Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. We previously found that microRNA-29b (miR-29b) downregulation was significantly associated with poor recurrence-free survival of HCC patients. Therefore, the role of miR-29b in tumor angiogenesis, invasion, and metastasis was further investigated in this study using in vitro capillary tube formation and transwell assays, in vivo subcutaneous and orthotopic xenograft mouse models, and Matrigel plug assay, and human HCC samples. Both gain-and loss-of-function studies showed that miR-29b dramatically suppressed the ability of HCC cells to promote capillary tube formation of endothelial cells and to invade extracellular matrix gel in vitro. Using mouse models, we revealed that tumors derived from miR-29b-expressed HCC cells displayed significant reduction in microvessel density and in intrahepatic metastatic capacity compared with those from the control group. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) was a direct target of miR-29b. The blocking of MMP-2 by neutralizing antibody or RNA interference phenocopied the antiangiogenesis and antiinvasion effects of miR-29b, whereas introduction of MMP-2 antagonized the function of miR29b. We further disclosed that miR-29b exerted its antiangiogenesis function, at least partly, by suppressing MMP-2 expression in tumor cells and, in turn, impairing vascular endothelial growth factor receptor 2-signaling in endothelial cells. Consistently, in human HCC tissues and mouse xenograft tumors miR-29b level was inversely correlated with MMP-2 expression, as well as tumor angiogenesis, venous invasion, and metastasis. Conclusion: miR-29b deregulation contributes to angiogenesis, invasion, and metastasis of HCC. Restoration of miR-29b represents a promising new strategy in anti-HCC therapy.

Abstract-There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT-induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT-induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT-induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport ( Key Words: smooth muscle cells Ⅲ serotonin Ⅲ Rho kinase Ⅲ ERK1/ERK2 Ⅲ pulmonary hypertension I n addition to its actions as a vasoconstrictor and neurotransmitter, serotonin (5-HT) is now recognized to be a cellular mitogen. [1][2][3] There is evidence that this mitogenic action is initiated by active transport via a cell surface transporter (SERT) of bovine, rat, and human pulmonary vascular smooth muscle cells (SMC). 1,4 -6 For other cells, the mitogenic action might be started through 1 or more of the cell surface receptors for 5-HT. A hierarchy of cell signaling responses occurs subsequent to ligation of the cell surface transporter or receptor. It has been well-established that these signaling responses include sequential activations of the small GTPase coupled protein, Rac-1, NADPH oxidase producing superoxide that is dismutated to H 2 O 2 , and extracellular signal-regulated kinase (ERK) 1/ERK2 MAP kinase. 2,[7][8][9] The small GTPase Rho A and its effector, Rho kinase (ROCK), also participate in cellular stress fiber formation and cell cycle progression. 10 -19 There has been limited study of the relationship of Rho A and ROCK to 5-HT. One study showed that Rho A bound to GTP is elevated in the rabbit aortic vascular ring preparation treated with 5-HT. 20 Another study suggested the activation of Rho A and ROCK in 5-HT-induced contraction of the bovine middle cerebral artery. 21 Serotonin participates in pulmonary hypertension, 5,22,23 and a polymorphism of the 5-HT transporter has been proposed to be involved in pulmonary hypertension in humans. 24 Because agents that block ROCK are currently available 25,26 and may be useful in pulmonary hypertension, 27-29 we have undertaken an investigation of the potential participation of ROCK in pulmonary arterial SMC signaling and proliferation produced by 5-HT. The results of our study show that ROCK is activated by 5-HT and that its activation is essential for SMC proliferation produced by 5-HT. Furthermore, with the use of a chemi...

Nanosized cerium oxide (CeO2) powders of different sizes were synthesized through homogeneous precipitation. Ferromagnetism was observed only in sub-20 nm powders. Ferromagnetic transition temperatures above room temperature and saturation magnetization values of 0.023 μB per CeO2 formula unit were measured. Chemical analysis of the powders showed that trace ferromagnetic impurities could not be responsible for the magnetic signals. Carefully controlled coulometric cyclic annealing studies combined with photoluminescence measurements showed that oxygen vacancies do not mediate the ferromagnetism in the samples.

We have previously found that both mitogen-activated protein kinase (MAPK)- and Rho kinase (ROCK)-related signaling pathways are necessary for the induction of pulmonary artery smooth muscle cell (SMC) proliferation by serotonin (5-hydroxytryptamine [5-HT]). In the present study, we investigated the possible additional participation of a phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (S6K1) pathway in this growth response. We found transient activation of Akt (Ser473) and more prolonged activation of S6K1 by 5-HT. Inhibition of PI3K with Wortmannin and LY294002 completely blocked these activations, but not that of MAPK or the ROCK substrate myosin phosphatase targeting subunit. Similarly, inhibition of MAPK and ROCK failed to block the Akt activation. Inhibition of Akt with NL-71-101 and downregulation of Akt expression with Akt small interfering RNA blocked 5-HT-induced S6K1 phosphorylation. Wortmannin, LY294002, and NL-71-101 dose-dependently inhibited 5-HT-induced SMC proliferation. 5-HT stimulated mTOR phosphorylation and the mTOR inhibitor, rapamycin, blocked activations of S6K1 and S6 ribosomal protein, and inhibited 5-HT-induced SMC proliferation. Akt phosphorylation and cell proliferation were also blocked by the antioxidants, N-acetyl-l-cysteine, Ginko biloba 501, and tiron, the reduced nicotinamide adenine dinucleotide phosphate oxidase inhibitor, diphenyleneiodonium, and the 5-HT2 receptor antagonists ketanserin and mianserin, but not by the 5-HT serotonin transporter or 5-HT 1B/1D receptor antagonists. We conclude from these studies that a parallel PI3K- and reactive oxygen species-dependent Akt/mTOR/S6K1 pathway participates independently from MAPK and Rho/ROCK in the mitogenic effect of 5-HT on pulmonary artery SMCs. From these and other studies, we postulate that independent signaling pathways leading to 5-HT-induced SMC proliferation are initiated through multiple 5-HT receptors and serotonin transporter at the cell surface.

Serotonin (5-HT) stimulates smooth muscle cell growth through 5-HT receptors and the 5-HT transporter (5-HTT), and has been associated with pulmonary hypertension (PH). Platelet-derived growth factor receptors (PDGFR) have also been associated with PH. We present evidence for the first time that 5-HT transactivates PDGFRbeta through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRbeta phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRbeta activation by 5-HT. Notably, 5-HTT binds the PDGFRbeta upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRbeta activation. Activation of PDGFRbeta may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRbeta phosphorylation is blocked by the antioxidant N-acetyl-L-cysteine and the NADPH oxidase inhibitor, DPI. Inhibition of PDGFR kinase with imatinib or AG1296 significantly inhibits SMC proliferation and migration induced by 5-HT in vitro. Infusion of 5-HT by miniosmotic pumps enhances PDGFRbeta activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRbeta in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.

Background: Water immersion during the first stage of labor can reduce the length of the first stage and epidural/ spinal analgesia use; however, there is limited information regarding other outcomes. Our purpose was to compare maternal and neonatal outcomes of women who underwent water immersion during the first stage of labor with those who underwent conventional labor and delivery.

The field of spintronics has attracted significant attention since it promises new semiconductor device functionality through functionalization of both electron charge and spin degrees of freedom. Dilute magnetic semiconductors (DMS) which are formed by partial replacement of cations in a nonmagnetic semiconductor by magnetic transition metal ions are promising materials for spintronic devices since they possess charge and spin degrees of freedom in a single substance. [1] Earlier work on Mn-substituted GaAs demonstrated the potentiality of DMS materials.[2] However, the ferromagnetic transition temperature was low (T c ∼ 150 K). Theoretical predictions [3,4] of room temperature ferromagnetism (FM) in DMS has generated considerable interest in studying transition metal doped ZnO. The origin of FM in these transition metal doped oxides is not yet fully understood. Mechanisms based on carrier-induced ferromagnetism [3,4] and percolation of bound magnetic polarons [5][6][7] have been proposed. Cobaltdoped ZnO is considered to be very promising for DMS. [8][9][10][11][12][13][14][15][16][17] While there have been reports of irreproducibility of sample properties [8] as well as uncertainties about whether Co clusters are responsible for ferromagnetism, [12] there is also very strong evidence for intrinsic, ferromagnetism, and in some cases switchable, in samples made by careful chemical synthesis routes. [18][19][20] The role of defects in mediating ferromagnetism in cobaltdoped ZnO has been demonstrated by several groups. [16,20,21] The defect chemistry of ZnO is very complex, with Zn interstitials, Zn vacancies, oxygen interstitials and vacancies all known to be present in varying concentrations. [22,23] Hence, experiments to change single variables are not trivial. On the other hand, depending on processing conditions, the predominant defects are Zn interstitals and/or oxygen vacancies [24,25] and so from careful annealing studies it should be possible to distinguish the lattice variations arising from these two defect types. This paper reports on the properties of as-grown and postannealed pure ZnO and Co-doped ZnO epitaxial films grown by ultrasonic assisted solution chemical vapour deposition (UASCVD) at low temperatures. Using this method, a wide variety of doping levels are easily explored simply through changing solution composition. We show that after only one short, low temperature anneal of Zn 0.98 Co 0.02 O, M s is reduced, and at the same time so is the 'c' axis lattice parameter. The results can only be explained by a reduction of Zn concentration. Hence, measurement of the 'c' parameter provides a simple diagnostic tool for assessing whether Zn interstitials are present or not. Considering the very wide range of properties of doped-ZnO (e.g., high transparency, piezoelectricity, wide bangap semiconductivity, magnetoresistivity, magnetooptic, electro-optic and chemical sensing properties) and the need to control defects and associated charge carriers in these applications, the result of this work has br...

Colloidal quantum dots (QDs) combined with a graphene charge transducer promise to provide a photoconducting platform with high quantum efficiency and large intrinsic gain, yet compatible with cost-efficient polymer substrates. The response time in these devices is limited, however, and fast switching is only possible by sacrificing the high sensitivity. Furthermore, tuning the QD size toward infrared absorption using conventional organic capping ligands progressively reduces the device performance characteristics. Here we demonstrate methods to couple large QDs (>6 nm in diameter) with organometal halide perovskites, enabling hybrid graphene phototransistor arrays on plastic foils that simultaneously exhibit a specific detectivity of 5 × 10 Jones and high video-frame-rate performance. PbI and CHNHI co-mediated ligand exchange in PbS QDs improves surface passivation and facilitates electronic transport, yielding faster charge recovery, whereas PbS QDs embedded into a CHNHPbI matrix produce spatially separated photocarriers leading to large gain.