N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model.
SUMMARYTo identify histamine-producing cells at the late phase of allergic in¯ammation, the expression of L-histidine decarboxylase (HDC) was examined in the in®ltrating leucocytes in the in¯ammatory locus. HDC activity and HDC mRNA levels in the in®ltrating leucocytes in the pouch¯uid of the immunized rats (that were injected with the antigen solution into the air pouch) were increased compared with those in the in®ltrating leucocytes of the non-immunized rats. When in®ltrating leucocytes collected 8 hr after antigen injection were cultured, histamine production by the cells from the immunized rats was higher than that from the non-immunized rats. In situ hybridization of HDC mRNA revealed that almost all the in®ltrating leucocytes of the immunized rats, 4 hr after injection of the antigen, expressed HDC mRNA with high intensity, while those of the nonimmunized rats showed only a weak intensity of HDC mRNA. In the immunized rats, < 90% of leucocytes in®ltrating in the pouch¯uid at 4 hr were neutrophils and 8% were monocytes/ macrophages. Neither mast cells nor basophils were detected in the in®ltrating leucocytes. When rat peritoneal neutrophils were incubated in the presence of 12-O-tetradecanoylphorbol 13-acetate, histamine production was signi®cantly increased. These ®ndings suggest that the leucocytes, mainly neutrophils, in®ltrating at the in¯ammatory locus are responsible for histamine production at the late phase of allergic in¯ammation.
BackgroundRoutine hemodynamic monitoring parameters under general anesthesia, such as heart rate (HR), systolic blood pressure (SBP), and perfusion index (PI), do not solely reflect intraoperative nociceptive levels. We developed a hemodynamic model combining these 3 parameters for nociceptive responses during general anesthesia, and evaluated nociceptive responses to surgical skin incision.Material/MethodsWe first retrospectively performed discriminant analysis using 3 values – HR, SBP, and PI – to assess response to skin incision during tympanoplasty, laparoscopic cholecystectomy, and open gastrectomy to determine if combined use of these parameters differentiates nociceptive levels among these 3 surgeries. Secondly, ordinal logistic regression analysis was applied using the 3 parameters to develop an equation representing nociceptive response during general anesthesia, and then evaluated its utility to discern nociceptive responses to skin incision.ResultsWe developed the following hemodynamic model as calculated nociceptive response= −1+2/(1+ exp(−0.01 HR −0.02 SBP +0.17 PI)), and prospectively determined that calculated nociceptive responses to small skin incision for laparoscopic surgery were significantly lower than responses to large skin incision for laparotomy.ConclusionsOur hemodynamic model using HR, SBP, and PI likely reflects nociceptive levels at skin incision during general anesthesia, and quantitatively discerned the difference in nociceptive responses to skin incision between laparoscopy and laparotomy. This model could be applicable to assess either real-time nociceptive responses or averaged nociceptive responses throughout surgery without using special equipment.
In recent years, we have experienced mega-flood disasters in Japan due to climate change. In the last century, we have been building disaster prevention infrastructure (artificial levees and dams, referred to as "grey infrastructure") to protect human lives and assets from floods, but these hard protective measures will not function against mega-floods. Moreover, in a drastically depopulating society such as that in Japan, farmland abandonment prevails, and it will be more difficult to maintain grey infrastructure with a limited tax income. In this study, we propose the introduction of green infrastructure as an adaptation strategy for climate change. If we can use abandoned farmlands as green infrastructure, they may function to reduce disaster risks and provide habitats for various organisms that are adapted to wetland environments. First, we present a conceptual framework for disaster prevention using a hybrid of green infrastructure and conventional grey infrastructure. In this combination, the fundamental green infrastructure, composed of forests and wetlands in the catchment (GI-1), and additional multilevel green infrastructures such as flood control basins that function when floodwater exceeds the planning level (GI-2) are introduced. We evaluated the flood attenuation function (GI-1) of the Kushiro Wetland using a hydrological model and developed a methodology for selecting suitable locations of GI-2, considering flood risk, biodiversity, and the distribution of abandoned farmlands, which represent social and economic costs. The results indicated that the Kushiro Wetland acts as a large natural reservoir that attenuates the hydrological peak discharge during floods, and suitable locations for introducing GI-2 are concentrated in floodplain areas developing in the downstream reaches of large rivers. Finally, we discussed the network structure of GI-1 as a hub and GI-2 as a dispersal site for conservation of the Red-crowned Crane, one of the symbolic species of Japan.
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