ABSTRACT. Six adult healthy Beagles were used to investigate the hepatic perfusion dynamics of Levovist, a contrast agent used in contrast harmonic imaging (CHI). In addition, 8 dogs with hepatocellular carcinoma (HCC) and 2 dogs with metastatic hepatic hemangiosarcoma (HSA) were used to characterize both the CHI findings with Levovist. In the Beagles, the start of intravenously injected Levovist into the aorta between the cranial mesenteric and renal arteries and the portal vein at the hepatic hilum were 5.47 ± 1.52 sec and 16.03 ± 3.39 sec, respectively. As a characteristic CHI finding in the 8 dogs with HCC, the early arterial phase showed a fine network of blood flow enhanced at the surrounding region and within the tumor in all the 8 dogs (100%), and the post vascular phase demonstrated a defect in the whole tumor and an enhancement of the surrounding hepatic tissues in 7 dogs (87.5%). In the 2 dogs with HSA, characteristic finding in which the early arterial and late vascular phases showed a rim contrast enhancement pattern, and the post vascular phase revealed that the whole tumor lacked contrast enhancement and the surrounding hepatic tissues was clearly enhanced. In dogs, the start of the early arterial and late vascular phases, and the characterizations of the CHI findings in HCC and HSA were suggested to be similar to those in humans. Therefore, CHI is thought to be useful for the diagnosis of HCC and metastatic hepatic HSA in dogs as well as in humans.
Calcium signals trigger the translocation of the Prz1 transcription factor from the cytoplasm to the nucleus. The process is regulated by the calcium-activated phosphatase calcineurin, which activates Prz1 thereby maintaining active transcription during calcium signalling. When calcium signalling ceases, Prz1 is inactivated by phosphorylation and exported to the cytoplasm. In budding yeast and mammalian cells, different kinases have been reported to counter calcineurin activity and regulate nuclear export. Here, we show that the Ca2+/calmodulin-dependent kinase Cmk1 is first phosphorylated and activated by the newly identified kinase CaMKK2 homologue, Ckk2, in response to Ca2+. Then, active Cmk1 binds, phosphorylates and inactivates Prz1 transcription activity whilst at the same time cmk1 expression is enhanced by Prz1 in response to Ca2+. Furthermore, Cdc25 phosphatase is also phosphorylated by Cmk1, inducing cell cycle arrest in response to an increase in Ca2+. Moreover, cmk1 deletion shows a high tolerance to chronic exposure to Ca2+, due to the lack of cell cycle inhibition and elevated Prz1 activity. This work reveals that Cmk1 kinase activated by the newly identified Ckk2 counteracts calcineurin function by negatively regulating Prz1 activity which in turn is involved in activating cmk1 gene transcription. These results are the first insights into Cmk1 and Ckk2 function in Schizosaccharomyces pombe.
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