Manuel Peitsch

sbv IMPROVER Diagnostic Signature Challenge

The sbv IMPROVER (systems biology verification—Industrial Methodology for Process Verification in Research) process aims to help companies verify component steps or tasks in larger research workflows for industrial applications. IMPROVER is built on challenges posed to the community that draws on the wisdom of crowds to assess the most suitable methods for a given research task. The Diagnostic Signature Challenge, open to the public from Mar. 5 to Jun. 21, 2012, was the first instantiation of the IMPROVER methodology and evaluated a fundamental biological question, specifically, if there is sufficient information in gene expression data to diagnose diseases. Fifty-four teams used publically available data to develop prediction models in four disease areas: multiple sclerosis, lung cancer, psoriasis, and chronic obstructive pulmonary disease. The predictions were scored against unpublished, blinded data provided by the organizers, and the results, including methods of the top performers, presented at a conference in Boston on Oct. 2–3, 2012. This paper offers an overview of the Diagnostic Signature Challenge and the accompanying symposium, and is the first article in a special issue of Systems Biomedicine, providing focused reviews of the submitted methods and general conclusions from the challenge. Overall, it was observed that optimal method choice and performance appeared largely dependent on endpoint, and results indicate the psoriasis and lung cancer subtypes sub-challenges were more accurately predicted, while the remaining classification tasks were much more challenging. Though no one approach was superior for every sub-challenge, there were methods, like linear discriminant analysis, that were found to perform consistently well in all.

Mechanistic Network Models in Safety and Toxicity Evaluation of Nutraceuticals

Abstract Nutraceuticals are food constituents with potential health benefits beyond their nutritional value. In vitro and in vivo studies suggest a protective effect of nutraceuticals against chronic diseases, but the results are not supported fully by clinical evidence. From a toxicological perspective, nutraceuticals are recognized generally as safe at dietary doses; however, they are often consumed at higher doses in the form of nutritional supplements. Exposure to supra-dietary doses of nutraceuticals is of toxicological concern, particularly because some substances may cause genomic changes in target tissues. This chapter describes a systems biology-based approach for the toxicological assessment of nutraceuticals that uses computable mechanistic network models to identify and quantify molecular pathways perturbed upon exposure to high doses of nutraceuticals. This chapter also provides specific examples of how microarray-based transcriptome analyses and high-content screening methods can be applied to evaluate the biological impacts of resveratrol, quercetin, astaxanthin, and epigallocatechin gallate in human cryopreserved hepatocytes and coronary artery endothelial cells.

Organs-on-a-chip: A new paradigm for toxicological assessment and preclinical drug development

In the last few years, considerable attention has been given to in vitro models in an attempt to reduce the use of animals and to decrease the rate of preclinical failure associated with the development of new drugs. Simple two-dimensional cultures grown in a dish are now frequently replaced by organotypic cultures with three-dimensional (3-D) architecture, which enables interactions between cells, promoting their differentiation and increasing their in vivo likeness. Microengineering now enables the incorporation of small devices into 3-D culture models to reproduce the complex microenvironment of the modeled organ, often referred to as organs-on-a-chip (OoCs). This review describes various OoCs developed to mimic liver, brain, kidney, and lung tissues. Current challenges encountered in attempts to recreate the in vivo environment are described, as well as some examples of OoCs. Finally, attention is given to the ongoing evolution of OoCs with the aim of solving one of the major limitations in that they can only represent a single organ. Multi-organ-on-a-chip (MOC) systems mimic organ interactions observed in the human body and aim to provide the features of compound uptake, metabolism, and excretion, while simultaneously allowing for insights into biological effects. MOCs might therefore represent a new paradigm in drug development, providing a better understanding of dose responses and mechanisms of toxicity, enabling the detection of drug resistance and supporting the evaluation of pharmacokinetic–pharmacodynamics parameters.

Where are we at regarding species translation? A review of the sbv IMPROVER challenge

Where are we at regarding species translation? A review of the sbv IMPROVER challenge J. Hoeng, M.C. Peitsch, P. Meyer and I. Jurisica* Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland IBM T.J. Watson Research Center, Computational Biology, Yorktown Heights, NY 10598, USA, Department of Computer Science and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

sbv IMPROVER Diagnostic Signature Challenge Preface to this special issue

The task of predicting disease phenotype from gene expression data has been addressed hundreds if not thousands of times in the recent literature. This expanding body of work is not only an indication that the problem is of great importance and general interest, but it also reveals that neither the experimental nor the computational limitations of translating data to disease information have been satisfactorily understood. To contribute to the advancement of the field, promote collaborative thinking and enable a fair and unbiased comparison of methods, IMPROVER revisited the problem of gene-expression to phenotype prediction using a collaborative-competition paradigm. This special issue of Systems Biomedicine reports the results of the sbv IMPROVER Diagnostic Signature Challenge designed to identify best analytic approaches to predict phenotype from gene expression data.

Next-generation tobacco and nicotine products: Substantiating harm reduction and supporting tobacco regulatory science

A framework for the assessment of novel next-generation tobacco and nicotine products with the potential to reduce health risks compared with cigarettes should integrate scientific studies incorporating nonclinical, clinical, and population studies approaches. These products should have lower emissions and exhibit reduced biological effects compared with those of cigarettes, ideally approaching those of smoking cessation. The products should also be acceptable cigarette alternatives for current smokers, while not appealing to nonsmokers or former smokers. Validating harm reduction and promoting regulatory acceptance of the assessment methods require a collaborative approach by industry, independent reviewers, the public health community, and regulatory agencies. This article summarizes the science and approaches applied and considered to substantiate tobacco harm reduction in the light of regulatory requirements, presented at the 53rd Congress of the European Societies of Toxicology, 2017.

Research Models of Neurodegenerative Diseases: Major Considerations for Translatability

The scientific evidence regarding potential neuroprotective effects of the tobacco-derived compounds has been obtained from different experimental model systems that mimic human pathological processes. Identification of mutations in familial forms of diseases has helped the development of a large number of genetically modified cell and animal models. When thoroughly characterized, these models are critical tools in the discovery and development of drugs that may efficiently prevent, slow down, and ideally reverse pathological processes. However, the use of these models appears to have shed light only on partial aspects of the various disorders, preventing true translation into new treatments, diagnostics, and prevention. One of the major shortcomings of the available models is that the pathologies they capture usually represent only part of the complex, incompletely understood human disease. This chapter describes major advantages and disadvantages of models used for neurodegenerative diseases.

Other Compounds From Tobacco With Potential Impact on Neurodegenerative Diseases

In the context of its pharmacological actions, nicotine is the most studied tobacco smoke constituent. Nonetheless, nicotine is not the only constituent of tobacco leaf and cigarette smoke that displays pharmacological activity. Given the complexity of data from clinical studies on nicotine and epidemiological data on smoking and Alzheimer’s and Parkinson’s diseases, it is possible that nicotine exerts its effects together with other bioactive, possibly inhalable, smoke constituents that should be studied separately, i.e. when decoupled from tobacco smoke and the overall harmful effects of smoking. This section describes some tobacco/smoke compounds for which neuronal effects have been reported.

Attention Deficit Hyperactivity Disorder in Children and Adults

Attention deficit hyperactivity disorder (ADHD) is a chronic condition that affects millions of children and often continues into adulthood. It is characterized by problems paying attention, excessive activity, or difficulty controlling behavior, which is not appropriate for a persons age. When comorbid with Tourette syndrome (TS), pre-natal maternal smoking strongly correlates with ADHD. High rates of comorbidity between ADHD and smoking have been described, but the etiology of this relationship is largely unknown. In addition to common genetic denominators, the relationship between smoking and ADHD can be explained by the impact of nicotine on neurotransmitter systems. The dopaminergic neurotransmission system is altered in ADHD patients, so that they exhibit lower levels of dopamine due to the elevated number of dopamine transporters. Clinical trials with nicotine patches conducted so far reported positive results such as improved cognitive performance and overall reduction of ADHD symptoms with some adverse effects (nausea, stomach ache, itching, and dizziness). Nicotine nasal spray and transdermal patches are proposed for ADHD patients to aid in quitting smoking. In this chapter the impact of smoking and nicotine on ADHD is described.

P010 Effects of cigarette smoke on the Dss-induced colitis model in C57bl/6 mice.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease affecting the gastrointestinal tract, which consists of two major forms: Crohns disease (CD) and Ulcerative Colitis (UC). The impact of cigarette smoking on IBD has been well established by a large number of epidemiologi