Yu Zhao

Risk factors associated with the occurrence of silent pulmonary embolism in patients with deep venous thrombosis of the lower limb

Objective The aim of our study is to investigate the prevalence of silent pulmonary embolism in patients with deep venous thrombosis in the lower limbs and to evaluate the associated risk factors. Methods A total of 322 patients with acute deep venous thrombosis confirmed by CT venography or Doppler ultrasonography were studied. The diagnosis of silent pulmonary embolism was established by computed tomography pulmonary arteriography (CTPA). The association between covariates and the prevalence of silent pulmonary embolism in patients with deep venous thrombosis in lower limbs were assessed using chi-square test and multivariable regression. Results The incidence of silent pulmonary embolism was 33.5% (108 in 322 patients) in all patients with deep venous thrombosis in lower limbs. Chi-square test showed male gender, the right lower limb, proximal location of the thrombus, unprovoked venous thrombosis and coexisting heart diseases were related to a higher incidence of silent pulmonary embolism in patients with deep venous thrombosis in lower limbs. The multivariate regression analysis confirmed that the risk factors associated with silent pulmonary embolism in deep venous thrombosis patients included the right side and proximal location of the thrombus (odds ratio: 2.023, 95% CI: 1.215–3.368; odds ratio: 3.610, 95% CI: 1.772–7.354), unprovoked venous thrombosis (odds ratio: 2.037, 95% CI: 1.188–3.493), coexisting heart diseases (odds ratio: 4.507, 95% CI: 2.667–7.618). Conclusion Silent pulmonary embolism occurred frequently in patients with deep venous thrombosis in lower limbs. The right side, the proximal location of the thrombus, unprovoked venous thrombosis and coexisting heart diseases increased the risk for the occurrence of silent pulmonary embolism.

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4.

Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRβ/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up-regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Krüppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4.

Early initiation of argatroban therapy in the management of acute superior mesenteric venous thrombosis

Acute superior mesenteric venous thrombosis (ASMVT) is an intractable disease with poor prognosis. Argatroban, a direct thrombin inhibitor, may be a novel anticoagulant method in the therapy of ASMVT. The aim of the present study was to assess the efficacy and safety of early argatroban therapy in ASMVT patients. The current retrospective study reviewed a consecutive series of ASMVT patients receiving early argatroban therapy during hospitalization between March 2013 and April 2014, with 18 ASMVT patients included in the study. Of these, 16 patients without hepatic dysfunction underwent anticoagulant therapy with argatroban with a mean dose of 1.57±0.34 µg/kg/min and a mean duration of 12.2±3.7 days, while their activated partial thromboplastin time (aPTT) was elevated to 1.95±0.26 times the baseline value. In addition, 2 hepatic dysfunction patients received therapy with a dose of 0.41 µg/kg/min and 0.46 µg/kg/min, and with aPTT of 1.68 and 1.62 times the baseline value, respectively. Overall, 94% (n=17) of the patients presented clinical improvement, while 88% (n=16) of patients presented partially or completely dissolved thrombus in contrast-enhanced computed tomography images. The incidence of surgery and bowel resection was 6% (excluding 1 case with intestinal necrosis detected on admission). Furthermore, 11% (n=2) of patients experienced a bleeding episode, however no major bleeding or mortality occurred during hospitalization. During the follow-up, the mortality and the recurrence rate were 6% and 11%, respectively. In conclusion, early initiation of argatroban treatment may be an effective and safe therapy in ASMVT, manifesting efficient resolution of the thrombus, rapid improvement of symptoms, low incidence of bowel resection and bleeding complication, and low mortality rate.

Profile of protein expression of the colon cancer cell line SW480 with survivin/shRNA.

Survivin has attracted abundant interest in tumor research since it was discovered in 1997. However, several studies indicate that the relationship between survivin expression and tumor behavior is still not fully understood. Among the current methods available, proteomics is an effective platform to globally detect and characterize proteins. Thus, we constructed the recombinant adenovirus [ad-survivin/ short hairpin RNA (shRNA)], which contains shRNA of survivin, and transfected it into SW480 cells. Then, we detected survivin gene expression after shRNA interference, and its influence on apoptosis and the cell cycle was analyzed. A comparative proteomic approach was used to identify the differential proteins between SW480/survivin (−) and SW480/survivin (+) cells. The results showed that survivin was expressed at a high level in SW480 cells and that the subcellular localization was observed in the cytoplasm. Recombinant adenovirus could suppress survivin-expression efficiency and induce apoptosis by affecting mitosis. The differentially expressed proteins identified by two-dimensional proteome analysis were related to various cellular programs involving cell proliferation, cell cycle, apoptosis, expression of nucleic acid metabolic genes, and the regulation of signal transduction. The proteomic approach implemented here offers a powerful tool for identifying novel tumor markers. Survivin plays an important role in controlling tumor growth by a variety of molecular regulatory mechanisms. Inhibition of survivin expression could effectively inhibit tumor growth.

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

Background/Aims: Skeletal muscle ischemia/reperfusion (I/R) injury is a common and severe disease. Sonic hedgehog (Shh) plays a critical role in post-natal skeletal muscle regeneration. In the present study, the role of Shh in skeletal muscle I/R injury and the mechanisms involved were investigated. Methods: The expression of Shh, AKT/mTOR/p70S6K and apoptosis pathway components were evaluated following tourniquet-induced skeletal muscle I/R injury. Then, mice were subjected to systemic administration of cyclopamine or one-shot treatment of a plasmid encoding the human Shh gene (phShh) to examine the effects of Shh on I/R injury. Moreover, mice were subjected to systemic administration of NVP-BEZ235 to investigate the role of the AKT/mTOR/p70S6K pathway in Shh-triggered skeletal muscle protection. Results: We found that the levels of Shh, AKT/mTOR/p70S6K pathway components and Cleaved Caspase 3 and the Bax/Bcl2 ratio initially increased and then decreased at different time points post-I/R injury. Moreover, Shh protected skeletal muscle against I/R injury by alleviating muscle destruction, reducing interstitial fibrosis and inhibiting apoptosis, and these protective effects were abrogated when the AKT/mTOR/p70S6K pathway was inhibited. Conclusion: Collectively, these data suggest that Shh signaling exerts a protective role through the AKT/mTOR/p70S6K signaling pathway during skeletal muscle I/R injury. Thus, Shh signaling may be a therapeutic target for protecting skeletal muscle from I/R injury.

Wall shear stress promotes intimal hyperplasia through the paracrine H2O2-mediated NOX-AKT-SVV axis

Aims: Oscillatory wall shear stress (WSS)‐linked oxidative stress promotes intimal hyperplasia (IH) development, but the underlying mechanisms are not completely understood. Materials and methods: We used an in vivo rabbit carotid arterial stenosis model representing different levels of WSS and found that WSS was increased at 1month with 50% stenosis and was accompanied by VSMCs proliferation and interstitial collagen accumulation. Increased WSS promoted the expression of NOX, AKT, and survivin (SVV) and the proliferation/migration of VSMCs and reduced apoptosis. Key findings: Our in vitro study suggested that H2O2 promoted proliferation and migration while suppressing apoptosis in cultured human umbilical vascular endothelial cells. Significance: We demonstrated that the elevation of WSS promotes VSMC proliferation and migration through the H2O2‐mediated NOX‐AKT‐SVV axis, thereby accelerating IH development.