慢性肺心病脂质过氧化物一氧化氮内源性纤溶酶原激活物及其抑制剂的变化

为了探讨脂质过氧化物、一氧化氮、纤溶系统与慢性肺心病肺动脉高压形成的关系,对３２例急性加重期和４０例缓解期肺心病患者血清丙二醛（ＭＤＡ）、超氧化物歧化酶（ＳＯＤ）、一氧化氮（ＮＯ）、血浆组织型纤溶酶原激活物（ｔ－ＰＡ）及ｔ—ＰＡ抑制剂（ＰＡＩ）含量进行测定,并与４２例正常人作对比研究。结果提示急性期肺心病患者血清ＭＤＡ、血浆ＰＡＩ显著高于肺心病缓解期患者及正常人,而急性期肺心病患者血清ＳＯＤ、ＮＯ、血浆ｔ—ＰＡ显著低于肺心病缓解期患者及正常人,差异均具显著性（Ｐ＜００１）;缓解期肺心病患者血清ＭＤＡ、血浆ＰＡＩ高于正常人,而血清ＳＯＤ、ＮＯ、血浆ｔ—ＰＡ低于正常人,但差异不具显著性（Ｐ＞００５）。总之,脂质过氧化、一氧化氮含量减少,纤溶系统功能失衡与肺心病肺动脉高压的形成或加重有关     

New in vivo model to assess venous endothelial cell functions. Effect of defibrotide

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18].Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions.In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.     

Bispecific targeting of thrombin activatable fibrinolysis inhibitor and plasminogen activator inhibitor‐1 by a heterodimer diabody

Summary. Background and objectives: Thrombin activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor‐1 (PAI‐1) play important roles in fibrinolysis. Both reduce plasmin generation, but they exert their antifibrinolytic effects via different mechanisms. This study reports the cloning and characterization of a heterodimer diabody that inhibits TAFI and PAI‐1 simultaneously. Methods and results: The diabody was derived from two inhibiting monoclonal antibodies, i.e. MA‐33H1F7, an anti‐PAI‐1 antibody that induces non‐inhibitory substrate behavior of PAI‐1, and MA‐T12D11, an anti‐TAFI antibody that inhibits activation of TAFI by the thrombin–thrombomodulin complex. A single‐chain variable fragment (scFv) was derived from MA‐T12D11 that displayed slightly reduced binding and inhibitory properties as compared to MA‐T12D11. Characterization of the diabody revealed a similar affinity for TAFI and PAI‐1 as that of the parental antibodies. Furthermore, the inhibitory properties of MA‐33H1F7 and MA‐T12D11 were fully preserved in the diabody format. In platelet‐free plasma (PFP) clots, addition of the diabody had a stronger effect in shortening lysis times than either MA‐T12D11 or MA‐33H1F7. A similar reduction in clot lysis time was observed in platelet‐rich plasma (PRP) clots. The same effect on clot lysis times in PFP and PRP was also achieved by the combined addition of MA‐T12D11 and MA‐33H1F7. The lysis rate of human model thrombi, made from whole blood, was approximately doubled after addition of the diabody. Moreover, this effect was significantly better than after the combined addition of the individual antibodies. Conclusions: These observations demonstrate that simultaneous inhibition of TAFI and PAI‐1 results in faster lysis of the formed thrombus.     

Semimetal nanomaterials of antimony as highly efficient agent for photoacoustic imaging and photothermal therapy

In this study we report semimetal nanomaterials of antimony (Sb) as highly efficient agent for photoacoustic imaging (PAI) and photothermal therapy (PTT). The Sb nanorod bundles have been synthesized through a facile route by mixing 1-octadecane (ODE) and oleyl amine (OAm) as the solvent. The aqueous dispersion of PEGylated Sb NPs, due to its broad and strong photoabsorption ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths, is applicable as a photothermal agent driven by 808 nm laser with photothermal conversion efficiency up to 41%, noticeably higher than most of the PTT agents reported before. Our in vitro experiments also showed that cancer cell ablation effect of PEGylated Sb NPs was dependent on laser power. By intratumoral administration of PEGylated Sb NPs, 100% tumor ablation can be realized by using NIR laser irradiation with a lower power of 1 W/cm² for 5 min (or 0.5 W/cm² for 10 min) and no obvious toxic side effect is identified after photothermal treatment. Moreover, intense PA signal was also observed after intratumoral injection of PEGylated Sb NPs and NIR laser irradiation due to their strong NIR photoabsorption, suggesting PEGylated Sb NPs as a potential NIR PA agent. Based on the findings of this work, further development of using other semimetal nanocrystals as highly efficient NIR agents can be achieved for vivo tumor imaging and PTT.     

Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3‐ and p53‐dependent fibrotic responses

Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)‐mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK‐2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI‐1, vimentin, α‐SMA and fibronectin expression, compared to HK‐2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53^Ser15 phosphorylation, with an accompanying decrease in population density and an increase in epithelial G₁ cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI‐1 rescued the PTEN loss‐associated epithelial proliferative arrest. Moreover, TGFβ1‐initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53‐dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3‐ and p53‐mediated fibrotic gene induction, with accompanying PAI‐1‐dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Tumor growth-promoting cellular host response during liver atrophy after portal occlusion.

BACKGROUND/AIMS: Clinical observations suggest cancer progression after preoperative segmental portal vein occlusion, a procedure to prevent liver failure after major hepatic resections. The aim of this study was to determine whether portal occlusion induces host reactions which promote cancer invasion and angiogenesis. METHODS: The rat model of portal branch ligation (PBL) was compared with partial hepatectomy (PH) and sham operation (SO) and evaluated for the expression of heat shock protein-70 (hsp70), heme oxygenase-1 (hmox1), early growth response gene-1 (Egr-1) and urokinase-type plasminogen activator (uPA), its inhibitor (PAI-1) and receptor (uPAR). RESULTS: Portal deprivation after PBL was associated with a regression of liver tissue to 25% of its original mass within 8 days with only modest fibrotic changes. During the progression of atrophy, there were significant inductions of hsp70-, hmox1- and Egr-1-mRNA in comparison with regenerating liver tissue. PAI-1-specific mRNA was transiently elevated at 3 - 48 h after PBL in the atrophying lobes, whereas uPA and uPAR were unaffected in comparison with PH or SO. CONCLUSION: Hepatic atrophy caused by PBL is associated with increased expression of genes known to promote tumor growth. These host events represent a possible explanation for the tumor progression after portal occlusion and require further evaluation.     

Personal Activity Intelligence and Mortality in Patients with Cardiovascular Disease: The HUNT Study

Objective

To test whether Personal Activity Intelligence (PAI), a personalized metric of physical activity (PA) tracking, is associated with all-cause and cardiovascular disease (CVD) mortality in patients with self-reported CVD and to determine whether these associations change depending on whether contemporary PA recommendations are met.