Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.     

Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y₁₂ could serve as components of dual anti-platelet therapy. We have found that a selective A_2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y₁₂ inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A_2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.     

The Antithrombotic Agent Pterostilbene Interferes with Integrin αIIbβ3-Mediated Inside-Out and Outside-In Signals in Human Platelets

Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2–8 μM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin α_IIbβ₃ activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin α_IIbβ₃-mediated outside-in signaling, such as integrin β₃, Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin α_IIbβ₃-mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders.     

The Role of Circulating Biomarkers in Peripheral Arterial Disease

Peripheral arterial disease (PAD) of the lower extremities is a chronic illness predominantly of atherosclerotic aetiology, associated to traditional cardiovascular (CV) risk factors. It is one of the most prevalent CV conditions worldwide in subjects >65 years, estimated to increase greatly with the aging of the population, becoming a severe socioeconomic problem in the future. The narrowing and thrombotic occlusion of the lower limb arteries impairs the walking function as the disease progresses, increasing the risk of CV events (myocardial infarction and stroke), amputation and death. Despite its poor prognosis, PAD patients are scarcely identified until the disease is advanced, highlighting the need for reliable biomarkers for PAD patient stratification, that might also contribute to define more personalized medical treatments. In this review, we will discuss the usefulness of inflammatory molecules, matrix metalloproteinases (MMPs), and cardiac damage markers, as well as novel components of the liquid biopsy, extracellular vesicles (EVs), and non-coding RNAs for lower limb PAD identification, stratification, and outcome assessment. We will also explore the potential of machine learning methods to build prediction models to refine PAD assessment. In this line, the usefulness of multimarker approaches to evaluate this complex multifactorial disease will be also discussed.     

城市交通干线的协调优化控制模型

对城市干线上一批相邻的交通信号进行协调控制,可减少干线上车辆的延误和停车次数。通过对城市干线常态与过饱和状态下的交通流状况分析,建立了对干线实施线控系统相位差优化调节的数学模型。该模型反应了沿干线行驶车辆在干线各交叉口延误情况的内在机理,是一种减少干线车辆延误的有效方法,对改善城市交通拥挤状况,提高干线道路服务能力具有积极的现实意义。     

城市主干路拥挤路段基于地点交通参数的行程速度估计

以提高基于地点交通参数估计主干路拥挤交通流平均行程速度的精度为目标,通过分析信号控制主干路的交通流特性及地点交通参数与平均行程速度之间的相关关系,以路段下游停车线前的截面平均速度为基础,提出了城市主干路拥挤交通流路段平均行程速度的3种估计模型,并采用仿真手段进行了对比分析。结果表明,所提出的全状态行程速度估计模型明显优于对比方法,所提出的两种分状态平均行程速度估计模型可以进一步改善全状态模型的估计效果,尤其是基于模比系数的分状态估计模型可显著提高拥挤条件下的行程速度估计精度。     

Signal‐to‐noise ratios for measuring saliency of features extracted by eigenvector methods from ophthalmic arterial Doppler signals

Abstract: Features are used to represent patterns with minimal loss of important information. The feature vector, which is composed of the set of all features used to describe a pattern, is a reduced‐dimensional representation of that pattern. Medical diagnostic accuracies can be improved when the pattern is simplified through representation by important features. By identifying a set of salient features, the noise in a classification model can be reduced, resulting in more accurate classification. In this study, a signal‐to‐noise ratio saliency measure was employed to determine the saliency of input features of recurrent neural networks (RNNs) used in classification of ophthalmic arterial Doppler signals. Eigenvector methods were used to extract features representing the ophthalmic arterial Doppler signals. The RNNs used in the ophthalmic arterial Doppler signal classification were trained for the signal‐to‐noise ratio screening method. The application results of the signal‐to‐noise ratio screening method to the ophthalmic arterial Doppler signals demonstrated that classification accuracies of RNNs with salient input features are higher than those of RNNs with salient and non‐salient input features.     

窗口流量控制的干线动态协调控制方法

城市交通干线在高峰时期经常处于饱和状态,排队车辆溢出至上游交叉口的"死锁"现象时有发生.为避免干线阻塞、提高饱和条件下干线交通流的运行效率,首先提出一种有效带宽评价方法对已有干线绿波协调控制系统的运行状态及控制效果进行监控;其次借鉴TCP/IP窗口流量控制思想,设计一种窗口流量控制的干线动态协调控制方法,控制城市干线拥挤交通流.模拟试验及对比结果表明,通过窗口流量通告的方式,下游交叉口可以向上游交叉口实时告知路段的有效容量,便于各交叉口信号机根据当前的交通需求及路段的有效容量重新分配各股车流的绿灯时间.     

VWF,Platelets and the Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Laboratory criteria for the classification of APS include the detection of lupus anticoagulant (LAC), anti-cardiolipin (aCL) antibodies and anti-β2glycoprotein I (aβ2GPI) antibodies. Clinical criteria for the classification of thrombotic APS include venous and arterial thrombosis, along with microvascular thrombosis. Several aPLs, including LAC, aβ2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have been associated with arterial thrombosis. The Von Willebrand Factor (VWF) plays an important role in arterial thrombosis by mediating platelet adhesion and aggregation. Studies have shown that aPLs antibodies present in APS patients are able to increase the risk of arterial thrombosis by upregulating the plasma levels of active VWF and by promoting platelet activation. Inflammatory reactions induced by APS may also provide a suitable condition for arterial thrombosis, mostly ischemic stroke and myocardial infarction. The presence of other cardiovascular risk factors can enhance the effect of aPLs and increase the risk for thrombosis even more. These factors should therefore be taken into account when investigating APS-related arterial thrombosis. Nevertheless, the exact mechanism by which aPLs can cause thrombosis remains to be elucidated.     

Attitude of Iranian physicians and nurses toward a clinical decision support system for pulmonary embolism and deep vein thrombosis

This research project sought to design and implement a computerized clinical decision support system (CDSS) that was able to identify patients who were at risk of pulmonary embolism (PE) and deep vein thrombosis (DVT), as well as produce reminders for prophylactic action for these diseases. The main purpose of the CDSS was to attempt to reduce the morbidity and mortality caused by embolism and thrombosis in patients admitted to hospitals. After implementation of this system in one of the large educational hospitals of Iran, a standard questionnaire was used, and interviews were conducted with physicians and nurses to evaluate the performance of the designed system for reducing the incidence of pulmonary embolism and thrombosis. From physicians and nurses’ point of view, a system which assists the medical staff in making better decisions regarding patient care, and also reminds pulmonary embolism and thrombosis preventive procedures with timely warnings, can influence patient care quality improvement and lead to the improved performance of the medical staff in preventing the incidence of pulmonary embolism and thrombosis.