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Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study-consisting of patients with recurrent, platinum-resistant ovarian cancer-was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration. We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS). Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS. This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer.

The effective design of an artificial photosynthetic system entails the optimization of several important interactions. Herein we report stopped-flow UV-visible (UV-vis) spectroscopy, X-ray crystallographic, density functional theory (DFT), and electrochemical kinetic studies of the Re(bipy- t Bu)(CO) ₃(L) catalyst for the reduction of CO ₂ to CO. A remarkable selectivity for CO ₂ over H ⁺ was observed by stopped-flow UV-vis spectroscopy of [Re(bipy- t Bu)(CO) ₃] ⁻¹. The reaction with CO ₂ is about 25 times faster than the reaction with water or methanol at the same concentrations. X-ray crystallography and DFT studies of the doubly reduced anionic species suggest that the highest occupied molecular orbital (HOMO) has mixed metal-ligand character rather than being purely doubly occupied [Formula], which is believed to determine selectivity by favoring CO ₂ (σ + π) over H ⁺ (σ only) binding. Electrocatalytic studies performed with the addition of Brönsted acids reveal a primary H/D kinetic isotope effect, indicating that transfer of protons to Re -CO ₂ is involved in the rate limiting step. Lastly, the effects of electrode surface modification on interfacial electron transfer between a semiconductor and catalyst were investigated and found to affect the observed current densities for catalysis more than threefold, indicating that the properties of the electrode surface need to be addressed when developing a homogeneous artificial photosynthetic system.

We report the ability to tune the catalytic activities for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) by applying mechanical stress on a highly n-type doped rutile TiO 2 films. We demonstrate through operando electrochemical experiments that the low HER activity of TiO 2 can reversibly approach those of the state-of-the-art non-precious metal catalysts when the TiO 2 is under tensile strain. At 3% tensile strain, the HER overpotential required to generate a current density of 1 mA/cm 2 shifts anodically by 260 mV to give an onset potential of 125 mV, representing a drastic reduction in the kinetic overpotential. A similar albeit smaller cathodic shift in the OER overpotential is observed when tensile strain is applied to TiO 2 . Results suggest that significant improvements in HER and OER activities with tensile strain are due to an increase in concentration of surface active sites and a decrease in kinetic and thermodynamics barriers along the reaction pathway(s). Our results highlight that strain applied to TiO 2 by precisely controlled and incrementally increasing (i.e. dynamic ) tensile stress is an effective tool for dynamically tuning the electrocatalytic properties of HER and OER electrocatalysts relative to their activities under static conditions.

We observed that teneral adults (<1 h post-molt) of Cimex lectularius L. appeared more adept at climbing a smooth surface compared to sclerotized adults. Differences in climbing ability on a smooth surface based on sclerotization status were quantified by measuring the height to which bed bugs climbed when confined within a glass vial. The average maximum height climbed by teneral (T) bed bugs (n = 30, height climbed = 4.69 cm) differed significantly (P< 0.01) from recently sclerotized (RS) bed bugs (n = 30, height climbed = 1.73 cm at ~48 h post molt), sclerotized group 1 (S1) bed bugs (n = 30, S1 = 2.42 cm at >72 h), and sclerotized group 2 (S2) bed bugs (n = 30, height climbed = 2.64 cm at >72 h post molt). When heights from all climbing events were summed, teneral bed bugs (650.8 cm climbed) differed significantly (P< 0.01) from recently sclerotized (82 cm climbed) and sclerotized (group 1 = 104.6 cm climbed, group 2 = 107.8 cm climbed) bed bugs. These findings suggested that the external surface of teneral bed bug exoskeletons possess an adhesive property. Using atomic force microscopy (AFM), we found that adhesion force of an exoskeletal (presumably molting) fluid decreased almost five-fold from 88 to 17 nN within an hour of molting. Our findings may have implications for laboratory safety and the effectiveness of bed bug traps, barriers, and biomimetic-based adhesives.

PurposeWe developed an accessible method for labeling small extracellular vesicles (sEVs) without disrupting endogenous ligands. Using labeled sEVs administered to conscious rats, we developed a multiple compartment pharmacokinetic model to identify potential differences in the disposition of sEVs from three different cell types.MethodsCrude sEVs were labeled with a non-homologous oligonucleotide and isolated from cell culture media using a commercial reagent. Jugular vein catheters were used to introduce EVs to conscious rats (n = 30) and to collect blood samples. Digital PCR was leveraged to allow for quantification over a wide dynamic range. Non-linear mixed effects analysis with first order conditional estimation – extended least squares (FOCE ELS) was used to estimate population-level parameters with associated intra-animal variability.Results86.5% ± 1.5% (mean ± S.E.) of EV particles were in the 45–195 nm size range and demonstrated protein and lipid markers of endosomal origin. Incorporated oligonucleotide was stable in blood and detectable over five half-lives. Data were best described by a three-compartment model with one elimination from the central compartment. We performed an observation-based simulated posterior predictive evaluation with prediction-corrected visual predictive check. Covariate and bootstrap analyses identified cell type having an influence on peripheral volumes (V2 and V3) and clearance (Cl3).ConclusionsOur method relies upon established laboratory techniques, can be tailored to a variety of biological questions regarding the pharmacokinetic disposition of extracellular vesicles, and will provide a complementary approach for the of study EV ligand-receptor interactions in the context of EV uptake and targeted therapeutics.

Membrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC) and the ATP Binding Cassette transporters (ABC). Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters. In this study, primary human hepatocytes (n = 7 donors) were cultured and treated for 24 h with rifampin and vehicle control. RNA was isolated from the hepatocytes, mRNA expression was measured by RNA-seq, and miRNA expression was analyzed by Taqman OpenArray. The effect of rifampin on the expression of selected transporters was also tested in kidney cell lines. The impact of rifampin on the expression of 410 transporter genes from 19 different transporter gene families was compared with vehicle control. Expression patterns of 12 clinically relevant drug transporter genes were changed by rifampin (FDR < 0.05). For example, the expressions of ABCC2, ABCB1, and ABCC3 were increased 1.9-, 1.7-, and 1.2-fold, respectively. The effects of rifampin on four uptake drug transporters (SLCO1B3, SLC47A1, SLC29A1, SLC22A9) were negatively correlated with the rifampin effects on specific microRNA expression (SLCO1B3/miR-92a, SLC47A1/miR-95, SLC29A1/miR-30d#, and SLC22A9/miR-20; r < -0.79; p < 0.05). Seven hepatic drug transporter genes (SLC22A1, SLC22A5, SLC15A1, SLC29A1, SLCO4C1, ABCC2, and ABCC4), whose expression was altered by rifampin in hepatocytes, were also present in a renal proximal tubular cell line, but in renal cells rifampin did not alter their gene expression. PXR expression was very low in the kidney cells; this may explain why rifampin induces gene expression in a tissue-specific manner. Rifampin alters the expression of many of the clinically relevant hepatic drug transporters, which may provide a rational basis for understanding rifampin-induced drug-drug interactions reported in vivo. The relevance of its effect on many other transporters remains to be studied.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78–1.18), serious ADEs (OR: 0.91, 95% CI: 0.58–1.40), or mortality (OR: 0.60, 95% CI: 0.28–1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12–0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 × 10−8), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor β (TGFβ)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 × 10−5). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations.

Outbreaks of avian influenza (AI) and other highly contagious poultry diseases continue to be a concern for those involved in the poultry industry. In the situation of an outbreak, emergency depopulation of the birds involved is necessary. In this project, two compressed air foam systems (CAFS) were evaluated for mass emergency depopulation of layer hens in a manure belt equipped cage system. In both experiments, a randomized block design was used with multiple commercial layer hens treated with one of three randomly selected depopulation methods: CAFS, CAFS with CO2 gas, and CO2 gas. In Experiment 1, a Rowe manufactured CAFS was used, a selection of birds were instrumented, and the time to unconsciousness, brain death, altered terminal cardiac activity and motion cessation were recorded. CAFS with and without CO2 was faster to unconsciousness, however, the other parameters were not statistically significant. In Experiment 2, a custom Hale based CAFS was used to evaluate the impact of bird age, a selection of birds were instrumented, and the time to motion cessation was recorded. The difference in time to cessation of movement between pullets and spent hens using CAFS was not statistically significant. Both CAFS depopulate caged layers, however, there was no benefit to including CO2.

Linepithema humile (Mayr), the Argentine ant, is an invasive pest that has spread throughout the United States and is a problem in natural and managed habitats in South Carolina. Foraging patterns and the effectiveness of liquid baits for control of this pest have been studied in urban areas. However, similar studies have not been conducted in natural areas such as parks, picnic grounds, or campsites. L. humile populations can be large and widespread, making them a major nuisance pest for visitors to these natural areas. The primary objective of this study was to determine an effective distance between bait stations for control of L. humile in a natural area. A double antibody-sandwich enzymelinked immunosorbent assay (DAS-ELISA) procedure was used to detect individual ants that consumed rabbit immunoglobin (IgG) protein for marking and tracking. In both lab and field conditions, there was a significant difference in the detection of IgG in ants fed protein marker mixed with sugar water compared with ants only fed sugar water. Additional field studies revealed that an individual ant could retain detectable levels of protein marker for 3 d and that an ant feeding on IgG containing bait could be detected over 15 m from the original bait source. Overall, we found that using liquid ant baits, with a placement of 20 m between stations, was effective in reducing L. humile numbers between April to October, 2012 in a natural park area of Lake Greenwood State Park, SC.