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Amyloid A (AA) amyloidosis, a complication of chronic inflammatory conditions, develops when proteolytic fragments of serum amyloid A protein are deposited in tissues as amyloid fibrils. This placebo-controlled trial investigated the effect of eprodisate, a small molecule that inhibits amyloid fibril polymerization and tissue deposition in patients with renal AA amyloidosis. As compared with placebo, the drug slowed a decline in renal function. Eprodisate is a member of a new class of compounds that interfere with interactions between amyloidogenic proteins and glycosaminoglycans. This trial investigated the effect of eprodisate, a small molecule that inhibits amyloid fibril polymerization and tissue deposition in patients with renal AA amyloidosis. As compared with placebo, the drug slowed a decline in renal function. The amyloidoses constitute a group of diseases in which proteins are deposited extracellularly in the tissues as insoluble fibrils, causing progressive organ dysfunction and death. 1 Amyloid A (AA) amyloidosis, also referred to as secondary amyloidosis, is a rare but serious complication of chronic inflammatory diseases and chronic infections. The amyloidogenic protein in AA amyloidosis is a proteolytic fragment of serum amyloid A protein (SAA), an acute-phase reactant produced by the liver. The kidney is the organ most frequently affected in AA amyloidosis. 2 Ongoing deposition of amyloid in the kidney results in proteinuria and progressive loss of renal function. The gastrointestinal . . .

A new method for catalysing the cross-coupling of two different aryl electrophiles is described; the principle of this method, which involves cooperation between two metal catalysts that are selective towards different substrates, should be generally useful in catalysis. Multiple catalysts for carbon–carbon bond formation Transition-metal-catalysed strategies for the formation of new carbon–carbon bonds are used to synthesize a broad range of small molecules, including pharmaceutical agents. In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation of two distinct catalysts — multimetallic catalysis — can be used instead. The application of this strategy has mainly been limited to the use of metals with distinct reactivities. These authors demonstrate that cooperativity between a nickel catalyst and a palladium catalyst can be used to couple aryl bromides with aryl triflates directly, eliminating the need to use arylmetal reagents. Each catalyst forms less than 5% cross product in isolation, but with both catalysts present the yields can reach 94%. These results reveal a new, general method for the synthesis of biaryls, heteroaryls, and dienes, and should simplify the synthesis of pharmaceutical agents, many of which are currently made with pre-formed organometallic reagents. The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules 1 , 2 , 3 . In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation 4 of two distinct catalysts—multimetallic catalysis—can be used instead. Many important reactions rely on multimetallic catalysis 5 , 6 , 7 , 8 , 9 , 10 , such as the Wacker oxidation of olefins 6 , 7 , 8 and the Sonogashira coupling of alkynes with aryl halides 9 , 10 , but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition 11 , 12 . Here, we demonstrate that cooperativity between two group 10 metal catalysts—(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium—enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles) 13 , 14 , 15 . Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon–hydrogen bonds that is required for direct arylation methods 16 , 17 . Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents 1 , 2 , 3 , and lead to the discovery of new multimetallic reactions.

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health. A genomic analysis of tumors in mice caused by known or suspected carcinogens shows that most carcinogens do not generate distinct mutational signatures.

Polymerization reactions conducted inside cells must be compatible with the complex intracellular environment, which contains numerous molecules and functional groups that could potentially prevent or quench polymerization reactions. Here we report a strategy for directly synthesizing unnatural polymers in cells through free radical photopolymerization using a number of biocompatible acrylic and methacrylic monomers. This offers a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules that have the ability to alter cellular motility, label cells by the generation of fluorescent polymers for long-term tracking studies, as well as generate a variety of nanostructures within cells. It is remarkable that free radical polymerization chemistry can take place within such complex cellular environments. This demonstration opens up a multitude of new possibilities for how chemists can modulate cellular function and behaviour and for understanding cellular behaviour in response to the generation of free radicals. A strategy for directly synthesizing unnatural polymers in cells through radical polymerization has now been developed. This approach provides a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules and a variety of nanostructures.

DCM was classified as probably carcinogenic to humans (Group 2A) on the basis of limited evidence that it causes biliary-tract cancer and non-Hodgkin lymphoma in humans and sufficient evidence of carcinogenicity in experimental animals (malignant lung and hepatocellular tumours in male and female mice).2,3,6-9 In making its overall assessment, the working group also took into account the strong evidence that DCM metabolism via glutathione-S-transferase T1 (GSTT1) leads to the formation of reactive metabolites, that GSTT1 activity is strongly associated with genotoxicity of DCM in vitro and in vivo, and that GSTT1-mediated metabolism of DCM does occur in humans. DNA reactivity was evident in various genotoxicity assays, including in animals and in human cells in vitro. Because 1,3-PS does not require metabolic activation and reacts directly with DNA and other macromolecules, the working group concluded that this mechanism probably operates both in animals and humans.

Poly(propylene carbonate) (PPC) is an emerging “carbon fixation” polymer that holds the potential to become a “biomaterial of choice” in healthcare owing to its good biocompatibility, tunable biodegradability and safe degradation products. However, the commercialization and wide application of PPC as a biomedical material are still hindered by its narrow processing temperature range, poor mechanical properties and hydrophobic nature. Over recent decades, several physical, chemical and biological modifications of PPC have been achieved by introducing biocompatible polymers, inorganic ions or small molecules, which can endow PPC with better cytocompatibility and desirable biodegradability, and thus enable various applications. Indeed, a variety of PPC-based degradable materials have been used in medical applications including medical masks, surgical gowns, drug carriers, wound dressings, implants and scaffolds. In this review, the molecular structure, catalysts for synthesis, properties and modifications of PPC are discussed. Recent biomedical applications of PPC-based biomaterials are highlighted and summarized.

The roles of dichloromethane (DCM) and 1,2,3-trichloropropane (1,2,3-TCP) in occupational cholangiocarcinoma, first reported in 2012, remain elusive. This study aimed to determine the potential of 1,2-dichloropropane (1,2-DCP), DCM, and 1,2,3-TCP to induce DNA damage-a hallmark of carcinogenicity-in human cholangiocytes. Monocultures of human immortalized cholangiocytes (MMNK-1 cholangiocytes) and co-cultures of MMNK-1 cholangiocytes with human THP-1 monocyte-derived macrophages and monocytes were each exposed to 1,2-DCP, DCM or 1,2,3-TCP at 0, 0.1, and 0.4 mM for 24 hours. DNA double-strand break marker γ-H2AX-positive foci and γ-H2AX pan-nuclear staining-which is known to be induced during early or intermediate stages of apoptosis or under replicative stress/checkpoint abrogation in cholangiocytes-were counted in 100 and 200 cholangiocytes, respectively. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. The increase in dense (≥55) γ-H2AX foci induced by all 3 chemical compounds was significantly greater in co-cultures with macrophages, but not with monocytes, than in monocultures. However, only 1,2-DCP decreased the number of γ-H2AX pan-nuclear-positive and TUNEL-positive cholangiocytes in co-cultures with macrophages, but not in monocultured cholangiocytes. Co-treatment with a pan-caspase inhibitor decreased the number of γ-H2AX pan-nuclear-positive cholangiocytes in each group by about 50%, suggesting that apoptotic signaling is involved, at least in part, in the induction of γ-H2AX pan-nuclear-positive cholangiocytes. Our study showed that co-culture with macrophages enhanced DNA double-strand breaks induced by all 3 tested chemical compounds, while only 1,2-DCP exhibited a proliferative effect in monocultures and anti-apoptotic effects in co-cultures with macrophages, which are key characteristics of carcinogens, thus distinguishing 1,2-DCP from DCM and 1,2,3-TCP.

Engineering enzymes to degrade anthropogenic compounds efficiently is challenging. We obtained Rhodococcus rhodochrous haloalkane dehalogenase mutants with up to 32-fold higher activity than wild type toward the toxic, recalcitrant anthropogenic compound 1,2,3-trichloropropane (TCP) using a new strategy. We identified key residues in access tunnels connecting the buried active site with bulk solvent by rational design and randomized them by directed evolution. The most active mutant has large aromatic residues at two out of three randomized positions and two positions modified by site-directed mutagenesis. These changes apparently enhance activity with TCP by decreasing accessibility of the active site for water molecules, thereby promoting activated complex formation. Kinetic analyses confirmed that the mutations improved carbon-halogen bond cleavage and shifted the rate-limiting step to the release of products. Engineering access tunnels by combining computer-assisted protein design with directed evolution may be a valuable strategy for refining catalytic properties of enzymes with buried active sites.

The blends of Poly(propylene carbonate) (PPC) and polyester-based thermoplastic polyurethane (TPU) were melt compounded in an internal mixer. The compatibility, thermal behaviors, mechanical properties and toughening mechanism of the blends were investigated using Fourier transform infrared spectra (FTIR), tensile tests, impact tests, differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic mechanical analysis technologies. FTIR and SEM examination reveal strong interfacial adhesion between PPC matrix and suspended TPU particles. Dynamic mechanical analyzer (DMA) characterize the glass transition temperature, secondary motion and low temperature properties. By the incorporation of TPU, the thermal stabilities are greatly enhanced and the mechanical properties are obviously improved for the PPC/TPU blends. Moreover, PPC/TPU blends exhibit a brittle-ductile transition with the addition of 20 wt % TPU. It is considered that the enhanced toughness results in the shear yielding occurred in both PPC matrix and TPU particles of the blends.

A new, eco-friendly process utilising the green solvent propylene carbonate (PC) has been developed to perform N-alkylation of N-, O- and/or S-containing heterocyclic compounds. PC in these reactions served as both the reagent and solvent. Importantly, no genotoxic alkyl halides were required. No auxiliary was necessary when using anhydrous PC. Product formation includes nucleophilic substitution with the concomitant loss of water and carbon dioxide. Substrates prepared, including the newly invented PROTAC drugs, are widely used.