102 research outputs found
Preclinical Evaluation of [18F]LCATD as a PET Tracer to Study Drug-Drug Interactions Caused by Inhibition of Hepatic Transporters
Acknowledgements: A.T. gratefully acknowledges SINAPSE (www.sinapse.ac.uk) and AstraZeneca (UK) for co-funding a studentship. P.S. and C.S.E. are employees of AstraZeneca Ltd., UK. This project has also received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 675417.Peer reviewedPublisher PD
Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas
The Epstein-Barr virus (EBV)-positive subtype of gastric adenocarcinoma is conventionally identified by in situ hybridization (ISH) for viral nucleic acids, but next-generation sequencing represents a potential alternative. We therefore determined normalized EBV read counts by whole genome, whole exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases. In pairwise comparisons, individual samples were either concordantly high or concordantly low by all genomic methods for which data were available. Empiric cut-offs of sequencing counts identified 26 (9%) tumors as EBV-positive. EBV-positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa=0.91). EBV-positive gastric tumors may be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research
In Vitro and In Vivo Metabolism of a Selective ␦-Opioid Receptor
ABSTRACT: 4-({4-[(2-Hydroxy-ethyl)-methyl-carbamoyl]-phenyl}-quinolin-8-ylmethylene)-1-thiazol-4-ylmethyl-piperidinium (compound I) is a selective agonist of ␦-opioid receptor developed for the treatment of depressive and anxiety disorders. The in vitro biotransformation studies using rat, dog, and human hepatocytes showed that the metabolites detected in human hepatocytes were also found in either rat or dog hepatocytes. M1 (N-dealkylation), M2 (Ndemethylation), and M4 (carboxylic acid metabolite) were major phase I metabolites observed in all three species. Human CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the formation of M1 and M2 in human liver microsomes. After single oral administration of [ 14 C]compound I, the major elimination route for [ 14 C]compound I and its metabolites in rat was through feces with 92.9% recovery. The results from the bile duct-cannulated study revealed that a minimum of 51% of administered dose was absorbed in rats. The pharmacokinetic analysis using unlabeled parent drug showed that compound I was rapidly absorbed and exhibited a mean apparent terminal half-life of approximately 2.7 h. A total of 15 metabolites of compound I were detected and profiled in rat urine, bile, and feces. In rat bile, compound I accounted for <1.5% of the excreted dose, suggesting that compound I underwent extensive metabolism before elimination. The structures of metabolites were elucidated by highresolution tandem mass spectrometry. M1, M4, and M6 were the most abundant metabolites observed in rat bile. Only a low level of parent [ 14 C]compound I was observed in rat plasma
Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms
<p>Abstract</p> <p>Background</p> <p>The infrarenal abdominal aorta exhibits increased disease susceptibility relative to other aortic regions. Allograft studies exchanging thoracic and abdominal segments showed that regional susceptibility is maintained regardless of location, suggesting substantial roles for embryological origin, tissue composition and site-specific gene expression.</p> <p>Results</p> <p>We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibited spatial expression differences. <it>HOXA4 </it>was chosen for further study, since it had decreased expression in the abdominal compared to the thoracic aorta. Western blot analysis from 24 human aortas demonstrated significantly higher HOXA4 protein levels in thoracic compared to abdominal tissues (<it>P </it>< 0.001). Immunohistochemical staining for HOXA4 showed nuclear and perinuclear staining in endothelial and smooth muscle cells in aorta. The <it>HOXA4 </it>transcript levels were significantly decreased in human abdominal aortic aneurysms (AAAs) compared to age-matched non-aneurysmal controls (<it>P </it>< 0.00004). Cultured human aortic endothelial and smooth muscle cells stimulated with INF-γ (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (<it>P </it>< 0.0007).</p> <p>Conclusions</p> <p>Our results demonstrated spatial variation in expression of HOXA4 in human aortas that persisted into adulthood and that downregulation of <it>HOXA4 </it>expression was associated with AAAs, an important aortic disease of the ageing population.</p
In vitro and in vivo metabolism of a selective δ -opioid receptor agonist
The results from the bile duct-cannulated study revealed that a minimum of 51% of administered dose was absorbed in rats. The pharmacokinetic analysis using unlabeled parent drug showed that Compound I was rapidly absorbed and exhibited a mean apparent terminal half-life of approximately 2.7 h. A total of 15 metabolites of Compound I were detected and profiled in rat urine, bile, and feces. In rat bile, Compound I accounted for <1.5% of the excreted dose, suggesting that Compound I underwent extensively metabolism before elimination. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. M1, M4, and M6 were the most abundant metabolites observed in rat bile. Only low level of parent [ 14 C]-Compound I was observed in rat plasma. DMD #40980
Efficacy of essential oil mouthwash with and without alcohol: a 3-Day plaque accumulation model
<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the antiplaque effect of a new alcohol free essential oil mouthwash with respect to a control of an essential oil with alcohol mouthwash, using an <it>in vivo </it>plaque regrowth model of 3-days.</p> <p>Methods</p> <p>The study was designed as a double-masked, randomized, crossover clinical trial, involving 30 volunteers to compare two different essential oil containing mouthwashes, during a 3-day plaque accumulation model. After receiving a thorough professional prophylaxis at the baseline, over the next 3-days each volunteer refrained from all oral hygiene measures and had two daily rinses with 20 ml of the test mouthwash (alcohol free essential oil) or the control mouthwash (essential oil with alcohol). At the end of the each experimental period, plaque was assessed and the panelists filled out a questionnaire. Each subject underwent a 14 days washout period and there was a second allocation.</p> <p>Results</p> <p>The essential oil mouthwash with ethanol shows a better inhibitory effect of plaque regrowth in 3-days than the mouthwash test with only essential oil in the whole mouth (plaque index = 2.18 against 2.46, respectively, p < 0.05); for the lower jaw (plaque index = 2.28 against 2.57, respectively, p < 0.05); for the upper jaw (plaque index = 2.08 against 2.35, respectively, p < 0.05); for the incisors (plaque index = 1.93 against 2.27, respectively, p < 0.05); and the canines (plaque index = 1.99 against 2.47, respectively, p < 0.05).</p> <p>Conclusion</p> <p>The essential oil containing mouthwash without alcohol seems to have a less inhibiting effect on the plaque regrowth than the traditional alcoholic solution.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01411618">NCT01411618</a></p
Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research
Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling
Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes
Glyphosate-Resistant Soybean Cultivar Response to Glyphosate
Glyphosate (N-(phosphonomethyl) glycine)-resistant (GR) soybean [Glycine max (L.) Merr.] technology is gaining acceptance in U.S. cropping systems, yet potential yield suppression from either cultivar genetic differentials, the GR gene/gene insertion process, or glyphosate is a concern. Other work shows that the GR gene/gene insertion process may suppress soybean yield. No one has reported the effects of glyphosate on a diverse group of commercially available GR soybean cultivars. In this study we evaluated one of the potential sources of GR yield suppression—the effect of glyphosate on yield, growth, and development of GR cultivars. Field experiments were conducted at four Nebraska locations with12 GR cultivars in 1998 and 13 GR cultivars in 1999. Soybean response to glyphosate, ammonium sulfate (AMS), and water application at 21 and 42 d after soybean emergence was compared with control plots treated with AMS and water in 1998. An additional control, water alone, was added in 1999. Grain yield among cultivars differed as expected with a range of 3.44 to 3.96 Mg ha-1 in the 2-yr averages. Glyphosate did not affect the majority of the soybean growth and development characteristics measured. Grain yield of GR soybean was not affected by glyphosate at any location or when averaged over locations. Two-year average grain yield of cultivars treated with glyphosate, AMS, and water was 3.74 Mg ha-1; this was not different from 3.79 Mg ha-1 with AMS and water treatment
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