Normalization of organ-on-a-Chip samples for mass spectrometry based proteomics and metabolomics via Dansylation-based assay.

Mass spectrometry based 'omics pairs well with organ-on-a-chip-based investigations, which often have limited cellular material for sampling. However, a common issue with these chip-based platforms is well-to-well or chip-to-chip variability in the proteome and metabolome due to factors such as plate edge effects, cellular asynchronization, effluent flow, and limited cell count. This causes high variability in the quantitative multi-omics analysis of samples, potentially masking true biological changes within the system.

Discovery of treatment for nerve agents targeting a new metabolic pathway.

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX.

Generalized Additive Mixed-Models for Pharmacology Using Integrated Discrete Multiple Organ Co-Culture.

Integrated Discrete Multiple Organ Co-culture (IDMOC) is emerging as an in-vitro alternative to in-vivo animal models for pharmacology studies. IDMOC allows dose-response relationships to be investigated at the tissue and organoid levels, yet, these relationships often exhibit responses that are far more complex than the binary responses often measured in whole animals. To accommodate departure from binary endpoints, IDMOC requires an expansion of analytic techniques beyond simple linear probit and logistic models familiar in toxicology.

The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human Pulmonary Cells.

Organophosphorus (OP) pesticides are known to induce pulmonary toxicity in both humans and experimental animals. To elucidate the mechanism of OP-induced cytotoxicity, we examined the effects of parathion and malathion and their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells. Exposure to paraoxon and malaoxon produced a dose-dependent increase in cytotoxicity following a 24-hour exposure, while treatment with parathion or malathion produced no effects at clinically relevant concentrations.

High content analysis of an in vitro model for metabolic toxicity: results with the model toxicants 4-aminophenol and cyclophosphamide.

In vitro models that accurately and rapidly assess hepatotoxicity and the effects of hepatic metabolism on nonliver cell types are needed by the U.S. Department of Defense and the pharmaceutical industry to screen compound libraries.

Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies?

Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high.

Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.

Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors.

Immune-mediated modulation of breast cancer growth and metastasis by the chemokine Mig (CXCL9) in a murine model.

Current immunotherapies are limited by several factors, including the failure to recruit sufficient numbers of immune effector cells to tumors. The chemokine monokine induced by gamma-interferon (Mig; CXCL9) attracts activated T cells and natural killer (NK) cells bearing the chemokine receptor CXCR3. We investigated Mig as an immunotherapeutic agent in a syngeneic murine model of metastatic breast cancer.

Immunotherapy with interleukin-10 depends on the CXC chemokines inducible protein-10 and monokine induced by IFN-gamma.

The cytokine interleukin (IL)-10 has potent antitumor activity in many model systems when expressed locally at very high levels from the time of tumor transplantation. We now demonstrate that systemic administration of recombinant human IL-10 to animals bearing established highly malignant mammary tumors also leads to significant growth inhibition. We had shown previously that expression of the CXC chemokines Mig (monokine induced by IFN-gamma) and IP-10 (inducible protein 10) is observed in IL-10 transduced but not neo-vector control tumors.

Expression of the Chemokines IP-10 and Mig in IL-10 Transduced Tumors.

SUMMARY: Several laboratories have reported marked tumor inhibition when the cytokine interleukin-10 (IL-10) is overexpressed as a transgene in a variety of tumor cells. To identify critical effector molecules, we compared the expression of the chemokine crg-2, the murine homolog of human inducible protein 10 (human IP-10) in murine mammary tumors derived from the transplantation of six IL-10 expressing clones of tumor cell line 66.1, parental 66.