The new HIV-1 NNRTI drug Etravirine (TMC125) and a promising drug candidate Rilpivirine (TMC278) in phase III clinical trial are compounds belonging to the diarylpyrimidine (DAPY) family. They are extremely high potent against both wild-type and many drug-resistant HIV-1 strains, providing new hope for HIV-infected patients who fail to use current drugs due to the emergence of drug-resistant HIV mutants. The discovery and development of DAPY derivatives as next-generation NNRTI drugs depend on multidisciplinary coordination and their success has encouraged new researches to explore more next-generation NNRTIs with new scaffolds. This review described the story of discovery and development of DAPY derivatives as next-generation NNRTIs and related progress.

Objective To study the effect and mechanisms of TW-37 on cell proliferation,apoptosis,invasion and angiogenesis in pancreatic cancer cells in vitro and further explore the potential mechanism.Methods BxPC3 and HPAC cells were pretreated with TW-37 using untransfected or transfected with NF-κB p65 cDNA(p65 cDNA)or NF-κB p65 siRNA(siRNA-p65)cells as controls.Cell viability was determined by MrTT assay.Cell apoptosis was assessed by enzyme-linked immunosorbent assay (ELISA).Cell invasion and angiogenesis was detected by Transwell and endothelial tube formation assay of HUVECs.ELISA assay was used to measure the activity of NF-κB,and its target proteins of MMP-9 and VEGF were detected by western blot.Results TW-37 suppressed cell growth and induced apoptosis (A405:1.29 ± 0.21 vs 0.09 ± 0.01,1.07 s0.18 vs 0.08 ± 0.01),inhibited NF-κB activity and protein expression of NF-κB p65,VEGF and MMP-9(all P ＜0.05)in a dose-and time-dependent manner.The number of cells that invaded across the matrigel in the transwell chamber was (46.7 ±5.24) and (10.3 ± 1.26)/×200 in BxPC3 control and 0.75 μmol/L TW-37 group (P=0.001).The number of tube formation was (39.4 ±4.36) and (7.84 ± 1.25)/×200,(P =0.001).NF-κB activity was increased by p65 cDNA transfection,and decreased by TW-37 treatment in both of the two cell lines (P ＜0.05).However,NF-κB activity was decreased by p65 siRNA transfection,and greatly decreased by TW-37 treatment in both two cell lines (P ＜0.05 or P ＜0.01).Transfection of p65 cDNA did not significantly affect cell apoptosis.Transfection of p65 siRNA increased cell apoptosis,and greatly increased by TW-37 treatment in both two cell lines (all P ＜ 0.01).Conclusions TW-37 could inhibit the proliferation,invasion and angiogenesis in pancreatic cancer cells by regulating NF-κB signal pathway.

The biotransformation, CYP reaction phenotyping, the impact of CYP inhibitors and enzyme kinetics of 3-cyanomethyl-4-methyl-DCK (CMDCK), a new anti-HIV preclinical candidate belonging to DCK analogs, were investigated in human intestinal microsomes and recombinant cytochrome P450 (CYP) enzymes. CMDCK (4 micromol L(-1)) was incubated with a panel of rCYP enzymes (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remaining parent drug in incubates was quantitatively analyzed by a LC-MS method. CYP3A4 was identified as the principal CYP isoenzyme responsible for its metabolism in intestinal microsomes. The major metabolic pathway of CMDCK was oxidation and a number of oxidative metabolites were screened with LC-MS. The Km, Vmax, CLint and T1/2 of CMDCK obtained from human intestinal microsome were 45.6 micromol L(-1), 0.33 micromol L(-1) min(-1), 12.1 mL min(-1) kg(-1) and 25.7 min, respectively. Intestinal clearance of CMDCK was estimated from in vitro data to be 3.3 mL min(-1) kg(-1), and was almost equal to the intestinal blood flow rate (4.6 mL min(-1) kg(-1)). The selective CYP3A4 inhibitors, ketoconazole, troleandomycin and ritonavir demonstrated significant inhibitory effects on CMDCK intestinal metabolism, which suggested that co-administration of CMDCK with potent CYP3A inhibitors, such as ritonavir, might decrease its intestinal metabolic clearance and subsequently improve its bioavailability in body.

Objective To study the changes of resting-state brain activity in knee osteoarthritis(KOA)patients with chronic pain.Methods The data of 21 KOA patients (KOA group) and 21 healthy controls (HC group) who underwent standard resting-state fMRI scan were analyzed with regional homogeneity (ReHo) method to observe the changes in the patients in contrast to the controls.Results Compared to HC group,patients of the KOA group showed ReHo changes in bilateral frontal lobe,bilateral parietal lobe,bilateral temporal lobe,bilateral cerebellum,limbic system and default-mode network.Conclusion Patients with chronic pain demonstrate abnormal neuron activities in the brain regions, and control loops not only related with pain but also related with emotive function disorder and cognitive impairment.

BACKGROUNDIn recent years, computers have been intensively used at home. In contrast to paper-based books and documents, computer screen is self-illuminated with larger screen-background luminance difference, which greatly induces visual discomfort. To compensate for that, one effective solution is to offer an additional background luminance. In this study, we investigated whether and to what extent additional background lighting is needed in looking at a computer display comfortably.

METHODSIn this study, 60 healthy children aged from 9 to 12 years and 58 adults aged from 21 to 39 years participated in the experiments. They were asked to choose their most preferred background luminance intensities at three screen luminance levels. The data were analyzed by Matlab (R2012b) and SPSS 20.0.

RESULTSBoth children and adult participants selected a non-dark background as their comfortable lighting condition when watching a computer display (children: t (59) = 22.0, P < 0.01, adults: t (57) = 15.5, P < 0.01). Comparatively, children preferred brighter background in general ( F (1,116) = 7.0, P < 0.01). More importantly, participants' preferred background luminance levels were linearly correlated with screen luminance intensities (children: slope = 0.97, R(2) = 0.98; adults: slope = 0.38, R(2) = 1.00).

CONCLUSIONThese results indicate that varying background luminance to maintain screen-background luminance ratio is beneficial to human visual comfort.

Adult ; Child ; Computers ; Contrast Sensitivity ; physiology ; Female ; Humans ; Lighting ; Male ; Myopia ; prevention & control ; Young Adult