Development and Applications of Patient-Derived Xenograft Models in Humanized Mice for Oncology and Immune-Oncology Drug Discovery.
Authors: Verma B, Ritchie M, Mancini M
Abstract
With the recent approval of four novel immune oncology agents for the treatment of various cancers, the emerging power of this drug class has been substantiated. However, the full potential of such agents is yet to be realized, with only a fraction of the patient population responding to these drugs. A more advanced pre-clinical and translational research platform may increase our understanding of the mechanisms associated with immune-mediated cancer cell death, thereby facilitating the design and development of more generally efficacious agents and drug regi...
Source: Current Protocols in Pharmacology - September 12, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
All-Optical Electrophysiology for Disease Modeling and Pharmacological Characterization of Neurons.
Authors: Werley CA, Brookings T, Upadhyay H, Williams LA, McManus OB, Dempsey GT
Abstract
A key challenge for establishing a phenotypic screen for neuronal excitability is measurement of membrane potential changes with high throughput and accuracy. Most approaches for probing excitability rely on low-throughput, invasive methods or lack cell-specific information. These limitations stimulated the development of novel strategies for characterizing the electrical properties of cultured neurons. Among these was the development of optogenetic technologies (Optopatch) that allow for stimulation and recording of ...
Source: Current Protocols in Pharmacology - September 12, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Murine Retrovirally-Transduced Bone Marrow Engraftment Models of MLL-Fusion-Driven Acute Myelogenous Leukemias (AML).
Authors: Stubbs MC, Krivtsov AV
Abstract
MLL-rearranged leukemia represents approximately 5% to 10% of adult acute myelogenous leukemia (AML) and nearly half of all infant/pediatric acute leukemia cases. These leukemias have a poor prognosis, and there are no approved therapeutic options. The rearrangement in the MLL gene leads to aberrant expression of MLL-fusion proteins. These are transforming in murine bone marrow and, in particular, on stem cells and myeloid progenitors derived from bone marrow or fetal liver. The commonality of the MLL fusions is the in-frame fusion of 8 to 11 N-terminal exons of MLL...
Source: Current Protocols in Pharmacology - September 12, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Label-Free Dynamic Mass Redistribution and Bio-Impedance Methods for Drug Discovery.
Authors: Grundmann M
Abstract
Label-free biosensors are increasingly employed in drug discovery. Cell-based biosensors provide valuable insights into the biological consequences of exposing cells and tissues to chemical agents and the underlying molecular mechanisms associated with these effects. Optical biosensors based on the detection of dynamic mass redistribution (DMR) and impedance biosensors using cellular dielectric spectroscopy (CDS) capture changes of the cytoskeleton of living cells in real time. Because signal transduction correlates with changes in cell morphology, DMR and CDS biosensors are e...
Source: Current Protocols in Pharmacology - June 24, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of Transgenic Mouse Models of Myeloproliferative Neoplasms (MPNs).
Authors: Dunbar A, Nazir A, Levine R
Abstract
Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies. From early retroviral tr...
Source: Current Protocols in Pharmacology - June 24, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
The Ussing Chamber Assay to Study Drug Metabolism and Transport in the Human Intestine.
Authors: Kisser B, Mangelsen E, Wingolf C, Partecke LI, Heidecke CD, Tannergren C, Oswald S, Keiser M
Abstract
The Ussing chamber is an old but still powerful technique originally designed to study the vectorial transport of ions through frog skin. This technique is also used to investigate the transport of chemical agents through the intestinal barrier as well as drug metabolism in enterocytes, both of which are key determinants for the bioavailability of orally administered drugs. More contemporary model systems, such as Caco-2 cell monolayers or stably transfected cells, are more limited in their use co...
Source: Current Protocols in Pharmacology - June 24, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Biomarkers-A General Review.
Authors: Aronson JK, Ferner RE
Abstract
A biomarker is a biological observation that substitutes for and ideally predicts a clinically relevant endpoint or intermediate outcome that is more difficult to observe. The use of clinical biomarkers is easier and less expensive than direct measurement of the final clinical endpoint, and biomarkers are usually measured over a shorter time span. They can be used in disease screening, diagnosis, characterization, and monitoring; as prognostic indicators; for developing individualized therapeutic interventions; for predicting and treating adverse drug reactions; for ...
Source: Current Protocols in Pharmacology - March 18, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
The Quantitative Characterization of Functional Allosteric Effects.
Authors: Kenakin T
Abstract
Seven-transmembrane receptors (7TMRs or GPCRs [G protein-coupled receptors]) are nature's prototypic allosteric proteins in that they mediate the interaction between ligand binding to the receptor and the receptor interacting with another cell signaling protein. A growing class of potential drugs acting through 7TMRs are allosteric in nature in that they bind to a separate site on the receptor protein to modify the interactions between the receptor, natural binding/orthosteric ligand, and signaling proteins. Two main allosteric compound categories are those that increase (positi...
Source: Current Protocols in Pharmacology - March 18, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Assessment of Ex Vivo Transport Function in Isolated Rodent Brain Capillaries.
Authors: Chan GN, Cannon RE
Abstract
The blood-brain barrier plays an important role in neuroprotection; however, it can be a major obstacle for drug delivery to the brain. This barrier primarily resides in the brain capillaries and functions as an interface between the brain and peripheral blood circulation. Several anatomical and biochemical elements of the blood-brain barrier are essential to regulate the permeability of nutrients, ions, hormones, toxic metabolites, and xenobiotics into and out of the brain. In particular, high expression of ATP-driven efflux transporters at the blood-brain barrier is a...
Source: Current Protocols in Pharmacology - March 18, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Logical Experimental Design and Execution in the Biomedical Sciences.
Authors: Holder DJ, Marino MJ
Abstract
Lack of reproducibility has been highlighted as a significant problem in biomedical research. The present unit is devoted to describing ways to help ensure that research findings can be replicated by others, with a focus on the design and execution of laboratory experiments. Essential components for this include clearly defining the question being asked, using available information or information from pilot studies to aid in the design the experiment, and choosing manipulations under a logical framework based on Mill's "methods of knowing" to build confidence in putat...
Source: Current Protocols in Pharmacology - March 18, 2017 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Visualization of 5-HT Receptors Using Radioligand-Binding Autoradiography.
Authors: Cortés R, Vilaró MT, Mengod G
Abstract
Described in this unit are techniques to visualize the majority of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes in sections of frozen brain tissue using receptor autoradiography. Protocols for brain extraction and sectioning, radioligand exposure, autoradiogram generation, and data quantification are provided, as are the optimal incubation conditions for the autoradiographic visualization of receptors using agonist and antagonist radioligands. © 2016 by John Wiley & Sons, Inc.
PMID: 27960027 [PubMed - in process] (Source: Current Pro...
Source: Current Protocols in Pharmacology - December 14, 2016 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview on Research and Clinical Applications of Optogenetics.
Authors: Towne C, Thompson KR
Abstract
Optogenetics is a method that uses light to control cells in living tissue, typically neurons, that have been modified to express light-sensitive ion channels and pumps. The approach facilitates neuromodulation in brain preparations and freely moving animals with unmatched spatial and temporal resolution. This optogenetics overview describes the vast array of light-sensitive proteins available and the methods used to deliver them to tissue and modulate them with light. How these methods have so far enhanced our knowledge of fundamental neuroscience and psychiatric dis...
Source: Current Protocols in Pharmacology - December 14, 2016 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Stability of Drugs, Drug Candidates, and Metabolites in Blood and Plasma.
Authors: Reed GA
Abstract
Determination of drug or drug metabolite concentrations in biological samples, particularly in serum or plasma, is fundamental to describing the relationships between administered dose, route of administration, and time after dose for achieving the optimal clinical response. While a well-characterized, accurate analytical method is needed to define these parameters, it must also be established that the analyte concentration in the sample at the time of analysis is identical to the concentration at sample acquisition. This is necessitated by the fact that drugs and their metabolite...
Source: Current Protocols in Pharmacology - December 14, 2016 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay.
Authors: Gomes I, Sierra S, Devi LA
Abstract
Although G protein-coupled receptor (GPCR) heteromerization has been extensively demonstrated in vitro using heterologous cells that overexpress epitope-tagged receptors, their presence in endogenous systems is less well established. This is because a criterion to identify receptor heteromerization is the demonstration that the two interacting receptors are present not only in the same cell but also in the same subcellular compartment in close enough proximity to allow for direct receptor-receptor interaction. This has been difficult to study in native tissues d...
Source: Current Protocols in Pharmacology - December 14, 2016 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Functional Studies of Sodium Channels: From Target to Compound Identification.
Authors: Bertrand D, Biton B, Licher T, Chambard JM, Lanneau C, Partiseti M, Lefevre IA
Abstract
Over the last six decades, voltage-gated sodium (Nav ) channels have attracted a great deal of scientific and pharmaceutical interest, driving fundamental advances in both biology and technology. The structure and physiological function of these channels have been extensively studied; clinical and genetic data have uncovered their implication in diseases such as epilepsy, arrhythmias, and pain, bringing them into focus as current and future drug targets. While different techniques have been established to recor...
Source: Current Protocols in Pharmacology - December 14, 2016 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
