Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug–cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug–cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug–cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.Pfizer Inc.Institute for Collaborative BiotechnologiesMIT Center for Cell Decision ProcessesNational Institute of Mental Health (U.S.) (grant P50-GM68762)National Institute of Mental Health (U.S.) (grant T32-GM008334)Massachusetts Institute of Technology. Biotechnology Process Engineering CenterMassachusetts Institute of Technology. Center for Environmental Health SciencesNational Institute of Mental Health (U.S.) (grant U19ES011399)Whitaker Foundatio

Kupffer cell activation by lipopolysaccharide in rats: Role for lipopolysaccharide binding protein and toll-like receptor 4

Lipopolysaccharide (LPS) binding protein (LBP) is a key serum factor that mediates LPS activation of mononuclear cells. In the presence of LBP, 1/1,000 the concentration of LPS is sufficient to activate peripheral blood monocytes. Previous studies with Kupffer cells have shown a variable effect of serum on LPS activation of these cells and led to the conclusion that, unlike extrahepatic mononuclear cells, Kupffer cells do not respond to LPS in an LBP-dependent fashion. Because there are multiple components in serum other than LBP that might affect LPS activation, these reports with serum are difficult to interpret. To investigate the specific role of LBP in LPS activation of Kupffer cells, we produced a functional recombinant rat LBP using a baculovirus expression system, which we used to selectively examine the role of LBP's on Kupffer-cell function. Isolated Kupffer cells exposed to increasing concentrations of LPS (0, 1, 10 ng/mL) showed a dose-dependent increase in TNF-Α production, which was augmented and accelerated by the presence of LBP. The effects of LBP on Kupffer cell activation by LPS are dependent on a functional Toll-like receptor 4 (Tlr 4) because Kupffer cells from C3H/HeJ mice failed to respond to LPS in the presence of LBP. LBP plays an important role in mediating Kupffer cell activation by LPS, and these effects are dependent on the presence of functioning Tlr 4.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34779/1/510310417_ftp.pd

Documentation of the one-person show of paper works

Includes bibliographical references.Includes photographs of exhibition pieces.The following work is presented in partial fulfillment of the requirements for the Master of Arts degree at Northern Illinois University. The work was produced between November, 1978 and March, 1979. It was presented in an exhibition from April 29, 1979 through May 4, 1979 in the Graduate Gallery of the Visual Arts Building, Northern Illinois University, Dekalb, Illinois.M.A. (Master of Arts

Development of a GPU Monte Carlo software for photon transport in voxel structures

Sendo o método mais preciso para estimar a dose absorvida em radioterapia, o Método de Monte Carlo (MMC) tem sido amplamente utilizado no planejamento de tratamento radioterápico. No entanto, a sua eciência pode ser melhorada para aplicações clínicas de rotina. Nesta dissertação é apresentado o código CUBMC, um código de Monte Carlo que simula o transporte de fótons para cálculo de dose, desenvolvido na plataforma CUDA (Compute Unified Device Architecture). A simulação de eventos físicos é baseada no algoritmo presente no código PENELOPE, e as tabelas de seção de choque utilizadas são geradas pela rotina MATERIAL, também presente no código PENELOPE. Os fótons são transportados em objetos simuladores descritos por voxels. Existem duas abordagens distintas utilizadas para a simulação. A primeira delas obriga o fóton a realizar uma parada toda vez que cruza a fronteira de um voxel, a segunda e pelo Método de Woodcock, onde o fóton ignora a existência de fronteiras e é transportado em um meio homogêneo fictício. O código CUBMC tem como objetivo ser uma opção de código simulador que, ao utilizar a capacidade de processamento paralelo de unidades de processamento gráfico (GPU), apresente alto desempenho em máquinas compactas e de baixo custo, podendo assim ser aplicado em casos clínicos e incorporado a sistemas de planejamento de tratamento em radioterapia.As the most accurate method to estimate absorbed dose in radiotherapy, Monte Carlo Method (MCM) has been widely used in radiotherapy treatment planning. Nevertheless, its efficiency can be improved for clinical routine applications. In this master thesis, the CUBMC code is presented, a GPU-based MC photon transport algorithm for dose calculation under the Compute Unified Device Architecture (CUDA) platform. The simulation of physical events is based on the algorithm used in PENELOPE, and the cross section table used is the one generated by the MATERIAL routine, also present in PENELOPE code. Photons are transported in voxel-based geometries with different compositions. There are two distinct approaches used for transport simulation. The first of them forces the photon to stop at every voxel frontier, the second one is the Woodcock method, where the photon ignores the existence of borders and travels in homogeneous fictitious medium. The CUBMC code aims to be an alternative for Monte Carlo simulator code that, by using the capability of parallel processing of graphics processing units (GPU), provides high performance simulations in low cost compact machines, and thus can be applied in clinical cases and incorporated in treatment planning systems for radiotherapy

One-person show of paperworks

Includes photographs of paperworks.The following work is presented in partial fulfillment of the requirements for the Master of Fine Arts degree at Northern Illinois University* The work was produced between June* 1980 and July, 1980* It was presented in an exhibition from July 28, 1980 through August 8, 1980 in Gallery 200 of the Visual Arts Building, Northern Illinois University, DeKalb, Illinois*M.F.A. (Master of Fine Arts