid metabolism, and phospholipid metabolism. HBCD suppressed the cell uptake of amino acids, mainly through inhibition of the activity of membrane transport protein Na(+)/K(+)-ATPase. HBCD down-regulated glycolysis and β-oxidation of long-chain fatty acids, causing a large decrease of ATP production. As a result, the across-membrane transport of amino acids was further inhibited. Meanwhile, HBCD induced a significant increase of total phospholipids, mainly through the remodeling of phospholipids from the increased free fatty acids. The obtained metabolomic results also provided some new evidence and clues regarding the toxicological mechanisms of HBCD that contribute to obesity, diabetes, nervous system damage, and developmental disorders.

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