Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor (F)VIIa. Recently, TF has been shown to promote cellular signaling, tumor growth, ...angiogenesis, and metastasis. In the present study, we examined the pathway by which TF-FVIIa complex induces cellular signaling in human breast cancer cells using the Adr-MCF-7 cell line. This cell line has high endogenous TF expression as measured by flow cytometry and expression of protease-activated receptors 1 and 2 (PAR1 and PAR2) as determined by reverse transcriptase-polymerase chain reaction analysis. Both PAR1 and PAR2 are functionally active as determined by induction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation using specific agonist peptides. We found that MAPK phosphorylation in this cell line was strongly induced by the combination of FVIIa and factor (F)X, but not by FVIIa alone at a concentration of FVIIa that approaches physiological levels. Induction of MAPK phosphorylation involved the formation of TF-FVIIa-FXa complex and occurred by a pathway that did not require thrombin formation, indicating a critical role for FXa generation. In addition, induction of MAPK phosphorylation was found to be independent of PAR1 activation. We then examined whether TF-FVIIa complex formation could promote tumor cell migration using a modified Boyden chamber chemotaxis assay. The combination of FVIIa and FX, but not FVIIa alone, strongly induced migration of tumor cells by a pathway that probably involves PAR2, but not PAR1 activation. MAPK phosphorylation was found to be required for the induction of cell migration by the combination of FVIIa and FX. These data suggest that TF-FVIIa-mediated signaling in human breast cancer cells occurs most efficiently by formation of the TF-FVIIa-FXa complex. One of the physiological consequences of this signaling pathway is enhanced cell migration that is probably mediated by PAR2, but not PAR1 activation.
Abstract Background and aims Drug-induced liver injury (DILI) is the most common cause of death from acute liver failure, and accounts for approximately 13% of cases of acute liver failure in the ...United States. The clinical presentation of DILI covers a wide spectrum, from asymptomatic liver test abnormalities to symptomatic acute liver disease, prolonged jaundice and disability, or overt acute or subacute liver failure. The aim of our study was to evaluate the number of DILI cases admitted to our Unit and to identify the drugs responsible. Thus, we reviewed all clinical records of patients with DILI admitted to our Unit from 1996 to 2006. Patients and methods A database was constructed, reporting demographic, clinical features at onset, laboratory results, suspected drugs and follow-up. Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data. Results Forty-six patients were admitted with a diagnosis of DILI. Presentation was jaundice in 22 patients and hepatic failure in 3 (all attributed to nimesulide). Liver damage was of a cytolytic pattern in 19 cases (41%), cholestatic in 15 (33%) and mixed in 12 (26%). Jaundice was found to be higher in nimesulide-induced liver damage compared to other drugs ( p = 0.007). Three out of 14 patients with nimesulide-induced DILI developed encephalopathy and/or ascites. Time of recovery in the nimesulide group was significantly lower than DILI from other drugs ( p < 0.001). Conclusion Non-steroidal anti-inflammatory drugs, psychotropic drugs and antimicrobials are the most common causes of DILI. Nimesulide-induced DILI is usually reversible upon discontinuation of the drug, but occasionally progresses to liver failure.
The increasing threat of emerging infectious diseases in both wildlife and humans has spurred interest in the causes of disease emergence, including the role of anthropogenic change. A prior field ...study of infection patterns in amphibians suggests that echinostome infection may be an emerging disease of green frogs Rana clamitans living in urbanized environments. We examined the impact of echinostome infection on green frog tadpoles at a wide range of developmental stages (Gosner stage 25-39). Echinostome infection was associated with green frog mortality rates of up to 40% in an early developmental stage, and none in later developmental stages. Tadpoles exposed to higher echinostome doses exhibited higher edema rates, a potential sign of compromised renal function. Histopathological analysis further supported the hypothesis that echinostome-induced tadpole mortality resulted from compromised renal function. Given that the timing of highest cercarial shedding can coincide with the most vulnerable stages of green frog tadpole development, echinostomes could significantly impact green frog survival in nature.
Recently, Flying Ad Hoc Networks (FANET) have been proposed to empower 5G networks to support complex missions and provide ubiquitous connectivity to heterogeneous devices. However, it is needed to ...cope with the limited UAV capabilities (e.g., limited available energy to supply engines and computing elements, limited computing capabilities), as well as with the need to provide network and application services as foreseen in highly dynamic and time varying 5G ecosystems. This paper presents for the first time a comprehensive framework that integrates a FANET with a 5G network, with the aim of providing services that can be even chained with each other. This model is comprehensive in the sense that it takes into account physical constraints of the devices, as well as features and requirements of traffic flows. For this framework, the paper proposes a mathematical optimization model, allowing Virtual Function (VF) placement and chaining, aimed at minimizing energy consumption and service unsatisfaction probabilities of the FANET as a whole without employing heuristics for the solution of the problem. Two placement strategies named MLP and WMP are introduced and compared with the standard placement strategy named NoShP. An extensive numerical analysis shows that MLP and WMP allow us to well catch network dynamics and to reduce the number of virtual functions needed while decreasing the power consumption, so increasing UAV flight time and network lifetime.
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