Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia.

Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors.

Moderate intensity static magnetic fields affect mitotic spindles and increase the antitumor efficacy of 5-FU and Taxol.

Microtubules are the fundamental components in mitotic spindle, which plays essential roles in cell division. It was well known that purified microtubules could be affected by static magnetic fields (SMFs) in vitro because of the diamagnetic anisotropy of tubulin. However, whether these effects lead to cell division defects was unknown.

Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia.

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM).

Angiopoietin-like protein 3 is an indicator of prognosis in esophageal cancer patients.

Angiopoietin-like protein 3 (ANGPTL3) plays an important role in angiogenesis. This study aimed to examine the protein expression of ANGPTL3, and to evaluate its clinical significance in esophageal cancer. ANGPTL3 expression was detected using immunohistochemistry in 98 pairs of esophageal cancer and adjacent non-cancerous tissues.

Sgf73, a subunit of SAGA complex, is required for the assembly of RITS complex in fission yeast.

RNA interference (RNAi) is a widespread gene-silencing mechanism and is required for heterochromatin assembly in a variety of organisms. The RNA-induced transcriptional silencing complex (RITS), composed of Ago1, Tas3 and Chp1, is a key component of RNAi machinery in fission yeast that connects short interference RNA (siRNA) and heterochromatin formation. However, the process by which RITS is assembled is not well understood.

Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells.

Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M 'gatekeeper' mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models.

Plasmonic silver quantum dots coupled with hierarchical TiO2 nanotube arrays photoelectrodes for efficient visible-light photoelectrocatalytic hydrogen evolution.

A plasmonic Ag/TiO2 photocatalytic composite was designed by selecting Ag quantum dots (Ag QDs) to act as a surface plasmon resonance (SPR) photosensitizer for driving the visible-light driven photoelectrocatalytic hydrogen evolution. Vertically oriented hierarchical TiO2 nanotube arrays (H-TiO2-NTAs) with macroporous structure were prepared through a two-step method based on electrochemical anodization. Subsequently, Ag QDs, with tunable size (1.

C60-decorated CdS/TiO2 mesoporous architectures with enhanced photostability and photocatalytic activity for H2 evolution.

Fullerene (C60) enhanced mesoporous CdS/TiO2 architectures were fabricated by an evaporation induced self-assembly route together with an ion-exchanged method. C60 clusters were incorporated into the pore wall of mesoporous CdS/TiO2 with the formation of C60 enhanced CdS/TiO2 hybrid architectures, for achieving the enhanced photostability and photocatalytic activity in H2 evolution under visible-light irradiation. Such greatly enhanced photocatalytic performance and photostability could be due to the strong combination and heterojunctions between C60 and CdS/TiO2.

The biological characteristics of a novel camptothecin-artesunate conjugate.

A novel conjugate of camptothecin and artesunate (C-Q) was prepared and its cytotoxicity was evaluated using the MTT assay. In addition, the antitumour activity and toxicity of C-Q were investigated in mice, and interaction between transferrin (TF) and C-Q was investigated to evaluate its interaction with biological macromolecules. In the MTT assay, C-Q showed better inhibitory activity against MCF7 breast cancer cells and SMMC-7721 liver cancer cells than camptothecin or artesunate.

Ionic liquid-aqueous solution ultrasonic-assisted extraction of three kinds of alkaloids from Phellodendron amurense Rupr and optimize conditions use response surface.

In this paper, we chose diffident kinds of ionic liquids to optimal selection an optimal one to extract alkaloids from Phellodendron amurense Rupr. Four ionic liquids with diffident carbon chains or anions have been investigated and 1-butyl-3-methylimidazolium bromide with best productivity. Then, selections have been optimized in different conditions, including concentration of ionic liquid, time for ultrasonic treatment, ultrasonic power and solid-liquid ratio.

Introduction on the fabrication technique of phosphor in glass by tape-casting and investigation on the chromaticity property.

We introduce a new fabrication technique of phosphor in glass (PiG) for light-emitting diodes (LEDs) employing the tape-casting. Through the detailed process described herein and the measurement results, it is clear that the PiG-on-glass not only share the same characteristic of those obtained from other techniques or the bulk PiG, but with more precisely controlled width from a few to hundreds micrometers. The samples are mounted on blue InGaN LED chips to test the color properties of the white light.

[Ash2, a subunit of histone H3K4 methyltransferase complex, is involved in the sporulation in Schizosaccharomyces pombe].

Schizosaccharomyces pombe undergoes meiosis instead of mitosis under conditions of nitrogen starvation and pheromone signalling, which results in conjugation and sporulation. During this progress, the pheromone-responsive MAPK(Mitogen-activated protein kinases) pathway plays an important role in regulating the conjuation and the transcriptional activation of genes required for meiosis. Spk1, a key component of MAPK pathway, activates Ste11 through protein phosphorylation and then induced the transcriptions of several genes requied for meiosis, including mei2(+), mam2(+) and map3(+).

Gene repression. H3K27me and PRC2 transmit a memory of repression across generations and during development.

For proper development, cells must retain patterns of gene expression and repression through cell division. Repression via methylation of histone H3 on Lys27 (H3K27me) by Polycomb repressive complex 2 (PRC2) is conserved, but its transmission is not well understood. Our studies suggest that PRC2 represses the X chromosomes in Caenorhabditis elegans germ cells, and this repression is transmitted to embryos by both sperm and oocytes.

Utility of the Asia-Pacific colorectal screening scoring system and the presence of metabolic syndrome components in screening for sporadic colorectal cancer.

Aim: To determine the utility of the Asia-Pacific colorectal screening (APCS) scoring system and metabolic syndrome components in individual screening for sporadic colorectal cancer.

Methods: The subjects were patients admitted to the Peking University People's Hospital for colonoscopy between October 2012 and July 2013. Clinical information, including patient willingness to undergo colonoscopy, medical history, endoscopic findings, histology, and other information, was collected, and the patients were grouped according to APCS scores and the presence of metabolic syndrome components.

Tetrachloro-p-benzoquinone induces hepatic oxidative damage and inflammatory response, but not apoptosis in mouse: the prevention of curcumin.

This study investigated the protective effects of curcumin on tetrachloro-p-benzoquinone (TCBQ)-induced hepatotoxicity in mice. TCBQ-treatment causes significant liver injury (the elevation of serum AST and ALT activities, histopathological changes in liver section including centrilobular necrosis and inflammatory cells), oxidative stress (the elevation of TBAR level and the inhibition of SOD and catalase activities) and inflammation (up-regulation of iNOS, COX-2, IL-1β, IL-6, TNF-α and NF-κB). However, these changes were alleviated upon pretreatment with curcumin.

Impact resistance of different factors on ammonia removal by heterotrophic nitrification-aerobic denitrification bacterium Aeromonas sp. HN-02.

To give reference for the application of heterotrophic nitrification-aerobic denitrification bacteria in actual wastewater treatment, the impact resistance of extreme pH, low temperature, heavy metals and high salinity on ammonia removal by a typical heterotrophic nitrifying-aerobic denitrifying bacterium Aeromonas sp. HN-02 was investigated. The results showed that HN-02 demonstrated strong acid- and alkali-resistance.

Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma.

BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM.

Protective effects of neohesperidin dihydrochalcone against carbon tetrachloride-induced oxidative damage in vivo and in vitro.

The purpose of this study was to investigate the possible hepatoprotective effects of neohesperidin dihydrochalcone (NHDC) on carbon tetrachloride (CCl4)-induced acute oxidative injury in vivo and in vitro. In a mouse model, intraperitoneal injection of CCl4 resulted in a significant increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities. Histopathological examination revealed severe hepatocyte necrosis and destruction of architecture in liver lesions, and immunohistochemical staining illustrated a remarkable enhancement of COX-2 and iNOS expression.

[The characteristics of gastroesophageal reflux disease overlapping with functional bowel diseases in gastrointestinal clinic].

Unlabelled: OBJECTIVE To analyze the common symptoms in our gastrointestinal (GI) clinic of a general hospital and the prevalence of gastroesophageal reflux disease (GERD) combined with functional bowel diseases (FBD) was also investigated.

Methods: Data of out-patients who visited GI clinic from April to June, 2011 were collected, including demographic information and chief complaints. A validated Chinese Reflux Disease Questionnaire (RDQ) was used to assess the frequency and severity of typical gastroesophageal reflux (GER) symptoms.

A new method for piercing the tentorium cerebelli for implanting fragile electrodes into the brain stem in the rhesus monkey (Macaca mulatta).

Recent developments in neuron recording techniques include the invention of some fragile electrodes. The fragility of these electrodes impedes their successful use in deep brain recordings because it is difficult to penetrate the electrodes through the dura mater, especially the tentorium cerebelli (TC) enclosing the cerebellum and brain stem. This paper reports a new method to pierce the TC for inserting fragile electrodes into the inferior colliculus of rhesus monkeys.

Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models.

Heterozygous germline mutations and deletions in PHOX2B, a key regulator of autonomic neuron development, predispose to neuroblastoma, a tumor of the peripheral sympathetic nervous system. To gain insight into the oncogenic mechanisms engaged by these changes, we used zebrafish models to study the functional consequences of aberrant PHOX2B expression in the cells of the developing sympathetic nervous system. Allelic deficiency, modeled by phox2b morpholino knockdown, led to a decrease in the terminal differentiation markers th and dbh in sympathetic ganglion cells.

Discovery of a selective irreversible BMX inhibitor for prostate cancer.

BMX is a member of the TEC family of nonreceptor tyrosine kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of prostate cancer cell lines.

G protein-coupled receptors participate in cytokinesis.

Cytokinesis, the last step during cell division, is a highly coordinated process that involves the relay of signals from both the outside and inside of the cell. We have a basic understanding of how cells regulate internal events, but how cells respond to extracellular cues is less explored. In a systematic RNAi screen of G protein-coupled receptors (GPCRs) and their effectors, we found that some GPCRs are involved in cytokinesis.

Dopamine receptor D3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI.

Macromolecules enter cells by endocytosis and are sorted to different cellular destinations in early/sorting endosomes. The mechanism and regulation of sorting are poorly understood, although transitions between vesicular and tubular endosomes are important. We found that the antihypertensive drug Prazosin inhibits endocytic sorting by an off-target perturbation of the G protein-coupled receptor dopamine receptor D(3) (DRD3).