PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy

Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation

Achieving blood pressure control targets in hypertensive patients of rural China - A pilot randomized trial

Background: This study aimed to test the feasibility and titration methods used to achieve specific blood pressure (BP) control targets in hypertensive patients of rural China. Methods: A randomized, controlled, open-label trial was conducted in Rongcheng, China. We enrolled 105 hypertensive participants aged over 60 years, and who had no history of stroke or cardiovascular disease. The patients were randomly assigned to one of three systolic-BP target groups: standard: 140 to \u3c 150 mmHg; moderately intensive: 130 to \u3c 140 mmHg; and intensive: \u3c 130 mmHg. The patients were followed for 6 months. Discussion: The optimal target for systolic blood pressure (SBP) lowering is still uncertain worldwide and such information is critically needed, especially in China. However, in China the rates of awareness, treatment and control are only 46.9%, 40.7%, and 15.3%, respectively. It is challenging to achieve BP control in the real world and it is very important to develop population-specific BP-control protocols that fully consider the population\u27s characteristics, such as age, sex, socio-economic status, compliance with medication, education level, and lifestyle. This randomized trial showed the feasibility and safety of the titration protocol to achieve desirable SBP targets (\u3c 150, \u3c 140, and \u3c 130 mmHg) in a sample of rural, Chinese hypertensive patients. The three BP target groups had similar baseline characteristics. After 6 months of treatment, the mean SBP measured at an office visit was 137.2 mmHg, 131.1 mmHg, and 124.2 mmHg, respectively, in the three groups. Home BP and central aortic BP measurements were also obtained. At 6 months, home BP measurements (2 h after drug administration) showed a mean SBP of 130.9 mmHg in the standard group, 124.9 mmHg in the moderately intensive group, and 119.7 mmHg in the intensive group. No serious adverse events were recorded over the 6-month study period. Rates of adverse events, including dry cough, palpitations, and arthralgia, were low and showed no significant differences between the three groups. This trial provided real-world experience and laid the foundation for a future, large-scale, BP target study. Trial registration: Feasibility Study of the Intensive Systolic Blood Pressure Control; ClinicalTrials.gov, ID: NCT02817503. Registered retrospectively on 29 June 2016

High-Dimensional Uncertainty Quantification in Electrical Impedance Tomography Forward Problem Based on Deep Neural Network

In electrical impedance tomography (EIT), the uncertainty of conductivity distribution may cause the uncertainty in the forward calculation and further affect the inverse problem. In this paper, an improved univariate dimension reduction method based on deep neural network (DNN-UDR) is proposed for the high-dimensional uncertainty quantification in EIT forward problem. Firstly, DNN is studied to build a substitute model for EIT forward problem in order to solve the high-dimensional problem. Three normalized circular finite element models are established with random uniform conductivity distribution. Then UDR is used to analyze and quantify the uncertainty in the simulation with the form of probability. Compared with Monte Carlo simulation (MCS), the probability distribution of voltage is fitted, and the quantification indicators such as mean, variance, variation coefficient and covariance, are also consistent. On the other hand, with the increase of parameter dimensions, DNN-UDR accelerates the computations obviously. This indicates that DNN-UDR is effective and has high structural stability, accurate prediction results and high computational efficiency

Liquid metal droplets bouncing higher on thicker water layer

Abstract Liquid metal (LM) has gained increasing attention for a wide range of applications, such as flexible electronics, soft robots, and chip cooling devices, owing to its low melting temperature, good flexibility, and high electrical and thermal conductivity. In ambient conditions, LM is susceptible to the coverage of a thin oxide layer, resulting in unwanted adhesion with underlying substrates that undercuts its originally high mobility. Here, we discover an unusual phenomenon characterized by the complete rebound of LM droplets from the water layer with negligible adhesion. More counterintuitively, the restitution coefficient, defined as the ratio between the droplet velocities after and before impact, increases with water layer thickness. We reveal that the complete rebound of LM droplets originates from the trapping of a thinly low-viscosity water lubrication film that prevents droplet-solid contact with low viscous dissipation, and the restitution coefficient is modulated by the negative capillary pressure in the lubrication film as a result of the spontaneous spreading of water on the LM droplet. Our findings advance the fundamental understanding of complex fluids’ droplet dynamics and provide insights for fluid control