Extracellular vesicles released by hypoxia-induced tumor-associated fibroblasts impart chemoresistance to breast cancer cells via long noncoding RNA H19 delivery.

Recently, extracellular vesicles (EVs) have been emphasized in regulating the hypoxic tumor microenvironment of breast cancer (BC), where tumor-associated fibroblasts (TAFs) play a significant role. In this study, we describe possible molecular mechanisms behind the pro-tumoral effects of EVs, secreted by hypoxia (HP)-induced TAFs, on BC cell growth, metastasis, and chemoresistance. These mechanisms are based on long noncoding RNA H19 (H19) identified by microarray analysis. We employed an in silico approach to identify differentially expressed lncRNAs that were associated with BC. Subsequently, we explored possible downstream regulatory mechanisms. We isolated EVs from TAFs that were exposed to HP, and these EVs were denoted as HP-TAF-EVs henceforth. MTT, transwell, flow cytometry, and TUNEL assays were performed to assess the malignant phenotypes of BC cells. A paclitaxel (TAX)-resistant BC cell line was constructed, and xenograft tumor and lung metastasis models were established in nude mice for in vivo verification. Our observation revealed that lncRNA H19 was significantly overexpressed, whereas miR-497 was notably downregulated in BC. HP induced activation of TAFs and stimulated the secretion of EVs. Coculture of HP-TAF-EVs and BC cells led to an increase in TAX resistance of the latter. HP-TAF-EVs upregulated methylation of miR-497 by delivering lncRNA H19, which recruited DNMT1, thus lowering the expression of miR-497. In addition, lncRNA H19-containing HP-TAF-EVs hindered miR-497 expression, enhancing tumorigenesis and TAX resistance of BC cells in vivo. Our study presents evidence for the contribution of lncRNA H19-containing HP-TAF-EVs in the reduction of miR-497 expression through the recruitment of DNMT1, which in turn promotes the growth, metastasis, and chemoresistance of BC cells.

[Enoxaparin for the prevention of post surgical pulmonary embolism].

OBJECTIVE: To evaluate the efficacy and safety of the administration of enoxaparin, a low molecular weight heparin (LMWH), in the prevention of post surgical deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: 1928 patients hospitalized for general surgery were randomly divided into: (1) test group (n = 960) to receive enoxaparin (40 mg, s.c., 12 hours before and after surgery, then once daily for 7 consecutive days); (2) control group (n = 968) without intervention. The incidence of DVT,PE and bleeding were recorded for statistical analysis during hospitalization and a 2 months follow-up after discharge. RESULTS: (1) No significant difference was found between the two groups in age, sex, average body mass index, type of surgery, and DVT / PE risk factors (obesity, varicose veins, and history of: venous thrombosis, chronic obstructive pulmonary disease, chronic heart failure, and hormone therapy). The percentage of non-malignant / malignant tumor surgery were 36.5% / 63.5% (average operation time 2.3 hours) in control group and 35.6% / 64.4% (2.2 hours) in test group (both P > 0.05). (2) During the hospitalization period, 59 cases (incidence=6.1%) of DVT and 14 cases (incidence=1.4%) of PE (among them 6 were fetal, 42.8% of all PE cases) were found in the control group, while 28 cases of DVT (2.9%) and 3 cases (0.3%) of PE (1 fetal, 33.3% of all PE cases) were found in test group. The incidence of DVT, PE (total), and PE (fetal) were significant lower in test group (P < 0.05 or P < 0.01). During the follow up, 14 more cases of DVT (1.4%) and 1 more case (0.1%) of PE (a fetal) were found in the control group, and 2 more DVT cases (0.2%) in test group, with the DVT incidence in test group significantly lower (P < 0.01). (3) During the enoxaparin administration, 30 cases (3.1%) minor bleeding and 8 cases (0.8%) major bleeding were found in the control group, while 33 cases (3.4%) minor bleeding events and 9 cases (0.9%) major bleeding events were found in the test group. THE RESULTS: in the two groups were not significantly different in either type of bleeding events (both P > 0.05). Also no significant difference was found in the bleeding events after the ending of enoxaparin administration and during the follow up. CONCLUSION: Enoxaparin may reduce the incidence of DVT and PE in patients undergoing general surgery without increased risk of bleeding.