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Xi Z.,University of Alberta | Khare S.,University of Alberta | Cheung A.,University of Alberta | Huang B.,University of Alberta | And 6 more authors.
Computational Biology and Chemistry | Year: 2014

In this paper, we present a new statistical pattern recognition method for classifying cytotoxic cellular responses to toxic agents. The advantage of the proposed method is to quickly assess the toxicity level of an unclassified toxic agent on human health by bringing cytotoxic cellular responses with similar patterns (mode of action, MoOA) into the same class. The proposed method is a model-based hierarchical classification approach incorporating principal component analysis (PCA) and functional data analysis (FDA). The cytotoxic cell responses are represented by multi-concentration time-dependent cellular response profiles (TCRPs) which are dynamically recorded by using the xCELLigence real-time cell analysis high-throughput (RTCA HT) system. The classification results obtained using our algorithm show satisfactory discrimination and are validated using biological facts by examining common chemical mechanisms of actions with treatment on human hepatocellular carcinoma cells (HepG2). © 2014 Elsevier Ltd. Source


Zheng M.,University of Michigan | Zheng M.,Zhejiang University | Yang J.,University of Michigan | Yang J.,Shanghai JiaoTong University | And 4 more authors.
Anticancer Research | Year: 2010

The p53 tumor suppressor is negatively regulated by murine double minute 2 (MDM2), which binds to p53 and promotes p53 ubiquitination and degradation. MDM2 inhibitor-219 (MI-219), a small molecule MDM2 inhibitor, was recently reported to disrupt p53-MDM2 binding, leading to p53 activation and suppression of tumor cell growth both in vitro and in vivo. This study tested the efficacy of MI-219 against a panel of lung cancer cell lines alone or in combination with MDM2 knockdown, an X-linked inhibitor of apoptosis protein (XIAP) inhibitor, or a chemotherapeutic drug, etoposide. When acting alone, MI-219 selectively inhibited growth of wild-type (wt) p53-containing lung cancer cells by induction of G1 or G2 arrest in a p53-dependent manner, but had a minor effect on wt p53-bearing immortalized cells. MDM2 knockdown had a minimal effect on MI-219 induced growth suppression. Although MI-219 increased XIAP expression, blockage of XIAP via SM-164, a Smac mimetic compound, did not selectively enhance MI-219 cytotoxicity. Significantly, MI-219 sensitized lung cancer cells to etoposide-induced cell killing. This study revealed that, when acting alone, MI-219 selectively inhibits the growth of lung cancer cells harboring a wt p53. In combination, MI-219-induced cytotoxicity was not affected by MDM2 knockdown nor by a XIAP inhibitor, but MI-219 sensitized cancer cells to etoposide, suggesting MI-219 could serve as a chemosensitizing agent. Source


Rinaldi G.,George Washington University | Loukas A.,James Cook University | Brindley P.J.,George Washington University | Irelan J.T.,ACEA Biosciences, Inc. | Smout M.J.,James Cook University
International Journal for Parasitology: Drugs and Drug Resistance | Year: 2015

Infection with helminth parasites causes morbidity and mortality in billions of people and livestock worldwide. Where anthelmintic drugs are available, drug resistance is a major problem in livestock parasites, and a looming threat to public health. Monitoring the efficacy of these medicines and screening for new drugs has been hindered by the lack of objective, high-throughput approaches. Several cell monitoring technologies have been adapted for parasitic worms, including video-, fluorescence-, metabolism enzyme- and impedance-based tools that minimize the screening bottleneck. Using the xCELLigence impedance-based system we previously developed a motility-viability assay that is applicable for a range of helminth parasites. Here we have improved substantially the assay by using diverse frequency settings, and have named it the xCELLigence worm real-time motility assay (xWORM). By utilizing strictly standardized mean difference analysis we compared the xWORM output measured with 10, 25 and 50 kHz frequencies to quantify the motility of schistosome adults (human blood flukes) and hatching of schistosome eggs. Furthermore, we have described a novel application of xWORM to monitor movement of schistosome cercariae, the developmental stage that is infectious to humans. For all three stages, 25 kHz was either optimal or near-optimal for monitoring and quantifying schistosome motility. These improvements in methodology sensitivity should enhance the capacity to screen small compound libraries for new drugs both for schistosomes and other helminth pathogens at large. © 2015 The Authors. Source


Pan T.,Jiangsu University | Pan T.,University of Alberta | Khare S.,University of Alberta | Ackah F.,Alberta Health | And 5 more authors.
Computational Biology and Chemistry | Year: 2013

Technological advances in cytotoxicity analysis have now made it possible to obtain real time data on changes in cell growth, morphology and cell death. This type of testing has a great potential for reducing and refining traditional in vivo toxicology tests. By monitoring the dynamic response profile of living cells via the xCELLigence real-time cell analyzer for high-throughput (RTCA HT) system, cellular changes including cell number (cell index, CI) are recorded and analyzed. A special scaled index defined as normalized cell index (NCI) is used in the analysis which reduces the influence of inter-experimental variations. To assess the extent of exposure of the tested chemicals, a two-exponent model is presented to describe rate of cell growth and death. This model is embodied in the time and concentration-dependent cellular response curves, and the parameters k1 and k2 in this model are used to describe the rate of cell growth and death. Based on calculated k2 values and the corresponding concentrations, a concentration-response curve is fitted. As a result, a cytotoxicity assessment named KC50 is calculated. The validation of the proposed method is demonstrated by exposing six cell lines to 14 chemical compounds. Our findings suggest that the proposed KC 50-based toxicity assay can be an alternative to the traditional single time-point assay such as LC50 (the concentration at which 50% of the cells are killed). The proposed index has a potential for routine evaluation of cytotoxicities. Another advantage of the proposed index is that it extracts cytotoxicity information when CI fails to detect the low toxicity. © 2013 Elsevier Ltd. Source


Irelan J.,ACEA Biosciences, Inc. | Schwengberg S.,ACEA Biosciences, Inc. | Ketterlinus R.,OMNI Life Science GmbH and Co. KG
BioSpektrum | Year: 2014

In cell-based research, stringent quality control is desirable for standardization and correct interpretation of results. This article demonstrates the power of real-time cell analysis (RTCA) to achieve this goal using a highly reproducible, yet convenient and comprehensive method. © Springer-Verlag 2014. Source

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