A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs

Enzymatic inactivation of endogenous IgG by IdeS enhances therapeutic antibody efficacy

Endogenous plasma IgG sets an immunological threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Here we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fcγ-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab) and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor seeking immune cells

Hunting the Unknown

International audienceData leakage causes significant losses and privacy breaches worldwide. In this paper we present a white-box data leakage detection system to spot anomalies in database transactions. We argue that our approach represents a major leap forward w.r.t. previous work because: i) it significantly decreases the False Positive Rate (FPR) while keeping the Detection Rate (DR) high; on our experimental dataset, consisting of millions of real enterprise transactions, we measure a FPR that is orders of magnitude lower than in state-of-the-art comparable approaches; and ii) the white-box approach allows the creation of self-explanatory and easy to update profiles able to explain why a given query is anomalous, which further boosts the practical applicability of the system

Heterogeneous stream processing and crowdsourcing for traffic monitoring: Highlights

We give an overview of an intelligent urban traffic management system. Complex events related to congestions are detected from heterogeneous sources involving fixed sensors mounted on intersections and mobile sensors mounted on public transport vehicles. To deal with data veracity, sensor disagreements are resolved by crowdsourcing. To deal with data sparsity, a traffic model offers information in areas with low sensor coverage. We apply the system to a real-world use-case. © 2014 Springer-Verlag