The Importance of Being Profiled: Improving Drug Candidate Safety and Efficacy Using Ion Channel Profiling

Profiling of putative lead compounds against a representative panel of relevant enzymes, receptors, ion channels, and transporters is a pragmatic approach to establish a preliminary view of potential issues that might later hamper development. An early idea of which off-target activities must be minimized can save valuable time and money during the preclinical lead optimization phase if pivotal questions are asked beyond the usual profiling at hERG. The best data for critical evaluation of activity at ion channels is obtained using functional assays, since binding assays cannot detect all interactions and do not provide information on whether the interaction is that of an agonist, antagonist, or allosteric modulator. For ion channels present in human cardiac muscle, depending on the required throughput, manual-, or automated-patch-clamp methodologies can be easily used to evaluate compounds individually to accurately reveal any potential liabilities. The issue of expanding screening capacity against a cardiac panel has recently been addressed by developing a series of robust, high-throughput, cell-based counter-screening assays employing fluorescence-based readouts. Similar assay development approaches can be used to configure panels of efficacy assays that can be used to assess selectivity within a family of related ion channels, such as Nav1.X channels. This overview discusses the benefits of in vitro assays, specific decision points where profiling can be of immediate benefit, and highlights the development and validation of patch-clamp and fluorescence-based profiling assays for ion channels (for examples of fluorescence-based assays, see Bhave et al., 2010; and for high-throughput patch-clamp assays see Mathes, 2006; Schrøder et al., 2008)

Meta-Analysis of the Alzheimer\u27s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

We present a consensus atlas of the human brain transcriptome in Alzheimer\u27s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington\u27s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies

Data management in support of TMDL efforts

Proceedings of the Seventh International Conference on Hydroscience and Engineering, Philadelphia, PA, September 2006. http://hdl.handle.net/1860/732Data management is the foundation for water resource assessment. The ability to successfully manage large amounts of data (>100MB to 1 GB) collected and submitted during an extended period is essential to evaluate long-term trends, conduct modeling and determine the effectiveness of remedial efforts. The Delaware River Basin Commission, on behalf of the U.S. Environmental Protection Agency, has concluded the Stage 1 Total Maximum Daily Loads (TMDLs) for polychlorinated biphenyls (PCBs) for the Delaware Estuary in December 2003, DRBC (2003). Monitoring efforts in support of the Stage 1 TMDLs and subsequent data submission posed significant difficulties in assimilating the analytical results into a comprehensive database. The use of different analytical methodologies, and reporting conventions by the various laboratories involved in this effort required extensive data manipulation and limited the usefulness of the reported results. The Delaware River Basin Commission is currently developing the Stage 2 Total Maximum Daily Loads (TMDLs) for PCBs for the Delaware Estuary. The objective of the Stage 2 TMDL is to develop more accurate TMDLs, which require a more precise quantification of the concentrations and/or loads from the various PCB source categories. This task is made more complex by the requirements to evaluate different source categories i.e. point source discharges, ambient river water, sediment, tributary and contaminated site runoff, analysis of 209 compounds, and the collection of multiple samples. To streamline the Stage 2 process, data quality objectives (DQOs) were specified to provide a consistent approach to sample collection, analysis and data reporting