Target-controlled infusion of remimazolam effect-site concentration for total intravenous anesthesia in patients undergoing minimal invasive surgeries.

Background: Although pharmacokinetic and pharmacodynamic models of remimazolam have been developed, their clinical application remains limited. This study aimed to administer a target-controlled infusion (TCI) of remimazolam at the effect-site concentration (Ce) in patients undergoing general anesthesia and to investigate the relationship of the remimazolam Ce with sedative effects and with recovery from general anesthesia. Methods: Fifty patients aged 20-75 years, scheduled for minimally invasive surgery under general anesthesia for less than 2 h, were enrolled. Anesthesia was induced and maintained using Schüttler's model for effect-site TCI of remimazolam. During induction, the remimazolam Ce was increased stepwise, and sedation levels were assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS). Following attainment of MOAA/S scale 1, continuous infusion of remifentanil was commenced, and rocuronium (0.6 mg/kg) was administered for endotracheal intubation. The target Ce of remimazolam and the remifentanil infusion rate were adjusted to maintain a BIS between 40 and 70 and a heart rate within 20% of the baseline value. Approximately 5 min before surgery completion, the target Ce of remimazolam was reduced by 20-30%, and anesthetic infusion ceased at the end of surgery. Nonlinear mixed-effects modeling was employed to develop pharmacodynamic models for each sedation level as well as emergence from anesthesia. Results: The remimazolam Ces associated with 50% probability (Ce50) of reaching MOAA/S scale ≤4, 3, 2, and 1 were 0.302, 0.397, 0.483, and 0.654 µg/mL, respectively. The Ce50 values for recovery of responsiveness (ROR) and endotracheal extubation were 0.368 and 0.345 µg/mL, respectively. The prediction probabilities of Ce and BIS for detecting changes in sedation level were 0.797 and 0.756, respectively. The sedation scale significantly correlated with remimazolam Ce (r = -0.793, P < 0.0001) and BIS (r = 0.914, P < 0.0001). Age significantly correlated with Ce at MOAA/S1 and ROR. Conclusion: Effect-site TCI of remimazolam was successfully performed in patients undergoing general anesthesia. The remimazolam Ce significantly correlated with sedation depth. The Ce50 for MOAA/S scale ≤1 and ROR were determined to be 0.654 and 0.368 µg/mL, respectively.

An Artificial Tactile Neuron Enabling Spiking Representation of Stiffness and Disease Diagnosis.

Mechanical properties of biological systems provide useful information about the biochemical status of cells and tissues. Here, an artificial tactile neuron enabling spiking representation of stiffness and spiking neural network (SNN)-based learning for disease diagnosis is reported. An artificial spiking tactile neuron based on an ovonic threshold switch serving as an artificial soma and a piezoresistive sensor as an artificial mechanoreceptor is developed and shown to encode the elastic stiffness of pressed materials into spike frequency evolution patterns. SNN-based learning of ultrasound elastography images abstracted by spike frequency evolution rate enables the classification of malignancy status of breast tumors with a recognition accuracy up to 95.8%. The stiffness-encoding artificial tactile neuron and learning of spiking-represented stiffness patterns hold a great promise for the identification and classification of tumors for disease diagnosis and robot-assisted surgery with low power consumption, low latency, and yet high accuracy.

Hand-ground fullerene-nanodiamond composite for photosensitized water treatment and photodynamic cancer therapy.

The unique capability of fullerene (C60) to absorb light and generate reactive oxygen species (ROS) has been extensively studied for photosensitized water treatment and cancer therapy. Various material synthesis strategies have been proposed in parallel to overcome its intrinsic hydrophobicity and to enhance availability in water and physiological media. We present here a strikingly simple approach to make C60 available to these applications by hand-grinding dry C60 powder with nanodiamond (ND) using a mortar and pestle. The resulting ND-C60 composite was found to form a stable aqueous colloidal suspension and efficiently drive photosensitized production of ROS under visible light illumination. ND-C60 rapidly adsorbed and oxidized organic contaminants by photogenerated ROS. In the experiments for photodynamic cancer therapy, ND-C60 was internalized by cancer cells and induced cell apoptosis without noticeable toxicity. Treatment of tumor-bearing mice with ND-C60 and light irradiation resulted in tumor shrinkage and prolonged survival time.

Activation of Hydrogen Peroxide by a Titanium Oxide-Supported Iron Catalyst: Evidence for Surface Fe(IV) and Its Selectivity.

Iron immobilized on supports such as silica, alumina, titanium oxide, and zeolite can activate hydrogen peroxide (H2O2) into strong oxidants. However, the role of the support and the nature of the oxidants produced in this process remain elusive. This study investigated the activation of H2O2 by a TiO2-supported catalyst (FeTi-ox). Characterizing the catalyst surface in situ using X-ray absorption spectroscopy (XAS), together with X-ray photoelectron spectroscopy (XPS) and electron paramagnetic resonance (EPR), revealed that the interaction between H2O2 and the TiO2 phase played a key role in the H2O2 activation. This interaction generated a stable peroxo-titania ≡Fe(III)-Ti-OOH complex, which reacted further with H2O to produce a surface oxidant, likely ≡Fe[IV] ═ O2+. The oxidant effectively degraded acetaminophen, even in the presence of chloride, bicarbonate, and organic matter. Unexpectedly, contaminant oxidation continued after the H2O2 in the solution was depleted, owing to the decomposition of ≡Fe(III)-Ti-OOH by water. In addition, the FeTi-ox catalyst effectively degraded acetaminophen over five testing cycles. Overall, new insights gained in this study may provide a basis for designing more effective catalysts for H2O2 activation.

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.

Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the ß-hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer.

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR.

Targeted removal of trichlorophenol in water by oleic acid-coated nanoscale palladium/zero-valent iron alginate beads.

A new material was developed and evaluated for the targeted removal of trichlorophenol (TCP) from among potential interferents which are known to degrade removal activity. To achieve TCP-targeted activity, an alginate bead containing nanoscale palladium/zero-valent iron (Pd/nZVI) was coated with a highly hydrophobic oleic acid layer. The new material (Pd/nZVI-A-O) preferentially sorbed TCP from a mixture of chlorinated phenols into the oleic acid cover layer and subsequently dechlorinated it to phenol. The removal efficacy of TCP by Pd/nZVI-A-O was not affected by co-existing organic substances such as Suwannee River humic acid (SRHA), whereas the material without the oleic acid layer (Pd/nZVI-A) became less effective with increasing SRHA concentration. The inorganic substances nitrate and phosphate significantly reduced the reactivity of Pd/nZVI-A, however, Pd/nZVI-A-O showed similar TCP removal efficacies regardless of the initial inorganic ion concentrations. The influence of bicarbonate on the TCP removal efficacies of both Pd/nZVI-A and Pd/nZVI-A-O was not significant. The findings from this study suggest that Pd/nZVI-A-O, with its targeted, constant reactivity for TCP, would be effective for treating this contaminant in surface water or groundwater containing various competitive substrates.

Oxidizing capacity of periodate activated with iron-based bimetallic nanoparticles.

Nanosized zerovalent iron (nFe0) loaded with a secondary metal such as Ni or Cu on its surface was demonstrated to effectively activate periodate (IO4-) and degrade selected organic compounds at neutral pH. The degradation was accompanied by a stoichiometric conversion of IO4- to iodate (IO3-). nFe0 without bimetallic loading led to similar IO4- reduction but no organic degradation, suggesting the production of reactive iodine intermediate only when IO4- is activated by bimetallic nFe0 (e.g., nFe0-Ni and nFe0-Cu). The organic degradation kinetics in the nFe0-Ni(or Cu)/IO4- system was substrate dependent: 4-chlorophenol, phenol, and bisphenol A were effectively degraded, whereas little or no degradation was observed with benzoic acid, carbamazepine, and 2,4,6-trichlorophenol. The substrate specificity, further confirmed by little kinetic inhibition with background organic matter, implies the selective nature of oxidant in the nFe0-Ni(or Cu)/IO4- system. The comparison with the photoactivated IO4- system, in which iodyl radical (IO3•) is a predominant oxidant in the presence of methanol, suggests IO3• also as primary oxidant in the nFe0-Ni(or Cu)/IO4- system.

Titanium dioxide nanofibers integrated stainless steel filter for photocatalytic degradation of pharmaceutical compounds.

A photocatalytically active stainless steel filter (P-SSF) was prepared by integrating electrospun TiO2 nanofibers on SSF surface through a hot-press process where a poly(vinylidene fluoride) (PVDF) nanofibers interlayer acted as a binder. By quantifying the photocatalytic oxidation of cimetidine under ultraviolet radiation and assessing the stability of TiO2 nanofibers integrated on the P-SSF against sonication, the optimum thickness of the TiO2 and PVDF layer was found to be 29 and 42 µm, respectively. At 10L/m(2)h flux, 40-90% of cimetidine was oxidized when the thickness of TiO2 layer increased from 10 to 29 µm; however, no further increase of cimetidine oxidation was observed as its thickness increased to 84 µm, maybe due to limited light penetration. At flux conditions of 10, 20, and 50 L/m(2) h, the oxidation efficiencies for cimetidine were found to be 89, 64, and 47%, respectively. This was attributed to reduced contact time of cimetidine within the TiO2 layer. Further, the degradation efficacy of cimetidine was stably maintained for 72 h at a flux of 10 L/m(2) h and a trans-filter pressure of 0.1-0.2 kPa. Overall, our results showed that it can potentially be employed in the treatment of effluents containing organic micropollutants.

Photocatalytic pre-treatment with food-grade TiO(2) increases the bioavailability and bioremediation potential of weathered oil from the Deepwater Horizon oil spill in the Gulf of Mexico.

Using the 2010 Deepwater Horizon oil spill in the Gulf of Mexico as an impetus, we explored the potential for TiO(2)-mediated photocatalytic reactive oxygen species (ROS) generation to increase the bioavailability (solubility) and biodegradability of weathered oil after a spill. Food grade TiO(2), which is FDA approved for use as food additive in the United States, was tested as a photocatalyst for this novel application. Photocatalytic pre-treatment (0.05 wt.% TiO(2), UV irradiation 18 W m(-2), 350-400 nm) for 24 h in a bench top photoreactor increased the soluble organic carbon content of weathered oil by 60%, and enhanced its subsequent biodegradation (measured as O(2) consumption in a respirometer) by 37%. Photocatalytic pre-treatment was also tested outdoors under sunlight illumination, but no significant increase in solubility or biodegradation was observed after 11 d of exposure. Although sunlight irradiation of food-grade TiO(2) generated ROS (assessed by the degradation of 4-chlorophenol as a probe compound), the efficacy of weathered oil pre-treatment was apparently hindered by sinking of the photocatalysts under quiescent conditions and illumination occlusion by the oil. Overall, results indicate that photocatalytic pre-treatment to stimulate bioremediation of weathered oil deserves further consideration, but controlling the buoyancy and surface hydrophobicity of the photocatalysts will be important for future efforts to enable ROS generation in proximity to the target compounds.

Apoptosis-mediated in vivo toxicity of hydroxylated fullerene nanoparticles in soil nematode Caenorhabditis elegans.

Although a number of manufactured nanoparticles are applied for the medical and clinical purposes, the understanding of interaction between nanomaterials and biological systems are still insufficient. Using nematode Caenorhabditis elegans model organism, we here investigated the in vivo toxicity or safety of hydroxylated fullerene nanoparticles known to detoxify anti-cancer drug-induced oxidative damages in mammals. The survival ratio of C. elegans rapidly decreased by the uptake of nanoparticles from their L4 larval stage with resulting in shortened lifespan (20 d). Both reproduction rate and body size of C. elegans were also reduced after exposure to 100 µg mL(-1) of fullerol. We found ectopic cell corpses caused by apoptotic cell death in the adult worms grown with fullerol nanoparticles. By the mutation of core pro-apoptotic regulator genes, ced-3 and ced-4, these nanoparticle-induced cell death were significantly suppressed, and the viability of animals consequently increased despite of nanoparticle uptake. The apoptosis-mediated toxicity of nanoparticles particularly led to the disorder of digestion system in the animals containing a large number of undigested foods in their intestine. These results demonstrated that the water-soluble fullerol nanoparticles widely used in medicinal applications have a potential for inducing apoptotic cell death in multicellular organisms despite of their antioxidative detoxifying property.

Oxidation on zerovalent iron promoted by polyoxometalate as an electron shuttle.

Most studies on zerovalent iron (ZVI) were mainly focused on the reductive transformation of halo- or nitrocompounds. Oxidation reactions occurring on ZVI have been recently recognized. In this study, we demonstrate that the oxidation pathways on ZVI can be accelerated by the presence of polyoxometalate (POM: nanosized metaloxygen cluster anion) serving as an electron shuttle. The ions, SiW12O40(4-) and PW12O40(3-), can mediate the electron transfer from the Fe0 surface to 02 while enhancing the production of H2O2, which subsequently initiates the OH radical-mediated oxidation through a Fenton-type reaction. The oxidation reaction was completely quenched by adding methanol as an OH radical-scavenger. On the other hand, PMo12O40(3-) completely inhibited the oxidative degradation by irreversibly scavenging an electron and holding it. We systematically investigated the effects of iron loading, the concentration of POM, and pH on the oxidative degradation kinetics of 4-chlorophenol in the POM-mediated ZVI system. The POM-mediated oxidations on ZVI were additionally tested for 12 organic contaminants and the rates were compared. Their oxidative degradation on ZVI was mostly enhanced in the presence of POM (SiW12O40(4-)). The present study provides a good model system upon which the ZVI-based oxidation technologies can be successfully enhanced and modified for further developments.

Simultaneous and synergistic conversion of dyes and heavy metal ions in aqueous TiO2 suspensions under visible-light illumination.

This study reports synergistic effects in the simultaneous conversion of dyes and heavy metal ions in aqueous TiO2/dye/metal ion systems (ternary components) under visible light (lambda > 420 nm). TiO2/Cr(VI)/Acid Orange 7 (AO7), TiO2/Cr(VI)/Rhodamine B (RhB), TiO2/Ag+/AO7, and TiO2/Ag+/RhB were chosen as test systems. Although dyes can be degraded in TiO2 suspensions under visible light, their removal rates were markedly enhanced in the presence of metal ions. Similarly, the reduction rates of metal ions in visible-light-illuminated TiO2 suspensions were negligible, but they were highly accelerated with dyes present. In particular, the synergistic effect in the ternary system of TiO2/Cr(VI)/AO7 was outstanding. The presence of dissolved oxygen increased the photoreduction rate of Cr(VI) despite the fact that Cr(VI) and O2 are competing electron acceptors. This is ascribed to in-situ photogenerated H2O2 from O2, which acts as a reductant of Cr(VI). RhB and Ag+ ions could be also converted simultaneously under visible light both in the presence and absence of TiO2. The visible-light-induced reduction of Ag+ did not occur at all in TiO2/Ag+ system, but it was enabled in both TiO2/Ag+/ RhB and TiO2/Ag+/AO7 to generate Ag particles. On the other hand, the binary systems of Cr(VI)/AO7, Ag+/AO7, and Ag+/RhB show significant visible-light activities for the conversion of both dye and metal ion. In this case, metal ions and dyes seem to form complexes that induce intracomplex electron transfers upon visible-light absorption. The Cr(VI)/RhB system, however, exhibited insignificant visible-light reactivity.