A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Communication methods and production techniques in fixed prosthesis fabrication: a UK based survey. Part 2: Production techniques

Aim The aim of this study was to identify the communication methods and production techniques used by dentists and dental technicians for the fabrication of fixed prostheses within the UK from the dental technicians' perspective. This second paper reports on the production techniques utilised.Materials and methods Seven hundred and eighty-two online questionnaires were distributed to the Dental Laboratories Association membership and included a broad range of topics, such as demographics, impression disinfection and suitability, and various production techniques. Settings were managed in order to ensure anonymity of respondents. Statistical analysis was undertaken to test the influence of various demographic variables such as the source of information, the location, and the size of the dental laboratory.Results The number of completed responses totalled 248 (32% response rate). Ninety percent of the respondents were based in England and the majority of dental laboratories were categorised as small sized (working with up to 25 dentists). Concerns were raised regarding inadequate disinfection protocols between dentists and dental laboratories and the poor quality of master impressions. Full arch plastic trays were the most popular impression tray used by dentists in the fabrication of crowns (61%) and bridgework (68%). The majority (89%) of jaw registration records were considered inaccurate. Forty-four percent of dental laboratories preferred using semi-adjustable articulators. Axial and occlusal under-preparation of abutment teeth was reported as an issue in about 25% of cases. Base metal alloy was the most (52%) commonly used alloy material. Metal-ceramic crowns were the most popular choice for anterior (69%) and posterior (70%) cases. The various factors considered did not have any statistically significant effect on the answers provided. The only notable exception was the fact that more methods of communicating the size and shape of crowns were utilised for large laboratories.Conclusion This study suggests that there are continuing issues in the production techniques utilised between dentists and dental laboratories