CATMoS: Collaborative Acute Toxicity Modeling Suite.

Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests.

Microphysiological heart-liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery.

Body-on-a-chip in vitro systems are a promising technology that aims to increase the predictive power of drug efficacy and toxicity in humans when compared to traditional animal models. Here, we developed a new heart-liver body-on-a-chip system with a skin surrogate to assess the toxicity of drugs that are topically administered. In order to test the utility of the system, diclofenac, ketoconazole, hydrocortisone and acetaminophen were applied topically through a synthetic skin surrogate (Strat-M membrane) and the toxicity results were compared to those of acute drug exposure from systemically applying the compounds.

Long-Term Electrical and Mechanical Function Monitoring of a Human-on-a-Chip System.

The goal of human-on-a-chip systems is to capture multi-organ complexity and predict the human response to compounds within physiologically relevant platforms. The generation and characterization of such systems is currently a focal point of research given the long-standing inadequacies of conventional techniques for predicting human outcome. Functional systems can measure and quantify key cellular mechanisms that correlate with the physiological status of a tissue, and can be used to evaluate therapeutic challenges utilizing many of the same endpoints used in animal experiments or clinical trials.

Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.

Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium.

Microphysiological flux balance platform unravels the dynamics of drug induced steatosis.

Drug development is currently hampered by the inability of animal experiments to accurately predict human response. While emerging organ on chip technology offers to reduce risk using microfluidic models of human tissues, the technology still mostly relies on end-point assays and biomarker measurements to assess tissue damage resulting in limited mechanistic information and difficulties to detect adverse effects occurring below the threshold of cellular damage. Here we present a sensor-integrated liver on chip array in which oxygen is monitored using two-frequency phase modulation of tissue-embedded microprobes, while glucose, lactate and temperature are measured in real time using microfluidic electrochemical sensors.

[Genetic diagnostics of pathogenic splicing abnormalities in the clinical laboratory--pitfalls and screening approaches].

In recent years, genetic diagnostics of pathogenic splicing abnormalities are increasingly recognized as critically important in the clinical genetic diagnostics. It is reported that approximately 10% of pathogenic mutations causing human inherited diseases are splicing mutations. Nonetheless, it is still difficult to identify splicing abnormalities in routine genetic diagnostic settings.

Report from the EPAA workshop: in vitro ADME in safety testing used by EPAA industry sectors.

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritization, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals.

Development of a mechanistic SAR model for the detection of phototoxic chemicals and use in an integrated testing strategy.

Phototoxicity is of increasing concern in dermatology, since modern lifestyle is often associated with exposure to sunlight. The most commonly reported process is via oxidative reactions. Therefore characterizing the "photo-pro-oxidant" potential of a compound early in its industrial development is of utmost interest, especially for compounds likely to undergo sunlight exposure in skin.

Developing structure-activity relationships for the prediction of hepatotoxicity.

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds.

Polarization-induced switching effect in graphene nanoribbon edge-defect junction.

With nonequilibrium Green's function approach combined with density functional theory, we perform an ab initio calculation to investigate transport properties of graphene nanoribbon (GNR) junctions self-consistently. Tight-binding approximation is applied to model the zigzag (ZGNR) electrodes, and its validity is confirmed in comparison to the GAUSSIAN03 periodic boundary condition calculation result of the same system. The origin of abnormal jump points usually appearing in the transmission spectrum is explained with the detailed tight-binding ZGNR band structure.

An expert system approach to the assessment of hepatotoxic potential.

Hepatotoxicity is a major cause of pharmaceutical drug attrition and is also a concern within other chemical industries. In silico approaches to the prediction of hepatotoxicity are an important tool in the early identification of adverse effects in the liver associated with exposure to a chemical. Here, we describe work in progress to develop an expert system approach to the prediction of hepatotoxicity, focussing particularly on the identification of structural alerts associated with its occurrence.

Current through single conjugated molecules: calculations versus measurements.

We use density functional theory based nonequilibrium Green's function to calculate the current through the different rodlike molecules at the finite temperatures self-consistently, which was compared to the experimental measurements presented by Reichert et al. [Phys. Rev.

First-principles study of length dependence of conductance in alkanedithiols.

Electronic transport properties of alkanedithiols are calculated by a first-principles method based on density functional theory and nonequilibrium Green's function formalism. At small bias, the I-V characteristics are linear and the resistances conform to the Magoga's exponential law. The calculated length-dependent decay constant gamma which reflects the effect of internal molecular structure is in accordance with most experiments quantitatively.

Ab initio study of single-molecule rotation switch based on nonequilibrium Green's function theory.

The bistable molecular switches have been studied theoretically based on the first-principles calculation. The geometry structures of the switches studied in this paper can be triggered between two symmetrical structures by using an external applied electric field. I-V characteristic curves of the different molecule configurations have been calculated, and distinguishability of these characteristic curves indicates a switching behavior, the performance of which can be improved significantly by some suitable donors and acceptors.

Self-consistent study of single molecular transistor modulated by transverse field.

We use a self-consistent method to study the current of the single molecular transistor modulated by the transverse field in the level of the density functional theory and the nonequilibrium Green function method. The numerical results show that both the polyacene-dithiol molecules and the fused-ring thiophene molecules are the potential high-frequency molecular transistors controlled by the transverse field. The longer molecules of the polyacene-dithiol or the fused-ring thiophene are in favor of realizing the gate-bias controlled molecular transistor.

Pristine semiconducting [110] silicon nanowires.

We report results of ab initio calculations on silicon nanowires oriented along the [110] direction and show for the first time that these pristine silicon nanowires are indirect band gap semiconductors. The nanowires have bulk Si core and are bounded by two (100) and two (110) planes in lateral directions. The (100) planes are atomically reconstructed with dimerization in a manner similar to the (100) surface of bulk Si but the dimer arrays are perpendicular to each other on the two (100) planes.

Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single- and three dual-NRTI treatments.

Although treatments with nucleoside reverse transcriptase inhibitors (NRTIs) can modify fat metabolism and fat distribution in humans, the mechanisms of these modifications and the roles of diverse NRTIs are unknown. We studied the mitochondrial and metabolic effects of stavudine (d4T), zidovudine (AZT), didanosine (ddI), lamivudine (3TC), zalcitabine (ddC), and three combinations (AZT-3TC, d4T-3TC, and d4T-ddI) in mice treated for 2 weeks with daily doses equivalent to the human dose per body area. Concentrations of AZT and d4T in plasma were lower when these drugs were administered with 3TC or ddI.

Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.

To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive.

"Mixed inhibitors" of HIV-reverse transcriptase: synthesis and antiviral activity.

Some "AZT-HEPT" and "ddC-HEPT" conjugates were designed, synthesized and evaluated for their anti-HIV activity.

[A comparative study of the ELISA and IF methods for antinuclear antibody test].

A new ELISA method for antinuclear antibody(ANA) test was investigated for its clinical usefulness by comparison with a widely used IF method. Both methods used Hep 2 cells as a substrate. ELISA method showed good reproducibility in both within-run(CV = 5.