25 research outputs found
Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome
Identifying genetic factors responsible for serious adverse drug reaction (SADR) is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI), a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN): all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4), whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703) enhances the unexpected binding of abacavir to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes
T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays
Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades
Von Karl Kasthofer zu Elias Landolt: Unterschiedliche Blickwinkel auf die Schweizer GebirgswÀlder am Beispiel des Vorderrheintals | From Karl Kasthofer to Elias Landolt: Differing points of view concerning the Swiss alpine forests, exemplified by the valley of «Vorderrhein»
Church Voting Recommendations, Voter Preferences, and Political Decisions
In Switzerland, two key church institutionsâthe Conference of Swiss Bishops and the Federation of Protestant Churchesâmake public recommendations on how to vote for certain referenda. We leverage this situation to directly measure religious organizationsâ power to reflect and shape human decision making. That is, using a direct measure of votersâ commitment to their religious institution, we analyze whether they are more likely to vote in line with this organization's voting recommendation. We find that these recommendations do indeed wield influence, implying that even in a secularized world, religion plays a crucial role in voting decisions. Our results hold for both aggregate and individual-level voting decisions.</p