Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.

[Effects of carbaryl production exposure on the sperm and semen quality of occupational male workers].

OBJECTIVE: To analyse the male reproductive toxicity of carbaryl. METHODS: Thirty-one male carbaryl exposure workers and 46 male administrators in the office in a pesticide factory were selected as the exposure group and internal control group respectively, and 22 male administrators in a center for disease control and prevention were served as the external control group. In order to evaluate the exposure levels, the concentrations of carbaryl, methyl isocyanate, ammonia and phenol in the ambient air of the work place in these three groups were monitored simultaneously for three consecutive days. Moreover, three workers in the exposure group and the external control group were selected to evaluate the amount of carbaryl of individual and dermal contamination for three consecutive days. After the semen were collected according to the standard method, the workers'semen qualities were analysed with WHO method, the sperm morphology and the sperm motility were evaluated using micro-cell slide spectrum technology and computer assisted sperm analysis (CASA) respectively. RESULTS: In the exposure group, the concentrations of carbaryl and phenol (52.41 mg/m(3) and 0.08 mg/m(3) respectively) were significantly higher than those in the internal and external control group (P < 0.01 or P < 0.05). Furthermore, in the carbaryl exposure area the geometric mean concentration of carbaryl with the individual sampling was 7.38 mg/m(3), and the geometric mean of dermal contamination detected in the carbaryl exposure area was 862.47 mg/m(2). Carbaryl was not found in the external control area (P < 0.01). The seminal volume [(2.39 +/- 1.44) ml] and the sperm motility [(1.77 +/- 0.61) grade] were significantly lower than those in the external control group (P < 0.05), and sperm motion parameters such as linearity (LIN, 39.89% +/- 6.00%), straightness (STR, 71.51% +/- 11.22%), straight line velocity [VSL, (26.29 +/- 7.84) microm/s] and beat cross frequency [BCF, (3.99 +/- 1.55) Hz] were lower than those in the internal and external control group (P < 0.05), while the abnormal rates of viscidity, sperm motility and total aberration rate were higher than those in the external control group (P < 0.05). CONCLUSION: Occupational exposure to carbaryl production can affect the workers'sperm and semen quality to certain extent.

[Effects of fenvalerate exposure on the semen quality of occupational workers].

OBJECTIVES: To study the effects of fenvalerate exposure on the semen quality of occupational workers in order to find out the early effective biomarkers. METHODS: Thirty-two male workers who exposed to fenvalerate and 46 male administrators in the office in a pesticide factory were selected as the exposure group and internal control group, respectively, and 22 male administrators in a center for disease control were served as the external control group. In order to evaluate the exposed levels, the concentration of fenvalerate, toluene and xylene in the ambient air of working place in these three groups were monitored simultaneously for three consecutive days. After the semen were collected according to the standard method, the workers' semen qualities were analysed with University of California at Davis (UCDavis) method and the sperm motility were evaluated using computer assisted sperm analysis(CASA). RESULTS: In the exposure group, the concentrations of fenvalerate were significantly higher than those in the internal and external control group (P < 0.01), while no significant difference of the concentration on toluene or xylene was found (P > 0.05). Sperm motion parameters in the exposure group such as linearity(LIN), straightness(STR), and the sperm count were decreased significantly, and the abnormality rate of viscidity, coagulation and sperm count were increased significantly as compared with the internal and the external control groups(P < 0.05). Furthermore, the sperm progression and beat cross frequency (BCF) in the exposure group were also lower significantly than those in the external control group(P < 0.05), while the abnormality rate of sperm progression was increased significantly. CONCLUSIONS: In such a low concentration, occupational exposure to fenvalerate can affect workers' semen quality, especially the sperm count and sperm movement ability.