Abstract  We study the influence of ultrasound on paclitaxel-loaded nanocapsules in vitro and in vivo. These nanocapsules possess a shell of poly(dl-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) and a liquid core of perfluorooctyl bromide (PFOB). In vitro experiments show that mechanical effects such as cavitation are negligible for nanocapsules due to their small size and thick and rigid shell. As the mechanical effects were unable to increase paclitaxel delivery, we focused on the thermal effects of ultrasound in the in vivo studies. A focused ultrasound sequence was therefore optimized in vivo under magnetic resonance imaging guidance to obtain localized mild hyperthermia with high acoustic pressure. Ultrasound-induced mild hyperthermia (41-43°C) was then tested in vivo in a subcutaneous CT-26 colon cancer murine model. As hyperthermia is applied, an inhibition of tumor growth for both paclitaxel-loaded nanocapsules and the commercial formulation of paclitaxel, namely Taxol® have been observed (p<0.05). Ultrasound-induced mild hyperthermia at high acoustic pressure appears as an interesting strategy to enhance cytotoxic efficacy locally.

Abstract  Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half-life and volume of distribution. The tissue-plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure.

Abstract  Gomisin N (GN) is a phytochemical derived from Schisandra chinensis. It has been reported to exert a protective effect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress. However, the detailed mechanism by which GN inhibits hepatic steatosis remains to be elucidated. In this study, we examined whether GN activates AMP-activated protein kinase (AMPK) and exerts therapeutic effects on liver X receptor (LXR)- or palmitic acid (PA)-induced triglyceride (TG) accumulation in HepG2 cells. Furthermore, in vivo protective effects of GN against hepatic steatosis were assessed in high-fat diet (HFD)-induced obese mice. GN stimulated the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein 1c (SREBP1c) in HepG2 cells. It decreased the expression of lipogenesis genes, but increased the expression of fatty acid oxidation genes. Additionally, GN decreased the expression of lipogenesis genes induced by the LXR agonist T0901317 or PA in HepG2 cells, resulting in reduced intracellular TG content. However, preincubation with compound C, an AMPK inhibitor, prevented GN-mediated effects. Administration of GN to HFD-induced obese mice decreased HFD-induced liver weight, hepatic TG accumulation, and cytoplasmic lipid droplet. These findings demonstrate that GN activates the AMPK pathway and ameliorates HFD-induced hepatic steatosis.

Abstract  Commercially available BiPh3was treated with perfluoroalkylphosphinic acids [for example, (C2F5)2P(O)OH] to generate novel, highly Lewis acidic bismuth(III) perfluoroalkylphosphinates of the type PhxBi[RF2PO2]3-x(x=0, 1, 2) (RF=-C2F5, -C4F9). The first bismuth(V) perfluoroalkylphosphinate, Ph3Bi[(C2F5)2PO2]2, was synthesized from Ph3BiCl2and Ag[(C2F5)2PO2]. Examples for the successful application of the catalytically active bismuth(III) and bismuth(V) phosphinates in carbon-carbon bond forming reactions, such as Friedel-Crafts acylation and alkylation, Diels-Alder, Strecker and Mannich reaction, are presented.

Abstract  A matrix removal procedure with ion-exchange resin prior to analysis for 18 fluorinated benzoic acids (FBAs) tracers in saline (>25% salt) reservoir water was optimized. The elimination of >98% of salt and the simultaneous matrix sample cleanup allowed the direct analysis using the supernatant by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). This resulted in a gain in detection limits for most of the tracers in comparison with the reference method (direct analysis after minimum required dilution). The limits of detection (LODs) were in the range of 0.01-0.15 ng/ml and compared to other studies the developed method provided comparable limits of detection and advantage of simplified and shorter sample preparation. The presented method offers a considerable gain in simplicity and analysis time. Recoveries for all the tracers reached 80-100%, except for 2-FBA and 2,6-dFBA for which they were ca. 60%. The low recoveries were corrected by the use of five isotopically labeled internal standards. The method was validated by the analysis of spiked samples and by an independent comparison of the results with those obtained by solid-phase extraction LC-MS/MS method.

Abstract  Although enzymes are highly efficient and selective catalysts, there have been problems incorporating them into fuel cells. Early enzyme-based fuel cells contained enzymes in solution rather than immobilized on the electrode surface. One problem utilizing an enzyme in solution is an issue of transport associated with long diffusion lengths between the site of bioelectrocatalysis and the electrode. This issue drastically decreases the theoretical overall power output due to the poor electron conductivity. On the other hand, enzymes immobilized at the electrode surface have eliminated the issue of poor electron conduction due to close proximity of electron transfer between electrode and the biocatalyst. Another problem is inefficient and short term stability of catalytic activity within the enzyme that is suspended in free flowing solution. Enzymes in solutions are only stable for hours to days, whereas immobilized enzymes can be stable for weeks to months and now even years. Over the last decade, there has been substantial research on immobilizing enzymes at electrode surfaces for biofuel cell and sensor applications. The most commonly used techniques are sandwich or wired. Sandwich techniques are powerful and successful for enzyme immobilization; however, the enzymes optimal activity is not retained due to the physical distress applied by the polymer limiting its applications as well as the non-uniform distribution of the enzyme and the diffusion of analyte through the polymer is slowed significantly. Wired techniques have shown to extend the lifetime of an enzyme at the electrode surface; however, this technique is very hard to master due to specific covalent bonding of enzyme and polymer which changes the three-dimensional configuration of enzyme and with that decreases the optimal catalytic activity. This chapter details encapsulation techniques where an enzyme will be immobilized within the pores/pockets of the hydrophobically modified micellar polymers such as Nafion®and chitosan. This strategy has been shown to safely immobilize enzymes at electrode surfaces with storage and continuous operation lifetime of more than 2 years.

Abstract  A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.

Abstract  Nano-sized Pd particles are uniformly dispersed on graphene nanosheets (GNSs) using a supercritical-fluid-assisted deposition technique to increase the electrochemical sensing properties. The incorporation of different kinds of ionic liquid (IL) can increase the electrode sensing current toward different analytes. Butylmethylpyrrolidinium-bis(trifluoromethanesulfonyl)imide (BMP-TFSI) IL is beneficial for glucose detection, whereas the electrode with butylmethylpyrrolidinium-dicyanamide (BMP-DCA) IL shows high sensitivity toward ascorbic acid (AA). The selective detection of glucose or AA from their mixture is for the first time demonstrated using a non-enzymatic electrode with the aid of an IL. Angle-resolved X-ray photoelectron spectroscopy analyses indicate that GNSs can create an aligned cation/anion orientation in the adsorbed IL film, with the anions preferentially occupying the topmost surface. As a result, the electrode sensitivity and selectivity are mainly determined by the IL constituent anions.

Abstract  Importance: Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke.

Objective: To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke.

Design, Setting, and Participants: Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia.

Exposures: Preoperatively diagnosed PFO.

Main Outcomes and Measures: Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS).

Results: Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63]; P < .001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48]; P < .001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO; P = .02).

Conclusions and Relevance: Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk.

Abstract  The contamination of groundwater and surface water from previous uses of perfluoroalkyl substances (PFASs), particularly products containing the contaminants perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), has become a concern for drinking water and as a potential exposure route to the food supply. In 2016, the Food and Drug Administration (FDA) was asked to investigate a bog in Massachusetts where the surface water was believed to be contaminated with PFASs. As a result, a method was developed for the analysis of PFASs in cranberries, and water and fruit from the affected bog were evaluated. A QuEChERS method was developed and validated for PFOA, PFOS, and six additional shorter-chain PFASs. Method recoveries ranged from 60% to 115% for validation spikes performed at 10, 20 and 40 ng g-1and method detection limits ranged from 0.2 to 5.6 ng g-1. Bog water samples were analysed using Environmental Protection Agency (EPA) method 537 for PFOA, PFOS and four additional short-chain PFASs. Surface water concentrations for PFOS ranged from 16 to 122 ng L-1and input water concentrations were 132 ng L-1and 206 ng L-1. Of the eight water samples, seven had water concentrations that exceeded the EPA health advisory level for PFOS of 70 ng L-1. Of the 42 cranberry samples analysed, none had detects of PFOA or PFOS above their method detection limits (0.4 and 0.5 ng g-1, respectively), nor any of the other short-chain PFASs.

Abstract  BACKGROUND: Emerging work has examined neurodevelopmental outcomes following prenatal exposure to per- and polyfluoroalkyl substances (PFAS), but few studies have assessed associations with autism spectrum disorder (ASD).

OBJECTIVES: Our objective was to estimate associations of maternal prenatal PFAS concentrations with ASD and intellectual disability (ID) in children.

METHODS: Participants were from a population-based nested case-control study of children born from 2000 to 2003 in southern California, including children diagnosed with ASD (n=553), ID without autism (n=189), and general population (GP) controls (n=433). Concentrations of eight PFAS from stored maternal sera collected at 15-19 wk gestational age were quantified and compared among study groups. We used logistic regression to obtain adjusted odds ratios for the association between prenatal PFAS concentrations (parameterized continuously and as quartiles) and ASD versus GP controls, and separately for ID versus GP controls.

RESULTS: Geometric mean concentrations of most PFAS were lower in ASD and ID groups relative to GP controls. ASD was not significantly associated with prenatal concentrations of most PFAS, though significant inverse associations were found for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) [adjusted ORs for the highest vs. lowest quartiles 0.62 (95% CI: 0.41, 0.93) and 0.64 (95% CI: 0.43, 0.97), respectively]. Results for ID were similar.

CONCLUSIONS: Results from this large case-control study with prospectively collected prenatal measurements do not support the hypothesis that prenatal exposure to PFAS is positively associated with ASD or ID. https://doi.org/10.1289/EHP1830.

Abstract  Surfactant-assisted ball milling is employed for preparation of metal powders for magnetodielectric composites. The iron powder is mechanically milled in various organic media (paraffin, polystyrene, polyethylene) with and without surfactant additives (perfluorononanoic acid and stearic acid). The structural characterization of the body and surface of the particles of the produced powders is performed and the magnetostatic and microwave properties of the powders are measured. It is shown that ball milling of Fe powder in organic media results in the formation of polyaromatic structures due to catalytic dehydrogenation on bare surface of Fe particles. Then, the polyaromatic carbon structures transform into carbides. The surfactant-assisted ball milling allows platelet powder particles to be fabricated with a decreased amount of carbides in the composition. The magnetic permeability of the composites filled with as-obtained particles is governed mainly by the shape of the filler particles. For the composites filled with the platelet particles, an organic surface layer formed during the surfactant-assisted ball milling is an important parameter determining the dielectric permittivity of the composites. (C) 2017 Elsevier B.V. All rights reserved.

Abstract  Some fluorochemical products are manufactured using N-methyl perfluorobutanesulfonamido ethanol (MeFBSE), a short-chain replacement for perfluorooctyl-based chemistries N-methyl and N-ethyl perfluorooctanesulfonamido ethanols (EtFOSE). The present study shows for the first time the anaerobic biodegradation of MeFBSE and EtFOSE in municipal digester sludge under methanogenic conditions. Both MeFBSE and EtFOSE were incubated for 108 d with anaerobic digester sludge. Although sterile controls did not remove MeFBSE, it was degraded in live sludge. The loss of MeFBSE coincided with production of N-methyl perfluorobutanesulfonamido acetate (MeFBSAA) and perfluorobutane sulfinate (PFBSI). The biodegradation appeared biphasic, with pseudo first-order loss between days 0 and 70, resulting in approximately 75% removal but no further depletion of MeFBSE between days 70 and 108. By day 108 MeFBSAA and PFBSI accounted for 57 and 40 mol% of initial dose, respectively. Mass balance values in live cultures on days 0, 10, 21, 29, 70, and 108 were 103, 92, 94, 100, 93, and 122%, respectively. The apparent first-order biodegradation rate constant for MeFBSE over the first 70 d was 0.0194 d-1, and the apparent half-life was 35.8 d. Incubation of EtFOSE with live digester sludge resulted in low-level formation of N-ethyl perfluorooctane-sulfonamido acetate and perfluorooctane sulfinate, which did not form in sterile controls. Although it was not measurably lost, 2 to 3% loss of EtFOSE was calculated based on product concentrations. The total product formation rate constant was determined by first-order kinetic evaluation over the first 72 d to estimate a first-order biodegradation rate constant for EtFOSE at 0.000374 d-1, and the apparent half-life time was 1860 d. Environ Toxicol Chem 2018;37:768-779. © 2017 SETAC.

Abstract  A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50=0.012μM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen. The fluorescence of compounds 3e and 3f depended on the solvent properties and showed significant changes when mixed with ERα or ERβ in vitro. Furthermore, target molecule 3e could cross the cell membrane, localize and image drug-target interaction in real time without cell washing. Thus, the coumarin-based platform represents a promising new ER-targeted delivery vehicle with potential imaging and therapeutic properties.

Abstract  Evidence has shown that leukocyte telomere length (LTL) at birth is related to the susceptibility to various diseases in later life and the setting of newborn LTL is influenced by the intrauterine environment. Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as a kind of persistent organic pollutants, are commonly used in commercial and domestic applications and are capable of crossing the maternal-fetal barrier during pregnancy. We hypothesized that intrauterine exposure to PFASs may affect fetal LTL by increasing oxidative stress. To verify this hypothesis, LTL, concentrations of PFASs and reactive oxygen species (ROS) were measured in umbilical cord blood of 581 newborns from a prospective cohort. Our results showed that there were interactions between PFOS/PFDA and sex on LTL and ROS. The LTL was significantly shorter (0.926 ± 0.053 vs 0.945 ± 0.054, P = .023 for PFOS; 0.919 ± 0.063 vs 0.940 ± 0.059, P = .011 for PFDA) and the ROS levels were extremely higher (252.9 ± 60.5 [M] vs 233.5 ± 53.6 [M], P = .031 for PFOS; 255.2 ± 62.9 [M] vs 232.9 ± 58.3 [M], P = .011 for PFDA) in the female newborns whose PFOS or PFDA concentrations fell in the upmost quartile compared with those in the lowest quartile after adjusting for potential confounders. ROS levels were inversely associated with LTL in female newborns (β = -1.42 × 10-4, P = .022). 13% of the effect of PFOS on female LTL was mediated through ROS approximately by the mediation analyses. However, in male newborns, no relationships among PFASs, ROS and LTL were observed. Our findings suggest a "programming" role of PFASs on fetal telomere biology system in females in intrauterine stage.

Abstract  6:2 fluorotelomer sulfonamide alkylbetaine (6:2 FTAB) is a major component of Forafac®1157, a novel perfluorooctane sulfonate (PFOS) alternative used globally in aqueous film forming foams (AFFFs). Although 6:2 FTAB has been recently detected in the aquatic environment, its toxic effects on aquatic organisms remain unclear. Here, zebrafish embryos were exposed to various concentrations of 6:2 FTAB (0, 5, 10, 20, 40, 60, 80, and 100 mg/L) from 6 to 120 h post-fertilization (hpf) to investigate its developmental toxicity and possible mechanism of action. Results showed that exposure to 40 mg/L or higher concentrations of 6:2 FTAB significantly decreased the survival percentage and increased the malformation percentage. The median lethal concentration (LC50) at 120 hpf was 43.73 ± 3.24 mg/L, and the corresponding benchmark dose lower limit (BMDL) of lethal effect was 33.79 mg/L. These values were both higher than those for PFOS, supporting the notion that 6:2 FTAB is less toxic than PFOS to zebrafish embryos. The most common developmental defect in 6:2 FTAB-treated embryos was rough-edged skin/fins. TUNEL assay showed that 6:2 FTAB exposure induced cell apoptosis in the tail region compared with that of the control, which might explain the rough-edged skin/fins. The increased transcriptional levels of p53, bax, and apaf1 and the increased activities of caspase-3, -8, and -9 provided further evidence of 6:2 FTAB-induced apoptosis. We also analyzed the effects of 6:2 FTAB on oxidative stress and the immune system. Results showed that reactive oxygen species and malondialdehyde accumulated in concentration-dependent manners after exposure to 6:2 FTAB, and antioxidant enzyme activities (catalase and glutathione peroxidase) also changed. Exposure to 6:2 FTAB also altered the transcriptional levels of ccl1, il-1β, il-8, tnfα, ifn, and cxcl-c1c, which play important roles in the innate immune system. Collectively, our data suggest that 6:2 FTAB exposure can induce cell apoptosis, oxidative stress, and immunotoxicity, thus highlighting the developmental toxicity of 6:2 FTAB in zebrafish embryos.

Abstract  PURPOSE: This study demonstrated the effects of perfluorobutane (Sonazoid®) with contrast-enhanced ultrasonography (CEUS) to identify the spread of local anesthetics in ultrasound-guided nerve block.

METHODS: This study consists of simulation, cadaveric, and animal studies. In a simulation study, 1% lidocaine with 10- to 1000-fold diluted Sonazoid®, a US-specific contrast agent to diagnose hepatic and breast cancers (0.5 mL), was injected into a resin-based phantom to determine the optimal concentration for ultrasound-guided peripheral nerve block. The enhanced area was measured by direct observation and ultrasonography (US). In the cadaver study, ultrasound-guided sciatic nerve block was performed at the popliteal fossa in the 9 extremities, and 5 mL of the optimally diluted Sonazoid®defined in the simulation study with X-ray contrast medium and blue dye was injected. Longitudinal spread of the solution was measured by CEUS, X-ray imaging and anatomical dissection. In the animal study, the optimally diluted Sonazoid®was injected around the sciatic nerve of rats (n = 6), and neuronal function and toxicity were evaluated by behavioral and histological estimation.

RESULTS: The simulation study proved that 100-fold diluted Sonazoid®was the optimal concentration. In the cadaver study, CEUS and anatomical dissection (r = 0.90, P = 0.0020) or radiography (r = 0.84, P = 0.0072) showed high agreement and correlation with the longitudinal spread. CEUS clearly showed a fine intraneuronal injection image compared to the usual B-mode imaging. The animal study suggested no adverse effects by co-administration of lidocaine and Sonazoid®.

CONCLUSIONS: CEUS with 100-fold diluted Sonazoid®could identify the spread of local anesthetic as well as radiography and anatomical dissection, and distinguish between intra- and extraneuronal injections without neurodegeneration.

Abstract  Mild hyperthermia generated using high intensity focused ultrasound (HIFU) and microbubbles (MBs) can improve tumor drug delivery from non-thermosensitive liposomes (NTSLs) and low temperature sensitive liposomes (LTSLs). However, MB and HIFU are limited by the half-life of the contrast agent and challenges in accurate control of large volume tumor hyperthermia for longer duration (>30min.). The objectives of this study were to: 1) synthesize and characterized long-circulating echogenic nanobubble encapsulated LTSLs (ELTSLs) and NTSLs (ENTSLs), 2) evaluate in vivo drug release following short duration (~20min each) HIFU treatments administered sequentially over an hour in a large volume of mouse xenograft colon tumor, and 3) determine the impact of the HIFU/nanobubble combination on intratumoral drug distribution. LTSLs and NTSLs containing doxorubicin (Dox) were co-loaded with a nanobubble contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create ELTSLs and ENTSLs, which then were characterized for size, release in a physiological buffer, and ability to encapsulate PFP. For the HIFU group, mild hyperthermia (40-42°C) was completed within 90min after liposome infusion administered sequentially in three regions of the tumor. Fluorescence microscopy and high performance liquid chromatography analysis were performed to determine the spatial distribution and concentration of Dox in the treated regions. PFP encapsulation within ELTSLs and ENTSLs did not impact size or caused premature drug release in physiological buffer. As time progressed, the delivery of Dox decreased in HIFU-treated tumors with ELTSLs, but this phenomenon was absent in the LTSL, NTSL, and ENTSL groups. Most importantly, PFP encapsulation improved Dox penetration in the tumor periphery and core and did not impact the distribution of Dox in non-tumor organs/tissues. Data from this study suggest that short duration and sequential HIFU treatment could have significant benefits and that its action can be potentiated by nanobubble agents to result in improved drug penetration.