Our Publications

To view any of our publications listed below, click the link provided.  For open access publications, this will take you directly to the pdf. 
For restricted access publications, your access will depend on your institutional or personal permissions.

TitleContentAuthorLinkAccessTags
Species-Specific Urothelial Toxicity With an Anti-HIV Noncatalytic Site Integrase Inhibitor (NCINI) Is Related to Unusual pH-Dependent Physicochemical Changes

GS-9695 and GS-9822 are next-generation noncatalytic site integrase inhibitors (NCINIs) with significantly improved potency against human immunodeficiency virus compared with previous drugs such as BI-224436.  These data provide useful insights to guide discovery and development of NCINIs, related compounds, and zwitterions.

Ruth A Roberts, Richard A Campbell, Phumzile Sikakana, Claire Sadler, Mark Osier, Yili Xu, Joy Y Feng, Michael Mitchell, Roman Sakowicz, (2021)LinkRestricted AccessN/A
AI-based Language Models Powering Drug Discovery and Development. Submitted.

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development.

Liu, Z, Roberts, R, Lal-Nag, M, Chen, X, Huang, R and Tong, W (2020) LinkRestricted AccessN/A
Justification for species selection for pharmaceutical toxicity studies. Toxicology Research

Toxicity studies using mammalian species are generally required to provide safety data to support clinical development and licencing registration for potential new pharmaceuticals…

Helen Prior, Richard Haworth, Briony Labram, Ruth Roberts, Alison Wolfreys and Fiona Sewell (2020)LinkOpenN/A
Can we panelise seizure? Toxicological Sciences, Online ahead of publication

Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study…

Roberts, RA, Authier, S, Mellon, D, Morton, M, Suzuki, I, Tjalkens, RB, Valentin, J-P and Pierson, J (2020) LinkOpenN/A
Deep Learning-Powered Drug-Induced Liver Injury Prediction Using Model-Level Representation. Submitted. Chemical Research in Toxicology

Drug-induced liver injury (DILI) is the most frequently reported single cause of safety-related withdrawal of marketed drugs. It is essential to identify drugs with DILI potential at the early stages of drug development. In this study, we describe a deep learning-powered DILI (DeepDILI) prediction model created by combining model-level representation generated by conventional machine learning (ML) algorithms with a deep learning framework based on Mold2 descriptors…

Li, T, Tong, W, Roberts, R, Liu, Z and Thakkar, S (2020) DeepDILI LinkRestricted AccessN/A
Advancing Genomics for Rare Disease Diagnosis and Therapy Development. Frontiers in Pharmacology 11, 1523.

Rare diseases affect only a small percentage of the population and are often chronic and potentially life-threatening. There are more than 7,000 known rare diseases, and yet fewer than 700 approved treatment options are available. Progress made with the use of emerging technologies such as next-generation sequencing (NGS) and bioengineering holds great promise in advancing rare disease diagnosis and therapy development (Liu et al., 2019)…

Liu, Z, Roberts, R, Shi, T, Mikailov, M and Tong, W (2020) LinkOpen
A decade of trends in toxicology. Tox Res, 9, 676-682

Here we look at popular trends and concepts in toxicology over the decade 2009–2019. The top 10 concepts included methodological approaches such as zebrafish and genomics as well as broader concepts such as personalized medicine and adverse outcome pathways. The total number and rank order for each of the top 10 were tracked year by year via PubMed with >9500 papers contributing to the analysis…

Sikakana, P and Roberts, R (2020) LinkRestricted AccessN/A
Opportunities for use of one species for longer-term toxicology testing during drug development: A cross-industry evaluation. Reg Tox Pharm. 113, 104624.

An international expert working group representing 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing exercise to evaluate the utility of two species within regulatory general toxicology studies…

Prior et al (2020) LinkOpenN/A
Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach. Frontiers in Pharmacology, 11, 927.

Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively…

Zhu, L, Roberts, R, Huang, R, Zhao, J, Xia, M, Delavan, B, Mikailov, M, Tong, W, and Liu, Z. (2020) LinkOpenN/A
Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury. Frontiers in Bioengineering and Biotechnology, 8. Online ahead of publication.

Drug-induced liver injury (DILI) is one of the most cited reasons for the high drug attrition rate and drug withdrawal from the market. The accumulated large amount of high throughput transcriptomic profiles and advances in deep learning provide an unprecedented opportunity to improve the suboptimal performance of DILI prediction. In this study, we developed an eight-layer Deep Neural Network (DNN) model for DILI prediction using transcriptomic profiles of human cell lines (LINCS L1000 dataset) with the current largest binary DILI annotation data [i.e., DILI severity and toxicity (DILIst)]. The developed models were evaluated by Monte Carlo cross-validation (MCCV), permutation test, and an independent validation (IV) set…

Li, T, Tong, W, Roberts, RA, Liu, Z, Thakkar, S (2020) LinkOpenN/A
Innovative models for in vitro detection of seizure. Toxicology Research 8 (6), 784-788.

Data show that toxicity to the central nervous system (CNS) is the most frequent cause of safety failures during the clinical phase of drug development. CNS endpoints such as seizure pose a safety risk to patients and volunteers and can lead to a loss of competitiveness, delays, and increased costs. Current methods rely on detection in the nonclinical rodent and non-rodent studies required to support clinical trials. There are two main issues with this approach; seizure may be missed in the animal studies and, even if seizure is detected, significant resource has already been invested in the project by this stage…

Rockley, K, Morton M and Roberts, R (2019) LinkRestricted AccessN/A
Can Transcriptomic Profiles from Cancer Cell Lines be Used for Toxicity Assessment? Toxicological Sciences, Chemical Research in Toxicology. 23 343-367.

In vitro toxicogenomics (TGx) has the potential to replace or supplement animal studies. However, TGx studies often suffer from a limited sample size and cell types. Meanwhile, transcriptomic data have been generated for tens of thousands of compounds using cancer cell lines mainly for drug efficacy screening. Here, we asked the question of whether these types of transcriptomic data can be used to support toxicity assessment…

Liu, Z, Zhu, L, Thakkar, S, Roberts, RA and Tong, W (2019) LinkOpenN/A
Towards Clinical Implementation of Next Generation Sequencing-based Genetic Testing in Rare Diseases: Where are we? Trends in Genetics. 45, 678-680.

Next-generation sequencing (NGS) technologies have changed the landscape of genetic testing in rare diseases. However, the rapid evolution of NGS technologies has outpaced its clinical adoption. Here, we re-evaluate the critical steps in the clinical application of NGS-based genetic testing from an informatics perspective. We suggest a ‘fit-for-purpose’ triage of current NGS technologies…

Liu, Z, Zhu, L, Roberts, RA and Tong, W (2019) LinkOpenN/A
Collaboration, Competition and Publication in Toxicology: view of British Toxicology Society members. Toxicology Research, 2019. E-pub ahead of print.

To ascertain attitudes to resourcing, collaboration and publication in toxicology, a survey was developed and distributed to British Toxicology Society (BTS) members. The survey comprised 14 questions with 5 response options (strongly agree; agree; conflicted; disagree; strongly disagree) and a free text box. One hundred completed surveys were received by the cut-off date for data analysis. Unsurprisingly, 60% of participants disagreed or strongly disagreed that toxicology research is adequately funded in the UK; only 12% agreed with this statement…

Walker, ES, Gill, JH and Roberts. RA (2019) LinkOpenN/A
Toxicogenomics: a 2020 vision. TiPS. 40: 92-103.

Toxicogenomics (TGx) has contributed significantly to toxicology and now hasgreat potential to support moves towards animal-free approaches in regulatorydecision making. Here, we discuss in vitro TGx systems and their potentialimpact on risk assessment. We raise awareness of the rapid advancement ofgenomics technologies, which generates novel genomics features essential forenhanced risk assessment. We specifically emphasize the importance of repro-ducibility in utilizing TGx in the regulatory setting…

Lui, Z, Huang, R, Roberts, R and Tong, W (2019). LinkOpenN/A
Drug Discovery and Development: biomarkers of neurotoxicity and neurodegeneration. Experimental Biology and Medicine. 243: 1037–1045

The discovery and development of new drugs are vital if we are to improve and expand treatment options available to improve outcomes for patients. Overall, therapeutic strategies fall into two broad categories: small molecules and biologics, although more recently there has been a growth in novel platforms such as miRNAs and oligonucleotides. On average, the development of a small molecule drug takes around 12 years and costs around $50m. Despite this huge investment of time and money, attrition remains a major challenge and very few molecules actually make it through to the market…

Walker, A, Imam, S and Roberts, RA (2018). LinkOpenN/A
Understanding drug targets: there’s no such thing as bad news. Drug Discovery Today, 23, 1925-1928.

How can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets? Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug…

Roberts, RA (2018) LinkRestricted AccessN/A
Collaboration and competition: ethics in toxicology. Toxicology Research, 7, 576-585.

From animal research through adverse events in clinical trials to health scares around food contamination, toxicology has frequently been a focus of scientific and societal concern. As these concerns shift with each new drug, new technology or public health scare, how can toxicology stay current, relevant and ethical? Two of the biggest ethical challenges in pharmaceutical toxicology are the use of animals in testing and the high safety-related attrition rates in new drug development. Both of these require progress in the discipline that will only be driven by research funding. Yet, very little is invested in these two fields compared with investment in new efficacy models, new disease targets and new technologies…

Walker, ES and Roberts, RA (2018). LinkOpenN/A
Gene Signature Reveals Differences among Preclinical Testing Systems for Rat Liver. Front. Genet., 9, 1-10

Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay?…

Liu, Z, Delavan, B, Roberts, R and Tong, W (2018). LinkOpenN/A
Changes in the metabolome and microRNA levels in biological fluids might represent biomarkers of neurotoxicity: A trimethyltin study. Experimental Biology and Medicine, 243, 228-236

Neurotoxicity has been linked with exposure to a number of common drugs and chemicals, yet efficient, accurate, and minimally invasive methods to detect it are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid have great potential due to the relative ease of sampling but at present, data on their expression and translation are lacking or inconsistent. In this pilot study using a trimethyl tin rat model of central nervous system toxicity, we have applied state-of-the-art assessment techniques to identify potential individual biomarkers and patterns of biomarkers in serum, plasma, urine or cerebral spinal fluid that may be indicative of nerve cell damage and degeneration…

Imam, S, He, Z, Cuevas, E, Rosas-Hernandez, H, Lantz, S, Sarkar, S, Raymick, J Robinson, B, Hanig, J, Herr ,D, MacMillan, D, Smith, A, Liachenko, S, Ferguson, S, O’Callaghan, J, Miller, D, Somps, C, Pardo, I, Slikker, W, Pierson, J, Roberts, R, Gong, B, Tong, W, Aschner, M, Kallman M-J, Calligaro, D and Paule M (2017) LinkRestricted AccessN/A
The Liver Toxicity Knowledge Base (LKTB) and Drug-Induced Liver Injury (DILI) Classification for Assessment of Human Liver Injury. Expert review of Gastroenterology and Hepatology. 12, 31-38.

Introduction: Drug-induced liver injury (DILI) is challenging for drug development, clinical practice and regulation. The Liver Toxicity Knowledge Base (LTKB) provides essential data for DILI study.

Areas covered: The LTKB provided various types of data that can be used to assess and predict DILI. Among much information available, several reference drug lists with annotated human DILI risk are of important…

Thakkar, S, Chen, M, Fang, H, Liu, Z, Roberts, R, Tong, W (2018). LinkRestricted AccessN/A
Computational Drug Repositioning for Rare Diseases in the era of Precision Medicine. Drug Discovery Today, 2, 382-394.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases…

Delavan, B, Roberts, R, Goldsmith, J, Fang, H, Thakkar, S, Huang, R, Bao, W, Tong, W and Liu, Z (2018). LinkRestricted AccessN/A
Lessons learned from two decades of anticancer drugs. TiPS 38, 852-872.

Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to target-based and immune-related therapies. Consequently, more than 200 anticancer drugs are available on the market. However, anticancer drug development still suffers high attrition during the later phases of clinical development and is considered to be a difficult and risky therapeutic category within the drug development arena…

Liu, Z, Delavan, B, Roberts, R and Tong, W (2017). LinkRestricted AccessN/A
In vitro to in vivo extrapolation (IVIVE) for drug-induced liver injury: A genome wide analysis using a drug pair ranking (DPRank) method. ALTEX.

Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours…

Liu, Z, Fang, H, Roberts, RA and Tong, W (2017). LinkRestricted AccessN/A
The Collaboration Gene. Royal Society of Chemistry blog

Collaborations play a vital role in innovation and in the pursuit of new translatable knowledge. These can range from very informal interactions through to the creation of start-up companies with unlimited opportunities for generation of societal and commercial value…

Roberts, RA (2016) LinkOpenN/A
Toxicology as an academic discipline in European Universities. Toxicology Letters, 254, 63.

No abstract available

Wallace, H, Roberts, R, Corsini, E, Bonefeld-Jorgensen, E, Orhan, H, Mach, M, Weiser, T, Carvalho, F, Iscan, M, Tsatsakis, A (2016) LinkRestricted AccessN/A
Target organ profiles in toxicity studies supporting human dosing: does severity progress with longer duration of exposure? Regulatory Tox. Pharm., 73, 737-746.

We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these ≤ 6 week FTiM studies with those observed in subsequent subchronic/chronic (≥ 3 month) studies…

Roberts, RA, Callander, R, Knight, R and Boobis, A. (2015) LinkRestricted AccessN/A
Translational Biomarkers of Neurotoxicity: a HESI Perspective on the Way Forward. Tox Sci., 148, 332-340.

Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues…

Roberts R.A, Aschner M., Calligaro D., Guilarte T.R., Hanig J. , Herr D.W, Hudzik, T.J., Jeromin, A., Kallman M.J. , Liachenko S., Lynch J.J. III, Miller D.B., Moser V.C. , O’Callaghan J.P. , Slikker W. Jr. , Paule, M.G. (2015). LinkRestricted AccessN/A
De novo LINE-1 Retrotransposition in HepG2 Cells Preferentially Targets Gene Poor Regions of Chromosome 13. Genomics. 104, 96-104.

Longinterspersednuclear elements(Line-1 orL1s) account for~17% of thehuman genome. While the majority ofhuman L1s are inactive, ~80–100 elements remain retrotransposition competent and mobilize through RNAintermediates to different locations within the genome. De novo insertions of L1s account for polymorphicvariation of the human genome and disruption of target loci at their new location…

Bojang, P., Anderton, M., Roberts R. and Ramos, K (2014) LinkRestricted AccessN/A
Target organ profiles in toxicity studies supporting human dosing: An assessment of recovery and chronic dosing. Reg Tox Pharm. 70 270-285.

We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these ≤ 6-week FTiM studies with those observed in subsequent subchronic/chronic (≥ 3 month) studies…

Horner, S, Robinson, S, Callander, R, Lees, D and Roberts R (2014) LinkRestricted AccessN/A
An integrated characterisation of the functional, structural, pathological and serological events associated with the development of chronic doxorubicin-induced cardiotoxicity in rat. Toxicological Sciences, 140, 3-15.

Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity…

Cove-Smith, L, Woodhouse, N, Hargreaves, A, Kirk, J, Smith, S, Price, S, Galvin, M, Betts, C, Brocklehurst, S, Backenγ, A, Radford, J, Linton, K, Roberts, R, Schmitt, M, Dive, C, Tugwood, J, Hockings, P and Mellor, H (2013). LinkRestricted AccessN/A
Reducing Attrition in Drug Development: smart loading pre-clinical safety assessment. Drug Discovery Today. 19 341 – 347.

Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca’s potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping (‘stopping toxicities’) showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase…

Roberts, RA, Kavanagh, S, Mellor, H, Pollard, C, Robinson, S and Platz, SJ (2014) LinkRestricted AccessN/A
Target organ toxicities in studies conducted to support first time in man dosing: an analysis across species and therapy areas. (2013) Regulatory Toxicology and Pharmacology 65 334 -343

An analysis of target organ toxicities in first time in man (FTiM) toxicity studies for 77 AstraZeneca candidate drugs (CDs) was conducted across a range of therapy areas. In the rodent, the most frequently affected organ was the liver followed by adrenal glands, kidney, spleen, bone marrow and thymus. In non-rodent, liver and thymus were the most frequently affected organs, followed closely by the testis and GI tract. The profile of affected organs was largely similar across the therapy areas of respiratory and inflammation, cardiovascular/gastrointestinal and CNS/pain. The oncology/infection therapy area differed with a larger range of organs affected…

Horner, Ryan, Robinson, Callander, Stamp and Roberts (2013). LinkRestricted AccessN/A
Epigenetics – Relevance to Drug Safety Science. Toxicology Research 1 3-6.

Epigenetics describes the study of heritable changes in gene expression that occur in the absence of a change to the DNA sequence. Specific patterns of epigenetic signatures can be stably transmitted through mitosis and cell division and form the molecular basis for developmental stage- and cell type-specific gene expression. Associations have been observed that endogenous and exogenous stimuli can change the epigenetic control of both somatic and stem cell differentiation and thus influence phenotypic behaviours and/or disease progression…

Priestley, C, Mellor, H, Duffy, P, Powell, H, Anderton M and Roberts, RA (2012) LinkRestricted AccessN/A
Toxicological and pathophysiological roles of reactive oxygen and nitrogen species, Toxicology 276: 85-94.

‘Oxidative and Nitrative Stress in Toxicology and Disease’ was the subject of a symposium held at the EUROTOX meeting in Dresden 15th September 2009. Reactive oxygen (ROS) and reactive nitrogen species (RNS) produced during tissue pathogenesis and in response to viral or chemical toxicants, induce a complex series of downstream adaptive and reparative events driven by the associated oxidative and nitrative stress. As highlighted by all the speakers, ROS and RNS can promote diverse biological responses associated with a spectrum of disorders including neurodegenerative/neuropsychiatric and cardiovascular diseases…

Roberts, RA, Smith, RA, Safe, S, Szaba, C, Tjalkens, RB and Robertson, F (2010) LinkRestricted AccessN/A