Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts.

The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional regulator critical in several types of diseases, including cancer, making it a promising therapeutic target. We have identified small-molecule inhibitors of HuR through a screening approach used in combination with fragment analysis. A total of 36 new compounds originating from fragment linking or structural optimization were studied to establish structure-activity relationships in the set. Two top inhibitors, 1c and 7c, were further validated by binding assays and cellular functional assays. Both block HuR function by directly binding to the RNA-binding pocket, inhibit cancer cell growth dependence of HuR, and suppress cancer cell invasion. Intraperitoneal administration of inhibitor 1c inhibits tumor growth as a single agent and shows a synergistic effect in combination with chemotherapy docetaxel in breast cancer xenograft models. Mechanistically, 1c interferes with the HuR-TGFB/THBS1 axis.

Design, synthesis, and cytotoxic activity of novel 2H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine derivatives.

In this study, a series of novel 2H-imidazo [1, 2-c] pyrazolo [3, 4-e] pyrimidine derivatives were designed, synthesized, and evaluated for their cytotoxic activities. The in vitro cell growth inhibition assay of the target compounds indicated their selectivity in inhibiting the proliferation of blood tumor cells (K562, U937) and solid tumor cells (HCT116, HT-29). Compound 9b exhibited the highest antiproliferative activities against K562 (IC50 = 5.597 µM) and U937 (IC50 = 3.512 µM). Based on the flow cytometry assays, compound 9b caused obvious induction of cell apoptosis and cell arrest at the S phase. Furthermore, western blot analysis revealed that compound 9b upregulated the expression of Bax, downregulated the levels of Bcl-2, and further activated caspase-3 in K562 cells. Therefore, compound 9b may be a potential anticancer agent that deserves further investigation.

A near-infrared fluorescent probe that can image endogenous hydrogen polysulfides in vivo in tumour-bearing mice.

Hydrogen polysulfides (H2Sn, n > 1), which are important reactive sulfur species, play crucial roles in H2S-related bioactivities, including antioxidation, cytoprotection, activation of ion channels, transcription factor functions and tumour suppression. Monitoring H2Snin vivo is of significant interest for exploring the physiological roles of H2Sn and the exact mechanisms of H2Sn-related diseases. Herein, we conceive a novel near-infrared fluorescent probe, NIR-CPS, that is used to detect H2Sn in living cells and in vivo. With the advantages of high sensitivity, good selectivity and a remarkably large Stokes shift (100 nm), NIR-CPS was successfully applied in visualizing H2Sn in living cells and mice. More importantly, NIR-CPS monitored H2Sn stimulated by lipopolysaccharide in tumour-bearing mice. These results demonstrate that the NIR-CPS probe is a potentially powerful tool for the detection of H2Snin vivo, thus providing a valuable approach in H2Sn-related medical research.

Design, synthesis, biological activity evaluation of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives as potent JAK 2/3 and aurora A/B kinases multi-targeted inhibitors.

In this study, a series of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives were designed, synthesized, and evaluated for their biological activities. Upon performing kinase assays, most of the compounds exhibited potent inhibition against JAK2/3 and Aurora A/B with the IC50 values ranging from 0.008 to 2.52 µM. Among these derivatives, compound 10e expressed the most moderate inhibiting activities against all the four kinases with the IC50 values of 0.166 µM (JAK2), 0.057 µM (JAK3), 0.939 µM (Aurora A), and 0.583 µM (Aurora B), respectively. Moreover, most of the derived compounds exhibited potent cytotoxicity against human chronic myeloid leukemia cells K562 and human colon cancer cells HCT116, while compound 10e expressed antiproliferative activities against K562 (IC50=6.726  µM). According to western blot analysis, compound 10e down-regulated the phosphorylation of STAT3, STAT5, Aurora A, and Aurora B in a dose-dependent manner in K562 and HCT116 cells. Cell cycle analysis revealed that compound 10e inhibited the proliferation of cells by inducing cell cycle arrest in the G2 phase. The molecular modeling suggested that compound 10e could maintain a binding mode similar to the binding mode of AT9832, a common JAK 2/3 and Aurora A/B kinases multi-target kinase inhibitor. Therefore, compound 10e might be a potential agent for cancer therapy deserving further research.

Design, synthesis and evaluation of calix[4]arene-based carbonyl amide derivatives with antitumor activities.

Calixarenes, with potential functionalization on the upper and lower rim, have been explored in recent years for the design and construction of anticancer agents in the field of drugs and pharmaceuticals. Herein, optimization of bis [N-(2-hydroxyethyl) aminocarbonylmethoxyl substituted calix [4] arene (CLX-4) using structure-based drug design and traditional medicinal chemistry led to the discovery of series of calix [4]arene carbonyl amide derivatives 5a-5t. Evaluation of the cytotoxicity of 5a-5t employing MTT assay in MCF-7, MDA-MB-231 (human breast cancer cells), HT29 (human colon carcinoma cells), HepG2 (human hepatocellular carcinoma cells), A549 (human lung adenocarcinoma cells) and HUVEC (Human Umbilical Vein Endothelial) cells demonstrated that the most promising compound 5h displayed the most superior inhibitory effect against A549 and MDA-MB-231 cells, which were 3.2 times and 6.8 times of CLX-4, respectively. In addition, the cell inhibition rate (at 10 µM) against normal HUVEC cells in vitro was only 9.6%, indicating the safty of compound 5h. Moreover, compound 5h could inhibit the migration of MDA-MB-231 cell in wound healing assay. Further mechanism studies significantly indicated that compound 5h could block MDA-MB-231 cell cycle arrest in G0/G1 phase by down regulating cyclin D1 and CDK4, and induce apoptosis by up-regulation of Bax, down-regulation of Caspase-3, PARP and Bcl-2 proteins, resulting in the reduction of DNA synthesis and cell division arrest. This work provides worthy of further exploration for the promising calixarene-based anticancer drugs.

Design, synthesis and biological evaluation of 4-aniline quinazoline derivatives conjugated with hydrogen sulfide (H2S) donors as potent EGFR inhibitors against L858R resistance mutation.

In this study, a series of 4-aniline quinazoline derivatives bearing hydrogen sulfide (H2S) donors were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for the enzymatic activities against EGFR and EGFR mutants by kinase target-based cell screening method. The results demonstrate that most compounds exhibit selectively inhibitory activities against TEL-EGFR-L858R-BaF3, especially compound 9h with GI50 = 0.008 µM (TEL-EGFR-L858R-BaF3), 0.0069 µM (TEL-EGFR-C797S-BaF3), >10 µM (BaF3), >10 µM (TEL-EGFR-BaF3) and 6.03 µM (TEL-EGFR-T790M-L858R-BaF3). The results from anti-proliferative assays in two NSCLC cell lines indicate that synthetic derivatives (9g, 9h, 15e and 15f) with H2S donor ACS81 display greater anti-proliferative potency against NSCLC cell line H3255 bearing EGFR mutant (L858R) with GI50 values ranging from 0.3486 to 1.348 µM. In addition, compound 9h exhibits weak anti-proliferative effects on other tumor cells (HepG2, MCF-7, HT-29 and A431) and has lower toxic effect on HUVEC cells than AZD9291 (positive control). Meanwhile, compound 9h inhibits the phosphorylation of EGFR in H3255 cells in a dose-dependent manner. Cell cycle analysis reveals that compound 9h suppresses the proliferation of cells by inducing cell cycle arrest in G0-G1 phase. The result of H2S release evaluation suggests that the H2S release of compound 9h is significantly more and faster than other compounds.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial.

OBJECTIVES: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. DESIGN: Prospective, randomized, controlled study. SETTING: Thirty-three hospitals in China. PATIENTS: A total of 710 adults 18-75 years old with severe community-acquired pneumonia. INTERVENTIONS: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9-21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4-15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). CONCLUSIONS: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

Preparation and in vitro bioactivity evaluation of N-heterocyclic-linked dihomooxacalix[4]arene derivatives.

Based on the superior prospects of calixarenes-based agents and N-heterocyclic pharmacophores in biomedical applications, 14 new dihomooxacalix[4]arene N-heterocyclic (pyridine, quinoline, and thiazole) derivatives 4a-4n were efficiently synthesized from the parent compound, namely, p-tert-butyldihomooxacalix[4]arene 1; they were further investigated by using their IR, 1H NMR, 13C NMR, and HRMS spectra. Among these derivatives, the crystal and molecular structures of 2-aminomethyl-pyridine-substituted dihomooxacalix[4]arene 4f (obtained from methanol) have been determined by X-ray diffraction. In the case of the inhibition assay of cell growth, we evaluated the effects on four select tumor cell lines (MCF-7, HepG2, SKOV3, and HeLa), as well as the normal cell lines of HUVEC, using paclitaxel as the positive control drug. It was found that the derivatives 4d-4f, 4i, 4k, and 4l could inhibit tumoral activity up to varying degrees. Mechanistically, the cell cycle analysis demonstrated that dihomooxacalix[4]arene N-heterocyclic derivatives could induce apoptosis of MCF cells. In addition, the results of the western blot and immunofluorescence studies revealed the upregulation of the protein expression levels of Bax and cleaved caspase-3, as well as the downregulation of Bcl-2, which are in good agreement with the corresponding inhibitory potencies. Therefore, these findings suggest that N-heterocyclic derivatives based on the dihomooxacalix[4]arene scaffold are promising candidates for use against cancer.

Structural Design, Synthesis, and Preliminary Biological Evaluation of Novel Dihomooxacalix[4]arene-Based Anti-tumor Agents.

Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives (n = 4, 6, 8) and found that 5,11,17,23-tetra-tert-butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene (CLX-4) displayed significant effect toward SKOV3, A549, SW1990, HeLa, Raji, and MDA-MB-231 cancer cells. In the present work, we find a replacement of calix[4]arene bone and synthesized 19 novel structurally related dihomooxacalix[4]arene amide derivatives 4A-4S to optimize its efficacy. Their abilities to induce cytotoxicity in human lung carcinoma (A549) cells, breast cancer (MCF-7) cells, cervical cancer (HeLa) cells, hepatocellular carcinoma (HepG2) cells, as well as human umbilical vein endothelial (HUVEC) cells are evaluated in vitro. Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC50 ranging from 0.6 to 20.1 µM. In particular, compounds 4A, 4D, and 4L explore markedly increased potency (IC50 value is 2.0 ± 0.5 µM, 0.7 ± 0.1 µM, and 1.7 ± 0.4 µM) over the cytotoxicity profiles of control CLX-4, whose IC50 value is 2.8 ± 0.3 µM. More interestingly, 4A also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC50 values of 1.0 ± 0.1 µM, 0.8 ± 0.2 µM, and 2.7 ± 0.4 µM. In addition, the results proved that our synthesized 4A has much lower toxicity (41%) to normal cells at a concentration of 10 µM than that of 4D (90%). To reveal the mechanisms, the key indicators including the cell cycle and apoptosis are observed by the flow cytometry analysis in MCF-7 cells. The results demonstrate that both 4A and 4D can induce the MCF-7 cell cycle arrest in G0/G1 phase and cell apoptosis. Therefore, our finding proves that the dihomooxacalix[4]arene amide derivatives are convenient platforms for potential supramolecular anticancer agents.

A reaction-based near-infrared fluorescent probe that can visualize endogenous selenocysteine in vivo in tumor-bearing mice.

Monitoring the fluctuations of endogenous selenocysteine (Sec) in vivo is of significant interest to understand the physiological roles of Sec and the mechanisms of Sec-relevant diseases. Herein, a new near-infrared fluorescent probe, Fsec-1, has been developed for the determination of endogenous Sec in living cells and in vivo. Fsec-1 exhibits large fluorescence enhancement (136-fold) and a remarkably large Stokes shift (195 nm) when reacted with Sec. With the advantages of high sensitivity (a detection limit of 10 nM), good selectivity and low cytotoxicity, Fsec-1 was able to recognize both exogenous and endogenous Sec in living cells. The probe was also successfully applied in visualizing both exogenous and endogenous Sec in living mice. Notably, endogenously generated Sec in living tumors xenografted in nude mice was selectively detected by our reaction-based NIR probe for the first time. These results indicated that our new probe could serve as an efficient tool in monitoring endogenous Sec in vivo and exploring the anticancer mechanism of selenium.

Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases.

The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins. In this study, a novel photoaffinity probe 11 was designed and synthesised to assess the target profiling of the reactive group in the photoaffinity probe 11. Biological evaluation was performed, and the results showed that the novel photoaffinity probe binds to EGFR and HER2 proteins and it hits targets by the reactive group.

Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors.

In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3 µM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50 = 0.0032 µM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.

Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives.

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 µM to 11.3 µM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.

Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticancer activities against HeLa, A549 and MCF-7 cell lines with IC50s of 35.26, 29.63 and 24.63 µM, respectively. Molecular docking studies suggested that M7594_0037 and its three derivatives could interact with HsPDF by several conserved hydrogen bonds. Moreover, the pharmacokinetic and toxicity properties of M7594_0037 and its derivatives were predicted using the OSIRIS property explorer. Thus, M7594_0037 and its derivatives might represent a promising scaffold for the further development of novel anticancer drugs.

Serum microRNA-365 in combination with its target gene TTF-1 as a non-invasive prognostic marker for non-small cell lung cancer.

BACKGROUND: MicroRNA (miR)-365 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) cells by targeting thyroid transcription factor 1 (TTF-1). AIM: To investigate miR-365 and TTF-1 mRNA expression in serum of NSCLC and their associations with patients' prognosis. METHODS: MiR-365 and TTF-1 mRNA expression in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR (qRT-PCR). RESULTS: MiR-365 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P<0.001), while TTF-1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P<0.001). In addition, low miR-365 expression and high TTF-1 expression, alone or in combination, were all significantly associated with poor differentiation (P=0.008, 0.008 and 0.001, respectively), advanced TNM stage (P=0.001, 0.005 and <0.001 respectively) and positive lymph node metastasis (P=0.02, 0.02 and 0.01, respectively) of NSCLC patients. Notably, NSCLC patients with combined low miR-365 expression and high TTF-1 expression (miR-365-low/TTF-1-high) had shortest overall survival (P<0.001). Furthermore, multivariate analysis showed that miR-365 expression (P=0.01), TTF-1 expression (P=0.01), and combined expression of miR-365 and TTF-1 (miR-365/TTF-1, P=0.001) were all independent prognostic factors for overall survival in NSCLC patients. CONCLUSIONS: Our data reveal that preoperative serum miR-365 and TTF-1 mRNA levels may be both effective indicators of tumor aggressiveness in human NSCLC. More interestingly, miR-365 and its target gene TTF-1 appear to be synergistic risk factors for the reduction in overall survival of patients with NSCLC.

Theoretical study on the structural and antioxidant properties of some recently synthesised 2,4,5-trimethoxy chalcones.

The free radical scavenging activity of a series of 2,4,5-trimethoxy chalcones has been computationally explored using the density functional theory (DFT) method. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The physiochemical parameters including O-H bond dissociation enthalpy (BDE), ionisation potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) have been calculated in gas phase and solvents. The order of antioxidant efficiencies predicted theoretically in this work is in good agreement with that reported by experimental results. The results obtained demonstrate that HAT would be the most favourable mechanism in the gas and benzene phases, whereas the SPLET mechanism is the thermodynamically preferred pathway in polar media. In addition, the importance of the A-ring on the radical scavenging capabilities of chalcones was also confirmed.

Down-regulation of microRNA-126 and microRNA-133b acts as novel predictor biomarkers in progression and metastasis of non small cell lung cancer.

OBJECTIVE: MiRNAs play crucial roles in progression of cancer. However, the underlying mechanisms of miRNAs in non small cell lung cancer are still poorly understood. The aim of this study was to investigate the expression level of microRNA-126 (miR-126) and microRNA-133b (miR-133b) and also their association with clinicopathological features in patients with non small cell lung cancer (NSCLC). METHODS: Total RNA was purified from NSCLC tissues and adjacent non-tumor tissues and then quantitative real-time PCR (qRT-PCR) was used to evaluate the expression rate of microRNAs. Furthermore, the association of miR-126 and miR-133b level with clinicopathological features and prognosis were evaluated. RESULTS: Our findings showed that expression of miR-126 was decreased in NSCLC tissues compared with adjacent non-tumor tissues. On the other hand, a lower expression of miR-133b was seen in NSCLC tissues when compared with adjacent non-tumor tissues. In term of miR-126, our results showed that miR-126 was associated with tumor stage and lymph nodes metastasis (P<0.05). In term of miR-133b, our finding indicated that decreased expression of miR-133b was correlated with advanced tumor stage and lymph nodes metastasis (P<0.05). Kaplan-Meier analysis and log-rank test indicated that patients with low expression of miR-126 and miR-133b had a shorter overall survival (log-rank test; P<0.05). Multivariate Cox proportional hazards model revealed that low expression of miR-126 and miR-133b, advanced tumor stage and lymph nodes metastasis were independent prognostic factors for overall survival of NSCLC patients. CONCLUSIONS: These findings suggested that miR-126 and miR-133b might play a key role in the progression and metastasis of NSCLC and would be applied as a novel therapeutic agent.

Effect of Avastin on the number and structure of tumor blood vessels of nude mice with A549 lung adenocarcinoma.

The aim of the present study was to investigate the effect of Avastin on the number and structure of tumor blood vessels of nude mice with A549 lung adenocarcinoma. A total of 30 nude mice were randomly divided into three groups, namely the control, the Avastin I (Avastin 3 mg/kg) and the Avastin II (Avastin 6 mg/kg) groups. Following treatment, ELISA was used to detect the expression level of vascular endothelial growth factor (VEGF) in tumor tissues. The microvascular density in tumor tissues and tumor vascular pericyte coverage was detected by immunofluorescence. The tumor growth and survival rate of mice in the three groups were also analyzed. Compared with the control group, the Avastin I and II groups exhibited significantly decreased VEGF levels and microvascular density in the tumor tissues, with the decrease in the Avastin II group being more prominent (P<0.05). After 7 days of treatment, the vascular pericyte coverage in the tumor tissues of mice in the Avastin I and II groups was significantly increased compared with that in the control group mice (P<0.05). Compared with the control group, the mice in the Avastin I and II groups exhibited a significantly decreased tumor growth rate and this effect was dose-dependent. The survival rate of mice in the Avastin I and II groups was significantly increased compared with that of the mice in the control group (P<0.05). In conclusion, Avastin significantly decreased the microvascular density of the tumor in nude mice with A549 lung adenocarcinoma and also significantly increased tumor vascular pericyte coverage, inhibited tumor growth and increased the survival rate of the mice, through its potent antiangiogenic activity.

Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer.

microRNA (miR)-138 has been recognized as a potential tumor suppressor via regulating 3-phosphoinositide-dependent protein kinase-1 (PDK1) expression in non-small cell lung cancer (NSCLC) cells. The aim of this study was to investigate miR-138 and PDK1 mRNA expression in serum of NSCLC and their associations with patients' prognosis. miR-138 and PDK1 mRNA expressions in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR. miR-138 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P < 0.001), while PDK1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P < 0.001). In addition, miR-138 downregulation and PDK1 upregulation were both significantly associated with advanced tumor-node-metastasis (TNM) stage (both P = 0.002) and positive lymph node metastasis (both P = 0.01) of NSCLC patients. Moreover, the overall survival of NSCLC patients with low miR-138 expression or high PDK1 mRNA expression was obviously shorter than those with high miR-138 expression or low PDK1 mRNA expression (both P < 0.001). Notably, NSCLC patients with combined miR-138 downregulation and PDK1 upregulation (miR-138-low/PDK1-high) had shortest overall survival (P < 0.001). Furthermore, multivariate analysis showed that miR-138 expression (P = 0.01), PDK1 expression (P = 0.01), and combined expression of miR-138 and PDK1 (miR-138/PDK1, P = 0.001) were all independent prognostic factors for overall survival in NSCLC patients. Deregulation of miR-138/PDK1 cascade may be implicated in carcinogenesis and cancer progression of human NSCLC. More importantly, miR-138 and PDK1 may synergistically predict patients' prognosis and their combination may represent a promising prognostic biomarker of human NSCLC.

Density functional theory study of the structure-antioxidant activity of polyphenolic deoxybenzoins.

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values. The results obtained prove that for the HAT mechanism, the most efficient system possessed ortho-dihydroxy functionality. The results suggested that HAT would be the most favourable mechanism for explaining the radical-scavenging activity of polyphenolic DOBs in the gas phase, whereas the SPLET mechanism is the thermodynamically favourable pathway in polar solvents.