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Supplementary Tables 1, 2, and 3 and Supplementary Figures 1 and 2

Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine. Mol Cancer Ther; 9(11); 2993–3002. ©2010 AACR.

Previous studies have demonstrated that complexity and variation of event images are the major challenges in event classification. We approach the problem through an integrated methodology by utilizing Long Short-Term Memory network (LSTM) to fuse multiple Convolutional Neural Networks (CNNs). To address the issue of complexity, we use three specific CNNs to extract the scene, object and human visual cues respectively. To reduce the semantic gap and utilize the complementarity of the features in different levels, we choose AlexNet and VGG-16 network as the basic structures, and concatenate their outputs of the first fully-connected layer and the second fully-connected layer. Considering the contextual correlations between visual cues, we arrange the concatenations of three CNNs in the sequence of scene, object and human as a whole and put into the LSTM network. Particularly for context, we crop the images into five blocks as input and an individual image is supplemented with contextual features due to the temporal characteristics of the LSTM. We evaluate our method on the Web Image Dataset for Event Recognition (WIDER), and the obtained results demonstrate the effectiveness of all the above points. Compared with the state-of-the-art methods, the proposed method gives a considerable way for improving the performance on event classification.

Our previous studies demonstrated that Curc-mPEG454, a curcumin derivative modified with short-chain polyethylene glycol (PEG), not only increased the blood concentration of curcumin, but also retained its anti-inflammatory activity. Here, we aimed to evaluate the anti-fibrotic effect of Curc-mPEG454 on a rat liver fibrosis model induced by carbon tetrachloride (CCl4), and to explore the underlying mechanisms by integrating our total liver RNA sequencing (RNA-seq) data with recent liver single-cell sequencing (scRNA-seq) studies. 50 mg/kg and 100 mg/kg Curc-mPEG454 treatment significantly reduced the elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) induced by CCl4, and the incidence of liver cirrhosis decreased from 75% to 37% and 35%, respectively. RNA-seq analysis revealed that Curc-mPEG454 significantly upregulated aldehyde oxidase 1 (AOX1) while downregulated cytochrome p450 26A1 (CYP26A1) and cytochrome p450 26B1 (CYP26B1) resulting in restoring liver retinoic acid (RA) level, increased glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) expression to synthesize hepatic glutathione (GSH), and inhibited liver inflammation via down-regulating the Prostaglandin E Synthase 2 (PTGES2)/prostacyclin E2 (PGE2) signaling. Integrating scRNA-seq data revealed that Curc-mPEG454 effectively inhibited the expansion of scar-associated macrophage subpopulation and scar-producing myofibroblasts in the damaged liver, and remodeled the fibrotic niche via regulation of ligand-receptor interactions including platelet-derived growth factor-B (PDGF-B)/platelet-derived growth factor receptor-α (PDGFR-α) signaling. As a multi-target prodrug, PEGylated curcumin deserves further attention and research.

From the perspective of improving the thermodynamic properties of epoxy resin, it has become the focus of research to enhance the operational stability of GIS (Gas Insulated Substation) basin insulators for UHV (Ultra-High Voltage) equipment. In this paper, three aminosilane coupling agents with different chain lengths, (3-Aminopropyl)trimethoxysilane (KH550), Aminoethyl)-γ-aminopropyltrimethoxysilane (KH792) and 3-[2-(2-Aminoethylamino)ethylamino]propyl-trimethoxysilane (TAPS), were used to modify nano-SiO2 and doped into epoxy resin, respectively, using a combination of experimental and molecular dynamics simulations. The experimental results showed that the surface-grafted KH792 model of nano-SiO2 exhibited the most significant improvement in thermal properties compared with the undoped nanoparticle model. The storage modulus increased by 276 MPa and the Tg increased by 61 K. The simulation results also showed that the mechanical properties of the nano-SiO2 surface-grafted KH792 model were about 3 times higher than that of the undoped nanoparticle model, the Tg increased by 36.5 K, and the thermal conductivity increased by 24.5%.

Abnormal osteoclastic activation and secretion of cysteine proteinases result in excessive bone resorption, which is one of the primary factors in the development of bone metabolic disorders, such as rheumatoid arthritis and osteoporosis. Mammalian cystatins have been demonstrated to restrain osteoclastic bone resorption and to alleviate severe osteolytic destruction via blocking the activity of cysteine proteinases. However, the specific effects of parasite cystatins on the formation and function of osteoclasts remain unclear. The purpose of the current study was to explore the effects of cystatins from Schistosoma japonicum (Sj‑Cys) on macrophage colony‑stimulating factor (M‑CSF) and receptor activator of NF‑κB ligand (RANKL)‑induced osteoclast differentiation, as well as the underlying molecular mechanisms. Recombinant Sj‑Cys (rSj‑Cys) dose‑dependently restrained osteoclast formation, with a half‑maximal inhibitory concentration (IC50) value of 0.3 µM, and suppressed osteoclastic bone resorptive capability in vitro. The findings were based on tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays, respectively. However, the cell viability assay showed that the repression of rSj‑Cys on osteoclast formation did not depend on effects on cell viability or apoptosis. Based on the results of reverse transcription‑quantitative PCR and western blot analysis, it was found that rSj‑Cys downregulated the expression levels of osteoclastogenesis‑related genes and proteins, by interfering with M‑CSF and RANKL‑induced NF‑κB signaling and downstream transcription factors during early‑phase osteoclastogenesis. Overall, the results of the present study revealed that rSj‑Cys exerted an inhibitory role in osteoclast differentiation and could be a prospective biotherapeutic candidate for the treatment and prevention of bone metabolic disorders.

The minipig has become an animal of considerable interest in preclinical drug development. It has been used in toxicology research and in examining/establishing regulatory guidelines as a nonrodent animal model. We have reviewed some basic issues that one would want to consider in the development and testing of any animal model for humans. The pig is a reasonable alternative to the dog, but there are some clear limitations and unexplained disparities in the literature, which require further study; primary among these is the need for standardization in choice of breed and sex and routine protocols. The minipig offers numerous advantages over other established animal models, and it has similarities to the human with regard to anatomy, physiology, and biochemistry. The gastrointestinal tract is structurally and functionally similar to humans. This appears to be true for enzymes and transporters in the gut as well, but more study is needed. One major concern is assessment of oral drug absorption, especially with regard to potential food effects due to gastric emptying differences, yet this does not appear to be a consistent observation. Hepatic metabolism seems to reflect enzymatic patterns in humans, with some differences. Kidney function seems similar to humans but requires further study. We have analyzed literature data that suggest the pig would offer a reasonable model for human oral bioavailability and for allometric predictions of clearance. The minipig appears to be the model for dermal absorption in humans, and we discuss this in terms of literature data and our own in-house experience.

In this paper we propose to train an ensemble of classifiers from a single convolutional neural network (CNN) and softly combine these classifiers for scene categorization. Specifically, we explore the hierarchical structure of a CNN to extract multiple types of features from images, and train a multi-class classifier corresponding to each type of features. To combine these classifiers effectively, a soft combination strategy is introduced. Considering the fact that different images may need to be discriminated by using different types of features, we train a set of auxiliary binary-class classifiers to estimate the quality of categorizing an image by using the corresponding multi-class classifiers, so that a dynamic weight can be assigned to each of the multi-class classifiers for combination. On the other hand, because features extracted from different layers of a CNN differ largely in their levels of abstraction, classifiers trained based on these features have quite different capabilities for scene categorization. To address this issue, in the soft combination strategy we adopt the genetic algorithm to learn another set of static weights for the multi-class classifiers for combination. The static weights are to adapt the multi-class classifiers to given datasets. Finally, to categorize an image, the multi-class classifiers are combined by using both dynamic and static weights. We conduct experiments on two challenging benchmark datasets, MIT-indoor scene 67 and SUN397. Experiment results show that the proposed method is effective for scene categorization and can give superior results to state-of-the-art approaches.

[Image: see text] The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

CuBr ligated with N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA) is a common catalyst for atom transfer radical polymerization (ATRP). A catalyst/initiator ratio of 0.5–1 is generally required...

A series of combinations of alkyl halide with tertiary amine such as ethyl α-bromophenylacetate/tris[2-(dimethylamino)ethyl)]amine (αEBP/Me6TREN), ethyl 2-bromoisobutyrate/triethylamine (EBiB/TEA), and ethyl 2-chloropropionate/N,N,N′,N′,N′′-pentamethyldiethylenetriamine (ECP/PMDETA) have been developed as novel free radical initiators and used for the polymerizations of methyl acrylate (MA), methyl methacrylate (MMA) and styrene (St). The effects of the structure of alkyl halide and tertiary amine on the polymerization of MA were investigated. Gel permeation chromatograph (GPC) and proton nuclear magnetic resonance (1H NMR) have been utilized to analyze the end group of the obtained poly(methyl acrylate). Electron spin resonance (ESR) spectroscopy was employed to identify the structure of the radicals produced by αEBP/Me6TREN, and the results indicated that αEBP reacted with Me6TREN via a single electron transfer (SET) nucleophilic mechanism to produce corresponding ethyl α-phenylacetate radicals which subsequently initiated the polymerization of MA. As both alkyl halide and tertiary amine are commercially available at low cost, non-explosive, and ease of use and storage in comparison with conventional azo, peroxide or persulfate initiators, the combination of alkyl halide and tertiary amine as a free radical initiator is promising for large-scale practical applications.

The transformer is the core equipment in the substation. The lifecycle and health of transformer will directly affect the reliability of substation, but the lifecycle of transformer depends on the oil-paper insulation status. Water, oxygen and temperature are the three factors that affect the performance of oil-paper insulation. The most important factor is the water. This paper designed an intelligent and safe dehydrating device based on the molecular sieve adsorption principle which can realize the on-line drying of transformer.

A facile and versatile approach for the synthesis of ultrahigh molecular weight poly(methyl methacrylate) (PMMA) at mild conditions was developed. Certain organic halides combined with a catalytical amount of palladium nanoparticles (Pd NPs) were found to be very effective in initiating polymerizations of methyl methacrylate (MMA), methyl acrylate, vinyl acetate and other vinyl monomers. An ultrahigh molecular weight PMMA with a number-average molecular weight of 4.65 &times, 106 Da and a weight-average molecular weight of 8.08 &times, 106 Da was synthesized at 70 &deg, C using 2-bromoisobutyric acid ethyl ester (EBiB) as an initiator in the presence of catalytical amount (10.1 ppm) of Pd NPs. A kinetic investigation found that the orders of polymerization with respect to EBiB, Pd NP and MMA were 0.23, 0.50, and 0.58, respectively. Proton nuclear magnetic resonance (1H NMR) combined with matrix-assisted laser desorption ionization time of flight mass spectroscopy (MALDI-TOF) and gel permeation chromatography (GPC) were used to prove that the macromolecular chain had an end-group of EBiB residue. The electron spin resonance (ESR), transmission electron microscope (TEM), and X-ray photoelectron spectroscopy (XPS) results reveal that the reaction of EBiB with Pd NPs caused a bromo atom (Br) transfer from EBiB to Pd NPs and resulted in the generation of EBiB residue radical to initiate the polymerization of MMA and the formation of PdIIBr2 on the surface of Pd nanoparticles.

ATRP, as one of the most successful controlled/“living” radical polymerization techniques, has been applied to a large variety of monomers including styrenes, (meth)acrylates, (meth)acrylamides, acrylonitrile, and vinyl acetate. However, ATRP of isoprene still remains a challenge due to poor solubility of copper catalysts in isoprene and low chain propagation rate constant of the monomer. In this work, CuBr/2,2′-bipyridine was found to effectively mediate ATRP of isoprene at 100 °C, 130 °C, and 150 °C with ethyl 2-bromopropionate as an initiator. The polymerizations proceeded smoothly and reached 48.1%, 53.3%, and 71.0% conversions, respectively, in 72 h, producing polyisoprenes with molecular weights close to theoretical values and relatively narrow distributions. A block copolymer of polystyrene-b-polyisoprene was prepared using CuBr/2,2″-bipyridine as a catalyst and polystyrene as a macroinitiator. The 1 H NMR and 13 C NMR analysis of polyisoprene indicated that the polymer had 88.8% 1,4-addition structure and 63.9% of the polymer backbone units were in trans-configuration.

We previously demonstrated that a PEGylated curcumin (Curc-mPEG454) significantly inhibited cyclooxygenase 2 (COX-2) expression and improved the progression of liver fibrosis. The current study systematically evaluates its anti-inflammatory and antioxidant activities in vitro in a comparative study with curcumin, aspirin, NS-398, and vitamin C. RAW264.7 murine macrophages were pretreated with Curc-mPEG454, curcumin, aspirin, NS-398, or vitamin C at the indicated concentration for 2 h; then, the cells were stimulated with 1 μg/mL lipopolysaccharide (LPS) for 24 h. The levels of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, PGE2, NO, and GSH, and the activities of COX-2, SOD, and CAT, and the transcription factors involved in inflammation, such as NF-κB, c-Jun, and Nrf2, were measured. Curc-mPEG454 showed lower cytotoxicity (IC50 57.8 μM) when compared with that of curcumin (IC50 32.6 μM) and inhibited the release of the inflammatory cytokines IL-6, TNF-α, IL-1β, and MCP-1 in a concentration-dependent manner. At 16 μM, Curc-mPEG454 was most potent in the suppression of COX-2 expression at a transcriptional level rather than in the suppression of the catalytic activity of COX-2. Like curcumin, Curc-mPEG454 significantly reduced intracellular ROS production and enhanced the activities of SOD and CAT and the level of GSH to protect cells from LPS-induced oxidative injury. Further, its anti-inflammatory and antioxidation mechanisms are related to inhibition of NF-κB p65 nuclear translocation and c-Jun phosphorylation and to activation of Nrf2. Taken together, these findings indicate that PEGylation of curcumin not only improves its biological properties but also interferes with multiple targets involved in the inflammatory response. Curc-mPEG454 is a powerful and beneficial anti-inflammatory and antioxidant agent that merits further investigation. Graphical Abstract ᅟ.

Transition metal-mediated atom transfer radical polymerization (ATRP) is a “living”/controlled radical polymerization. Recently, there has been widely increasing interest in reducing the high costs of catalyst separation and post-polymerization purification in ATRP. In this work, trolamine was found to significantly enhance the catalytical performance of CuBr/ N , N , N ′, N ′-tetrakis(2-pyridylmethyl) ethylenediamine (CuBr/TPEN) and CuBr/tris[2-(dimethylamino) ethylamine] (CuBr/Me 6 TREN). With the addition of 25-fold molar amount of trolamine relative to CuBr, the catalyst loadings of CuBr/TPEN and CuBr/Me 6 TREN were dramatically reduced from a catalyst-to-initiator ratio of 1 to 0.01 and 0.05, respectively. The polymerizations of methyl acrylate, methyl methacrylate and styrene still showed first-order kinetics in the presence of trolamine and produced poly(methyl acrylate), poly(methyl methacrylate) and polystyrene with molecular weights close to theoretical values and low polydispersities. These results indicate that trolamine is a highly effective and versatile promoter for ATRP and is promising for potential industrial application.

Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50 mg/kg or 100 mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-γ (PPAR-γ), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-γ expression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-γ/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.

Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50 mg/kg or 100 mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-γ(PPAR-γ), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-γexpression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-γ/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.

Atom transfer radical polymerization (ATRP) is a transition metal complex-catalyzed controlled/‘living’ radical process. Recently, there has been a lot of interest focused on decreasing the catalyst loading and reducing the cost of post-polymerization purification for ATRP. In this work, urotropine was found to significantly enhance the ATRP of methyl acrylate (MA), methyl methacrylate (MMA) and styrene (St) catalyzed by CuBr/N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDETA) and CuBr/tris(2-(dimethylamino)ethylamine) (Me6TREN). With the addition of 25 times the amount of urotropine relative to CuBr, well-controlled polymerizations of MA, MMA and St were obtained at catalyst-to-initiator ratios of 0.01, 0.05 and 0.05, respectively, producing the corresponding polymers with molecular weights close to theoretical values and low polydispersities. The catalyst concentration could even be reduced to ppm level at a catalyst-to-initiator ratio as low as 0.001 in the polymerization of MA. These results indicate that urotropine is a very effective and versatile promoter for both CuBr/PMDETA and CuBr/Me6TREN. In the presence of urotropine, the catalyst loading could be reduced by as much as 1000 times. As PMDETA is one of the cheapest ATRP ligands, the combination of urotropine with CuBr/PMDETA could substantially reduce the catalyst loading and the cost of post-polymerization purification at the industrial scale and thus is promising for potential industrial applications. © 2014 Society of Chemical Industry

Curcumin, a polyphenol derived from the rhizome turmeric, has potential as an anticancer agent. We synthesized an amphipathic/surfactant pegylated curcumin (curcumin-PEG) designed for parenteral administration. Objectives of these investigations were to assess side-effects of a therapeutic regimen of curcumin-PEG in a preclinical model. Intraperitoneal (ip) tumor burdens were reduced in athymic female mice grafted with human SKOV-3 ovarian adenocarcinoma cells and injected intravenously (iv) with curcumin-PEG. There were no gross anatomical or histopathological effects detected in non-reproductive organs. Uteri (luminal fluid imbibition) and ovaries (decreased folliculogenesis) were affected by treatment. Curcumin-PEG ip hastened the onset of puberty in immature female mice. Live births were reduced in mature females housed with males and treated iv with curcumin-PEG; mating (vaginal plugs) was not affected. Accessory gland weights, testicular testosterone concentrations, and spermatogenesis were diminished in mature male mice following iv curcumin-PEG. Estrogenic/antiandrogenic and pregnancy-disrupting effects of a water soluble/bioavailable curcumin were demonstrated.

This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity.

Curcumin has been shown highly cytotoxic towards various cancer cell lines, but its water-insolubility and instability make its bioavailability exceedingly low and thus it generally demonstrates low anticancer activity in in vivo tests. Herein, we report a novel type of polymer-drug conjugates — the high molecular weight curcumin polymers (polycurcumins) made by condensation polymerization of curcumin. The polycurcumins as backbone-type conjugates have advantages of high drug loading efficiency, fixed drug loading contents, stabilized curcumin in their backbones, and tailored water-solubility. The polycurcumins may have many potential applications and their antitumor activities are investigated in this work. The polycurcumins are cytotoxic to cancer cells, but a polyacetal-based polycurcumin (PCurc 8) is highly cytotoxic to SKOV-3, OVCAR-3 ovarian cancers, and MCF-7 breast cancer cell lines. It can be quickly taken up by cancer cells into their lysosomes, where PCurc 8 hydrolyzes and releases active curcumin. It arrests SKOV-3 cell cycle at G0/G1 phase in vitro and induces cell apoptosis partially through the caspase-3 dependent pathway. In vivo, intravenously (i.v.) injected PCurc 8 shows remarkable antitumor activity in SKOV-3 intraperitoneal (i.p.) xenograft tumor model.

Endostatin, a 20-kDa C-terminal proteolytic fragment of collagen XVIII, is a specific endogenous angiogenesis inhibitor discovered more than a decade. The structure, stability, and mechanism of actions of endostatin have been extensively investigated during the past 12 years, among which controversial reports remain unclarified. The mysteries include the following: 1) Why controversial efficacies were observed with endostatin regarding tumor inhibition? Particularly, why does an N-terminal modified endostatin show good clinical responses in China, whereas the clinical trials of the wild type endostatin were terminated at the early stage of phase II in the USA? 2) What is the contribution of zinc-binding to the stability and biological functions of endostatin? 3) Why does insoluble endostatin shrink tumors? 4) How to ensure that endostatin is correctly refolded? 5) How does endostatin exert its biological functions? Recent progress regarding the biophysical properties, biological functions, signaling pathways, and clinical trials of endostatin are reviewed here. Surprising findings show that the integrity of the N-terminal sequence, the capability of zinc-binding, and the correct folding are three essential elements for assurance of structural stability and biological functions of endostatin. This review provides clues to understand the mysteries of endostatin and its derivatives.

Highly active catalysts mediating atom transfer radical polymerization (ATRP) at low concentrations, therefore requiring no postpolymerization catalyst removal, are highly desirable for wide commer...

Endostatin is a potent inhibitor of tumor angiogenesis. Interestingly, nonnative endostatin also exhibits an anti-tumor effect, which remains a mystery so far. Here, we show that intravenous injection of nonnative endostatin results in tumor inhibition effect. Soluble and active endostatin is isolated from human blood after the addition of nonnative endostatin in vitro. By fractionation of the whole blood, we surprisingly identify fibrinogen specifically binding to and inhibiting the aggregation of nonnative endostatin. Moreover, the anti-tumor activity of nonnative endostatin is substantially impaired in fibrinogen-deficient mice. Our studies demonstrate that fibrinogen facilitates the anti-tumor effect of nonnative endostatin, which also provides new insights into the novel physiological function of fibrinogen.

The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg.

Atom transfer radical polymerizations (ATRPs) of 1-(4-methacryloyloxy-benzyl)thymine (MAT) and 9-(2-methacryloyloxyethyl)adenine (MAA) were conducted for the synthesis of DNA-base functionalized polymers. The association equilibrium constant Kasso between MAT and MAA and the complexation equilibrium constant Kcomp between the corresponding polymers PMAT and PMAA were determined. A zipper-like diblock copolymer, PMAT-b-PMAA, was prepared by anchoring the PMAT and PMAA blocks on the ortho-positions of a pyridine ring via a successive two-step ATRP. Dynamic light scattering and atom force microscopy confirmed that the block copolymer had a V-shaped configuration in dimethylsulfoxide/N,N-dimethylformamide. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5995–6006, 2006

Allometrically scaled data sets (138 compounds) used for predicting human clearance were obtained from the literature. Our analyses of these data have led to four observations. (1) The current data do not provide strong evidence that systemic clearance (CL(s); n = 102) is more predictable than apparent oral clearance (CL(po); n = 24), but caution needs to be applied because of potential CL(po) prediction error caused by differences in bioavailability across species. (2) CL(s) of proteins (n = 10) can be more accurately predicted than that of non-protein chemicals (n = 102). (3) CL(s) is more predictable for compounds eliminated by renal or biliary excretion (n = 33) than by metabolism (n = 57). (4) CL(s) predictability for hepatically eliminated compounds followed the order: high CL (n = 11) > intermediate CL (n = 17) > low CL (n = 29). All examples of large vertical allometry (% error of prediction greater than 1000%) occurred only when predicting human CL(s) of drugs having very low CL(s). A qualitative analysis revealed the application of two potential rules for predicting the occurrence of large vertical allometry: (1) ratio of unbound fraction of drug in plasma (f(u)) between rats and humans greater than 5; (2) C logP greater than 2. Metabolic elimination could also serve as an additional indicator for expecting large vertical allometry.

A highly active and versatile CuBr 2 /N,N,N',N'-tetra[(2-pyridal)methyl]ethylenediamine (CuBr 2 /TPEN)-tertiary amine catalyst system has been developed for atom transfer radical polymerization via activator-generated-by-electron-transfer (AGET ATRP). The catalyst mediates good control of the AGETATRPs of methyl acrylate, methyl methacrylate, and styrene at 1 mol-% catalyst relative to initiator. A mechanism study shows that tertiary amines such as triethylamine reduces the CuBr 2 /TPEN complex to CuBr/TPEN.