Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling. CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. .
6-Benzimidazolylpyridyl-2-carboximidic half-titanocene complexes, Cp 0 TiLCl (Cp 0 ¼ C 5 H 5 , MeC 5 H 4 , C 5 Me 5 , L ¼ 6-benzimidazolylpyridine-2-carboxylimidic, C1-C13), were synthesized and characterized along with single-crystal X-ray diffraction. The half-titanocene chlorides containing substituted cyclopentadienyl groups, especially pentamethylcyclopentadienyl groups were more stable, while those without substituents on the cyclopentadienyl groups were easily transformed into their dimeric oxo-bridged complexes, (CpTiL) 2 O (C14 and C15). In the presence of excessive amounts of methylaluminoxane (MAO) or modified methylaluminoxane (MMAO), all half-titanocene complexes showed high catalytic activities for ethylene polymerization. The substituents on the Cp groups affected the catalytic behaviors of the complexes significantly, with less substituents favoring increased activities and higher molecular weights of the resultant polyethylenes. Effects of reaction conditions on catalytic behaviors were systematically investigated with catalytic systems of mononuclear C1 and dimeric C14. With C1/MAO, large MAO amount significantly increases the catalytic activity, while the temperature only has a slight effect on the productivity. In the case of C14/MAO catalytic system, temperature above 60 8C and Al/Ti value higher than 5000 were necessary to observe good catalytic activities. In both systems, higher reaction temperature and low cocatalyst amount gave the polyethylenes with higher molecular weights. V
Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae) infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC) around 32–512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive) were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.
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