NSD2 inhibition suppresses metastasis in cervical cancer by promoting TGF-ß/TGF-ßRI/SMADs signaling.

The molecular mechanisms revealing cervical cancer progression remain unclear. NSD2 belongs to the NSD family of histone lysine methyltransferases (HMTases), and is a histone methyltransferase that regulates dimethylation of histone 3 lysine 36 (H3K36me2). In this study, we explored the effects of NSD2 on the tumorigenesis and metastasis in cervical cancer. We found that NSD2 exhibited a pattern of gradual up-regulation from normal cervix (NC) to cervical carcinoma in situ (CIS) and then to invasive cervical cancer (ICC). NSD2 knockdown markedly reduced the cervical cancer cell proliferation. Loss of function assay in vitro suggested that NSD2 deletion markedly prevented the cervical cancer cell migration and invasion. Consistently, the in vivo results demonstrated that NSD2 knockdown not only reduced tumor growth, but also prevented the development of tumor metastasis. In addition, NSD2 knockdown clearly reduced the expression levels of transforming growth factor-ß1 (TGF-ß1), TGF-ßRI, phosphorylated SMAD2 and SMAD3 in cervical cancer cells, accompanied with the decreased expression of genes that promoted tumor metastasis. Importantly, we found that NSD2 knockdown-regulated expression levels of metastasis-associated genes were reversed by TGF-ß1 incubation. Therefore, our findings demonstrated that NSD2-modulated activation of TGF-ß1/TGF-ßRI/SMADs signaling pathway was crucial for cervical cancer progression, which might be a promising therapeutic strategy to overcome metastasis in cervical cancer.

Achieving better connections between deposited lines in additive manufacturing via machine learning.

Additive manufacturing is becoming increasingly popular because of its unique advantages, especially fused deposition modelling (FDM) which has been widely used due to its simplicity and comparatively low price. All the process parameters of FDM can be changed to achieve different goals. For example, lower print speed may lead to higher strength of the fabricated parts. While changing these parameters (e.g. print speed, layer height, filament extrusion speed and path distance in a layer), the connection between paths (lines) in a layer will be changed. To achieve the best connection among paths in a real printing process, how these parameters may result in what kind of connection should be studied. In this paper, a machine learning (deep neural network) model is proposed to predict the connection between paths in different process parameters. Four hundred experiments were conducted on an FDM machine to obtain the corresponding connection status data. Among them, there are 280 groups of data that were used to train the machine learning model, while the rest 120 groups of data were used for testing. The results show that this machine learning model can predict the connection status with the accuracy of around 83%. In the future, this model can be used to select the best process parameters in additive manufacturing processes with corresponding objectives.

LINC00511 is associated with the malignant status and promotes cell proliferation and motility in cervical cancer.

LINC00511 is a newly identified lncRNA that is up-regulated in many types of human cancers and may serve as an oncogenic lncRNA. However, there was no report about the role of LINC00511 in cervical cancer. Therefore, we investigated the clinical value of LINC00511 in cervical cancer patients via analyzing the correlation between LINC00511 expression and clinicopathological features. Moreover, we performed loss-of-function study to estimate the effect of LINC00511 on cervical cancer cell proliferation, migration, and invasion. In our study, we found LINC00511 expression levels were increased in cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cell line, respectively. High LINC00511 expression was correlated with advanced clinical stage, large tumor size, histological type of adenocarcinoma, and present lymph node metastasis, distant metastasis, and poor overall survival in cervical cancer patients. The in vitro studies indicated that knockdown of LINC00511 inhibited cervical cancer cell proliferation, migration, and invasion. In conclusion, LINC00511 acts as oncogenic lncRNA in cervical cancer, and may be a novel biomarker and potential therapeutic target for cervical cancer patients.

In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits.

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.