Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 Å. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.angiogenesis | cancer | phosphorylation | protein kinases | surface receptors V ascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis by binding to and activating the three members of the VEGF-receptor (VEGFR) family of receptor tyrosine kinases (RTKs) (1). VEGFR1 (Flt1), VEGFR2 (KDR/Flk1) and VEGFR3 (Flt4) are members of type-V RTK; a family containing a large extracellular region composed of seven Ig-like domains (D1-D7), a single transmembrane (TM) helix and cytoplasmic region with a tyrosine kinase activity, and additional regulatory sequences. The second and third Ig-like domains, D2 and D3, of VEGFR ectodomains function as binding sites for the VEGF family of cytokines (i.e., VEGF-A, -B, -C, -D, and placenta growth factor) (2, 3). These growth factors are covalently linked homodimers. Each protomer is composed of four-stranded β-sheets arranged in an antiparallel fashion in a structure designated cysteine-knot growth factors (4). It was shown that VEGF-A stimulation of VEGFR2 induces endothelial cell proliferation, survival, and migration resulting in blood vessel formation and sprouting (5). On the other hand, VEGF-C activation of VEGFR3 plays an important role in the formation of the lymphatic vessel system (6, 7). Aberrant activation or expression of VEGF receptors and their ligands has been implicated in tumor angiogenesis, coronary artery disease, diabetic blindness, and other diseases (5).Other members of the cysteine-knot family of cytokines include nerve growth factor and platelet-derived growth factors (PDGFs). However, the ectodomains of the PDGF-receptor (PDGFR) fami...

Objective: This study was designed to compare the clinical efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma (HCC). Methods: From March 2015 to August 2015, a total of 44 patients with moderate and advanced HCC, who were admitted in the Navy General Hospital of China, were included into this study. These patients were randomly divided into 2 groups: group A and group B. Patients in group A underwent TACE alone, while patients in group B underwent the combined treatment of TACE with apatinib. Differences in preoperative general data between these 2 groups were not statistically significant (P > 0.05). All patients were followed up for 12-18 months. Changes in a-fetal protein (AFP) at 3 months after treatment and the objective response rate (ORR) at 3, 6, 9 and 12 months after treatment were compared between these 2 groups. Furthermore, progression-free survival (PFS) and the incidence of adverse reactions were also compared between these 2 groups. Results: AFP levels in groups A and B significantly decreased after 3 months of treatment, compared with the levels before treatment, and the differences were statistically significant (P < 0.05). However, at 3 months after treatment, the difference between these 2 groups was not statistically significant (P > 0.05). ORR at 3, 6, 9 and 12 months after treatment was 36.36%, 27.27%, 13.64% and 9.09%, respectively, in group A; and 60%, 50%, 45% and 35%, respectively, in group B. At 3 and 6 months after treatment, the differences between these 2 groups were not statistically significant (P > 0.05); while at 9 and 12 months after treatment, the differences between these 2 groups were statistically significant (P < 0.05). The median PFS was 6.0 months in group A and 12.5 months in group B, and the difference was statistically significant (P < 0.05). The incidences of complications were related to oral apatinib, such as hypertension, hand-foot syndrome and proteinuria, were higher in group B than in group A, and the differences were statistically significant (P < 0.05). These symptoms all alleviated after symptomatic treatments. Conclusions: For intermediate and advanced HCC, the long-term curative effect of TACE combined with apatinib is better than that of TACE alone. The former can obviously prolong the PFS of patients and has a confirmed safety.

(18)F-FDG uptake, as measured by the SUV(max) before radiotherapy and metabolic response after radiotherapy, may predict the prognosis in locally advanced NPC. High (18)F-FDG uptake before and after radiotherapy may be useful for identifying patients requiring more aggressive treatment.

Long non-coding RNAs (lncRNAs) have been proved to play important roles in the tumorigenesis and development of several human malignancies. Our study aims to investigate the expression and function of lncRNA-UCA1 in osteosarcoma. lncRNA-UCA1 expression was detected in osteosarcoma tissues and cell lines by using qRT-PCR. Association between lncRNA-UCA1 levels and clinicopathological factors and patient's prognosis was analyzed. The roles of lncRNA-UCA1 in regulating osteosarcoma cell proliferation, apoptosis, migration, and invasion were evaluated in vitro. We found that lncRNA-UCA1 expression was upregulated in osteosarcoma tissues and cell lines. High lncRNA-UCA1 expression was significantly correlated with large tumor size, high tumor grade, positive distant metastasis, and advanced clinical stage. Multivariate regression analysis identified lncRNA-UCA1 overexpression as an independent unfavorable prognostic factor. lncRNA-UCA1 knockdown inhibited osteosarcoma cell proliferation, promoted cell apoptosis, and suppressed cell invasion and migration, whereas lncRNA-UCA1 overexpression showed opposite effects. These findings suggested that lncRNA-UCA1 may contribute to osteosarcoma initiation and progression, and would be not only a novel prognostic marker but also a potential therapeutic target for this disease.

Oxindoles are important heterocycles found in a wide range of bioactive natural products and pharmaceutical molecules. [1,2] In addition, functionalized oxindoles are versatile synthetic blocks for the preparation of natural products and in asymmetric synthesis. As a result, considerable efforts were directed toward the development of efficient methods for their synthesis, [1][2][3][4][5][6][7] with metal-catalyzed cyclization/functionalization approaches becoming increasingly popular because of their particular efficiency. [2][3][4][5][6] However, these approaches suffer from use of both expensive and commercially not available ortho-functionalized anilines and noble-metal catalysts, thereby limiting their wide application in organic chemistry research and industry. [2][3][4] Recently, ortho-nonfunctionalized anilines were found to be viable substrates for metal-mediated direct aryl C(sp 2 )-H functionalization/cyclization reactions, however, these transformations are quite rare. [5, 6] In 2003, Hennessey and Buchwald first used ortho-nonfunctionalized anilines (achloroacetanilides) in the formation of oxindole by a variant of the Friedel-Crafts procedure through palladium-catalyzed CÀH functionalization in the presence of 2-(di-tert-butylphosphino)-biphenyl (ligand) and Et 3 N (base). [5a] Subsequently, Jia and Kündig developed a direct intramolecular oxidative coupling of an aryl C(sp 2 )-H bond and a C(sp 3 )-H center for the preparation of 3,3-disubstituted oxindoles, even though these reactions needed a stoichiometric amount of Cu catalyst combined with a base. [5b,c] Very recently, the groups of Neuville and Zhu [6a] and Liu and co-workers [6b-d] independently established a very useful access to oxindoles by Pdcatalyzed oxidative difunctionalization of alkenes in Narylacrylamides under acidic or neutral conditions. These Pd-catalyzed oxidative transformations are more fascinating than the methods reported earlier, [5] because additional functional groups can be introduced into the oxindole framework; however, use of highly expensive Pd/hypervalent iodine reagent systems make their application less desirable. [6] Herein, we report a new oxidative 1,2-alkylarylation of activated alkenes with an aryl C(sp 2 )ÀH bond and a C(sp 3 )À H bond adjacent to a heteroatom for selective synthesis of functionalized 3-(2-oxoethyl)indolin-2-ones. This oxidative 1,2-alkylarylation is catalyzed by economical and environmentally benign iron [8] and involves the use of tert-butyl hydrogenperoxide (TBHP) as oxidant and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, L5) as ligand (Scheme 1). To the best of our knowledge, this work represents the first example of metal-catalyzed difunctionalization of an alkene with an aryl C(sp 2 ) À H bond and a C(sp 3 ) À H bond adjacent to a heteroatom. [6b-d, 9] We initially studied the reaction of N-methyl-N-phenylmethacrylamide (1 a; 0.3 mmol) with Et 2 O (2 a; 20 equiv), FeCl 3 (5 mol %) in benzene at 120 8C under argon atmosphere (entry 1 in Table 1), and were able to isolate the d...