Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers.Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay.Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day).Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260)

Activating Transcription Factor 4 Confers a Multidrug Resistance Phenotype to Gastric Cancer Cells through Transactivation of SIRT1 Expression

BACKGROUND: Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD(+)-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells. CONCLUSIONS/SIGNIFICANCE: We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis

MTMG: A multi-task model with multi-granularity information for drug-drug interaction extraction

Drug-drug interactions (DDIs) extraction includes identifying drug entities and interactions between drug pairs from the biomedical corpus. The discovery of potential DDIs aids in our understanding of the mechanisms underlying adverse reactions or combination therapy to improve patient safety. The manual extraction of DDIs is very time-consuming and expensive; therefore, computer-aided extraction of DDIs is vital. Many neural network-based methods have been proposed and achieved good efficiency in the extraction of DDIs over the years. However, most studies improved the performance of DDIs extraction with various external drug features while directly using golden drug entities, leading to error propagation and low universality in practical application. In this paper, we propose a new multi-task framework called MTMG, which changes DDIs extraction from a sentence-level classification task to a sequence labeling task named Drug-Specified Token Classification (DSTC). The proposed approach, MTMG, jointly trains DSTC with drug named entity recognition (DNER) and two sentence-level auxiliary tasks we designed. We aim to improve the performance of the entire DDIs extraction pipeline by better using the correlation between entities and relationships and, to the extent possible, using the information of varying granularity implied in the dataset. Experimental results show that MTMG can both improve the accuracy of DNER and DDIs extraction and outperforms state-of-the-art technique

Association of survivin polymorphisms with tumor susceptibility: a meta-analysis.

BACKGROUND: The survivin polymorphisms have been shown to confer genetic susceptibility to various tumors, but the results are inconsistent. In order to accomplish a more precise estimation of the relationship, a meta-analysis was performed. RESULTS: For rs9904341, a significantly increased tumor risk was found in overall meta-analysis under C/C vs. G/G (OR = 1.40, 95% CI = 1.13-1.74, p = 0.002), dominant (OR = 1.18, 95% CI = 1.01-1.38, p = 0.039) and recessive (OR = 1.34, 95% CI = 1.13-1.58, p = 0.001) genetic models and Asians group. In subgroup analyses of tumor types, we found a significant association between this SNP and an increased risk of gastric, colorectal, bladder and other tumors as well as a decreased risk of hepatocellular cancer. For rs17878467, a significantly decreased tumor risk was identified in overall meta-analysis for allele contrast (T vs. C: OR = 0.69, 95% CI = 0.51-0.92, p = 0.012), C/T vs. C/C (OR = 0.61, 95% CI = 0.42-0.88, p = 0.009) and dominant (OR = 0.62, 95% CI = 0.43-0.88, p = 0.007) genetic models and Asians group. For rs2071214, we found a significant association between this SNP and an increased tumor risk in overall meta-analysis under G/G vs. A/A (OR = 1.51, 95% CI = 1.04-2.18, p = 0.029) and recessive (OR = 1.54, 95% CI = 1.07-2.22, p = 0.020) genetic models and Asians group. Besides, there was a significant association of rs8073069 with an increased tumor risk under recessive genetic model (OR = 1.37, 95% CI = 1.01-1.84, p = 0.040), while no significant association between rs1042489 and tumor risk was detected. CONCLUSIONS: The survivin rs9904341 most likely contributed to increased susceptibility to tumor in Asians as well as to gastric, colorectal and bladder cancers. As for rs17878467, the T allele might be a protective factor for tumor, especially in Asians. Moreover, the survivin rs8073069 and rs2071214 seemed to be associated with an increased tumor risk in Asians, while there was no association between the survivin rs1042489 and tumor risk

Stability Evaluation on Surrounding Rocks of Underground Powerhouse Based on Microseismic Monitoring

To study the stability of underground powerhouse at Houziyan hydropower station during excavation, a microseismic monitoring system is adopted. Based on the space-time distribution characteristics of microseismic events during excavation of the main powerhouse, the correlation between microseismic events and blasting construction is established; and the microseismic clustering areas of the underground powerhouse are identified and delineated. The FLAC3D code is used to simulate the deformation of main powerhouse. The simulated deformation characteristics are consistent with that recorded by microseismic monitoring. Finally, the correlation between the macroscopic deformation of surrounding rock mass and microseismic activities is also revealed. The results show that multiple faults between 1# and 3# bus tunnels are activated during excavation of floors V and VI of the main powerhouse. The comprehensive method combining microseismic monitoring with numerical simulation as well as routine monitoring can provide an effective way to evaluate the surrounding rock mass stability of underground caverns

Kinematics and workspace analysis of a robotic arm for medical delivery robots

For the control of the robot arm of a medical delivery robot, firstly, the forward kinematic equations of this 7-degree-of-freedom redundant robot arm are constructed according to a modified D-H method. Secondly, the analytical solution of the inverse kinematics of the redundant robotic arm is solved using the parameterised arm angle. Thirdly, kinematic simulation experiments were carried out by gazebo and RVIZ in ROS to verify the correctness of the forward and inverse kinematic solution process. Finally, the Monte Carlo method was used to generate the point cloud map of the workspace of the redundant robotic arm within the allowed range of joints, and the boundary points of the workspace were extracted, and the extracted boundary points were fitted with least squares curves to find the workspace of the robotic arm, which laid the foundation for future research directions such as motion control and path planning of medical delivery robots

Configuration optimization and kinematic analysis of a wearable exoskeleton arm

In order to evaluate the kinematic performance and determine the proper design parameters, the kinematic characteristics of human upper-limb are modelled and analyzed in this paper. Based on the model, different mechanical configurations of wearable upper-limb exoskeleton robots are proposed and the singularity orientation in the upper limb workspace is analyzed. The optimal configuration of the shoulder mechanism without limiting the spherical-joint motion is determined to avoid the singularity in the control procedure. According to the configuration, the workspaces of the upper limb and the exoskeleton robots are simulated by the matlab software. And the results prove that the optimized configuration works well in the most frequently used workspace of human upper-limb. The optimizing method of singularity elimination is helpful for the configuration design and active control of upper limb exoskeleton system