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Clinical and Translational Science

Pascale Fisel, Elke Schaeffeler, Matthias Schwab
The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge...
April 16, 2018: Clinical and Translational Science
Marc Cantillon, Robert Ings, Laxminarayan Bhat
RP5063 is a multimodal dopamine (D)-serotonin (5-HT) stabilizer with a high affinity for D2/3/4 and 5-HT1A/2A/2B/7 receptors and moderate affinity for the serotonin transporter. Single-dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple-dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single-dose study, 32 treatment-emergent adverse events (TEAEs) were observed. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common...
April 10, 2018: Clinical and Translational Science
Christopher Cabanski, Houston Gilbert, Sofia Mosesova
Visualizations are a powerful tool for telling a story about a dataset or analysis. If done correctly, visualizations not only display data but also help the audience digest key information. However, if done haphazardly, visualization has the potential to confuse the audience and, in the most extreme circumstances, deceive. In this tutorial we provide a set of general principles for creating informative visualizations that tell a complete and accurate story of the data. This article is protected by copyright...
March 30, 2018: Clinical and Translational Science
Shlomit Radom-Aizik, Frank P Zaldivar, Dwight M Nance, Fadia Haddad, Dan M Cooper, Gregory R Adams
Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air...
March 30, 2018: Clinical and Translational Science
Joan Korth-Bradley, Jeremy Rupon, Anna Plotka, Robert Charnigo, Pablo Rendo
An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. FVIII: C was assayed using a chromogenic substrate assay...
March 25, 2018: Clinical and Translational Science
Rebecca Racz, Theodoros G Soldatos, David Jackson, Keith Burkhart
Case reports suggest an association between second-generation antipsychotics (SGAs) and serotonin syndrome (SS). The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) was analyzed to generate hypotheses about how SGAs may interact with pharmacological targets associated with SS. FAERS was integrated with additional sources to link information about adverse events with drugs and targets. Using Proportional Reporting Ratios, we identified signals that were further investigated with the literature to evaluate mechanistic hypotheses formed from the integrated FAERS data...
March 25, 2018: Clinical and Translational Science
Sangeeta Raje, Ernesto Callegari, Vaishali Sahasrabudhe, Alfin Vaz, Haihong Shi, Eric Fluhler, Eric J Woolf, Klaas Schildknegt, Kyle Matschke, Christine Alvey, Susan Zhou, Dimitris Papadopoulos, Robert Fountaine, Didier Saur, Steven G Terra, Lloyd Stevens, Daniel Gaunt, David L Cutler
Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with14 C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa ) of ertugliflozin. Eight healthy adult men received 100-μg i.v.14 C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg14 C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2)...
March 25, 2018: Clinical and Translational Science
Andrey Postnov, Mark E Schmidt, Darrel J Pemberton, Jan de Hoon, Anne van Hecken, Maarten van den Boer, Peter Zannikos, Peter van der Ark, James A Palmer, Stef Rassnick, Sofie Celen, Guy Bormans, Koen van Laere
Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ-42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ-42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study...
March 25, 2018: Clinical and Translational Science
Xiajing Gong, Meng Hu, Liang Zhao
Additional value can be potentially created by applying big data tools to address pharmacometric problems. The performances of machine learning (ML) methods and the Cox regression model were evaluated based on simulated time-to-event data synthesized under various preset scenarios, i.e., with linear vs. nonlinear and dependent vs. independent predictors in the proportional hazard function, or with high-dimensional data featured by a large number of predictor variables. Our results showed that ML-based methods outperformed the Cox model in prediction performance as assessed by concordance index and in identifying the preset influential variables for high-dimensional data...
March 13, 2018: Clinical and Translational Science
(no author information available yet)
No abstract text is available yet for this article.
March 10, 2018: Clinical and Translational Science
Hans Ericsson, Karin Nelander, Maria Lagerstrom-Fermer, Clare Balendran, Maria Bhat, Ligia Chialda, Li-Ming Gan, Maria Heijer, Magnus Kjaer, John Lambert, Eva-Lotte Lindstedt, Gun-Britt Forsberg, Carl Whatling, Stanko Skrtic
We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed...
March 8, 2018: Clinical and Translational Science
Susan M Keating, D Lansing Taylor, Anne L Plant, E David Litwack, Peter Kuhn, Emily J Greenspan, Christopher M Hartshorn, Caroline C Sigman, Gary J Kelloff, David D Chang, Gregory Friberg, Jerry S H Lee, Keisuke Kuida
The high-content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care...
March 2, 2018: Clinical and Translational Science
Burhan A Khan, Renee Robinson, Alison E Fohner, LeeAnna I Muzquiz, Brian D Schilling, Julie A Beans, Matthew J Olnes, Laura Trawicki, Holly Frydenlund, Cindi Laukes, Patrick Beatty, Brian Phillips, Deborah Nickerson, Kevin Howlett, Denise A Dillard, Timothy A Thornton, Kenneth E Thummel, Erica L Woodahl
Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites...
February 13, 2018: Clinical and Translational Science
Valentina Shakhnovich
No abstract text is available yet for this article.
February 9, 2018: Clinical and Translational Science
Yan Ji, Jin Y Jin, David M Hyman, Geoffrey Kim, Ajit Suri
No abstract text is available yet for this article.
February 1, 2018: Clinical and Translational Science
Morgan D McSweeney, Zina C Versfeld, Delesha M Carpenter, Samuel K Lai
Antibodies against polyethylene glycol (PEG) can critically jeopardize the efficacy and safety of PEGylated therapeutics. For some PEG-drugs, a sizeable fraction of patients develop anti-PEG antibodies (APA), leading to reduced efficacy and potential adverse events. We surveyed physicians from several specialties to assess their awareness of APA. Overall, 83% of the physicians surveyed indicated that they have recently prescribed PEGylated drugs. Although 91% of respondents were aware of antidrug antibodies in general, only 22% were aware of APA responses...
January 31, 2018: Clinical and Translational Science
Kristin W Weitzel, D Max Smith, Amanda R Elsey, Benjamin Q Duong, Benjamin Burkley, Michael Clare-Salzler, Yan Gong, Tara A Higgins, Benjamin Kong, Taimour Langaee, Caitrin W McDonough, Benjamin J Staley, Teresa T Vo, Dyson T Wake, Larisa H Cavallari, Julie A Johnson
Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme)...
March 2018: Clinical and Translational Science
John A Wagner, Andrew M Dahlem, Lynn D Hudson, Sharon F Terry, Russ B Altman, C Taylor Gilliland, Christopher DeFeo, Christopher P Austin
Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure...
March 2018: Clinical and Translational Science
Stephanie Faucette, Santosh Wagh, Ashit Trivedi, Karthik Venkatakrishnan, Neeraj Gupta
No abstract text is available yet for this article.
March 2018: Clinical and Translational Science
Jamie R Robinson, Joshua C Denny, Dan M Roden, Sara L Van Driest
No abstract text is available yet for this article.
March 2018: Clinical and Translational Science
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