Publications by authors named "Alison Foster"

51 Publications

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Eur J Hum Genet 2021 Apr 12;29(4):625-636. Epub 2021 Jan 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
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http://dx.doi.org/10.1038/s41431-020-00769-7DOI Listing
April 2021

Carpal tunnel syndrome in paediatric patients: A novel association with Kosaki overgrowth syndrome.

JPRAS Open 2020 Sep 27;25:83-87. Epub 2020 Jul 27.

Hand and Upper Limb Service, Plastic and Reconstructive Surgery, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Carpal tunnel syndrome in a paediatric population is vanishingly rare and usually associated with lysosomal storage disorders such as mucopolysaccharidosis (MPS). Overgrowth syndromes similarly are rare and are characterised by increased skeletal growth alongside typical dysmorphic features and intellectual delay and as such the acronym OGID (overgrowth intellectual delay) is now widely used. Kosaki overgrowth syndrome (KOGS) is a newly recognised OGID with only 6 cases to date reported in the literature. Here we report a 7th case of KOGS with a new finding of carpal tunnel syndrome not previously described. We discuss similarities between the intraoperative findings during carpal tunnel decompression with findings seen in patients with MPS.
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http://dx.doi.org/10.1016/j.jpra.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451825PMC
September 2020

Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications.

Clin Genet 2020 07 4;98(1):19-31. Epub 2020 May 4.

Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.
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http://dx.doi.org/10.1111/cge.13752DOI Listing
July 2020

Analysis of β-catenin gene mutations and gene expression in liver tumours of C57BL/10J mice produced by chronic administration of sodium phenobarbital.

Toxicology 2020 01 10;430:152343. Epub 2019 Dec 10.

Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.

In this study liver tumours produced in male and female mice of the low spontaneous liver tumour incidence C57BL/10J strain treated for 99 weeks with 1000 ppm in the diet with the model constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) were analysed for β-catenin mutations by Western immunoblotting and DNA/RNA analysis. Some gene array analysis was also performed to identify genes involved in CAR activation and in β-catenin and Hras gene mutations. Analysis of 8 male and 2 female NaPB-induced liver tumour samples (comprising 2 adenomas, 6 carcinomas and 2 samples containing separate adenomas and carcinomas) revealed truncated β-catenin forms in just 4 male liver tumour samples, with the presence of the truncated β-catenin forms being confirmed by β-catenin exon 1-3 mutation analysis. Microarray gene expression analysis was performed with three of the NaPB-induced male mouse liver tumour samples where β-catenin mutations had not been identified by Western immunoblotting and DNA/RNA analysis and with three liver samples from both NaPB-induced non-tumour tissue and control animals. Treatment with NaPB resulted in induction of Cyp2b subfamily gene expression in both NaPB-induced mouse liver tumours and in NaPB-treated non-tumour tissue. In addition, the gene expression analysis demonstrated that the β-catenin and Hras pathways were not modified in NaPB-induced mouse liver tumours not exhibiting truncated β-catenin forms. Overall, while chronic administration of the model CAR activator NaPB results in both hepatocellular adenoma and carcinoma in the low spontaneous liver tumour incidence C57BL/10J mouse strain, only 40 % of the liver tumours evaluated in this study had β-catenin mutations. These results are in agreement with previous studies with the CAR activator oxazepam and demonstrate that mouse liver tumours induced by nongenotoxic CAR activators in the absence of initiation with a genotoxic agent are due to a number of mechanisms, including those largely independent of either the Wnt/β-catenin signalling pathway or Hras oncogene mutations.
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http://dx.doi.org/10.1016/j.tox.2019.152343DOI Listing
January 2020

Nocturnal bilevel positive airway pressure for the treatment of asthma.

Respir Physiol Neurobiol 2020 03 2;274:103355. Epub 2019 Dec 2.

Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, San Diego, CA, United States.

Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We hypothesized that mimicking deep inspiration using nocturnal mechanical support would improve symptoms in patients with asthma. Subjects with asthma underwent usual care and bilevel positive airway pressure (PAP) therapy for 4 weeks, separated by 4 weeks, and methacholine challenge (PC) and subjective assessments. 13 patients with asthma alone and 8 with asthma + OSA completed the protocol. Change in bronchoreactivity (ratio of Post/Pre PC) was not significantly different during usual care and bilevel PAP [0.86 (IQR 0.19, 1.82) vs 0.94 (IQR 0.56, 2.5), p = 0.88], nor was the change in Asthma Control Test different: 0.1 ± 2.2 vs. -0.2 ± 2.9, p = 0.79, respectively. Bilevel PAP therapy for four weeks did not improve subjective or objective measures of asthma severity in patients with asthma or those with asthma and OSA, although there was heterogeneity in response.
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http://dx.doi.org/10.1016/j.resp.2019.103355DOI Listing
March 2020

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

Am J Med Genet C Semin Med Genet 2019 12 13;181(4):557-564. Epub 2019 Nov 13.

David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, California.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
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http://dx.doi.org/10.1002/ajmg.c.31749DOI Listing
December 2019

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

Am J Med Genet C Semin Med Genet 2019 12 12;181(4):638-643. Epub 2019 Nov 12.

South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
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http://dx.doi.org/10.1002/ajmg.c.31750DOI Listing
December 2019

Predicting Drug-Induced Liver Injury with Bayesian Machine Learning.

Chem Res Toxicol 2020 01 2;33(1):239-248. Epub 2019 Oct 2.

Drug induced liver injury (DILI) can require significant risk management in drug development and on occasion can cause morbidity or mortality, leading to drug attrition. Optimizing candidates preclinically can minimize hepatotoxicity risk, but it is difficult to predict due to multiple etiologies encompassing DILI, often with multifactorial and overlapping mechanisms. In addition to epidemiological risk factors, physicochemical properties, dose, disposition, lipophilicity, and hepatic metabolic function are also relevant for DILI risk. Better human-relevant, predictive models are required to improve hepatotoxicity risk assessment in drug discovery. Our hypothesis is that integrating mechanistically relevant hepatic safety assays with Bayesian machine learning will improve hepatic safety risk prediction. We present a quantitative and mechanistic risk assessment for candidate nomination using data from assays (hepatic spheroids, BSEP, mitochondrial toxicity, and bioactivation), together with physicochemical (cLogP) and exposure (Cmax) variables from a chemically diverse compound set (33 no/low-, 40 medium-, and 23 high-severity DILI compounds). The Bayesian model predicts the continuous underlying DILI severity and uses a data-driven prior distribution over the parameters to prevent overfitting. The model quantifies the probability that a compound falls into either no/low-, medium-, or high-severity categories, with a balanced accuracy of 63% on held-out samples, and a continuous prediction of DILI severity along with uncertainty in the prediction. For a binary yes/no DILI prediction, the model has a balanced accuracy of 86%, a sensitivity of 87%, a specificity of 85%, a positive predictive value of 92%, and a negative predictive value of 78%. Combining physiologically relevant assays, improved alignment with FDA recommendations, and optimal statistical integration of assay data leads to improved DILI risk prediction.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00264DOI Listing
January 2020

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Am J Med Genet C Semin Med Genet 2019 12 3;181(4):502-508. Epub 2019 Sep 3.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
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http://dx.doi.org/10.1002/ajmg.c.31738DOI Listing
December 2019

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid.

Arch Toxicol 2019 04 26;93(4):1021-1037. Epub 2019 Mar 26.

Drug Safety and Metabolism, AstraZeneca IMED Biotech Unit, Cambridge, CB4 0WG, UK.

Drug-induced liver injury remains a frequent reason for drug withdrawal. Accordingly, more predictive and translational models are required to assess human hepatotoxicity risk. This study presents a comprehensive evaluation of two promising models to assess mechanistic hepatotoxicity, microengineered Organ-Chips and 3D hepatic spheroids, which have enhanced liver phenotype, metabolic activity and stability in culture not attainable with conventional 2D models. Sensitivity of the models to two hepatotoxins, acetaminophen (APAP) and fialuridine (FIAU), was assessed across a range of cytotoxicity biomarkers (ATP, albumin, miR-122, α-GST) as well as their metabolic functionality by quantifying APAP, FIAU and CYP probe substrate metabolites. APAP and FIAU produced dose- and time-dependent increases in miR-122 and α-GST release as well as decreases in albumin secretion in both Liver-Chips and hepatic spheroids. Metabolic turnover of CYP probe substrates, APAP and FIAU, was maintained over the 10-day exposure period at concentrations where no cytotoxicity was detected and APAP turnover decreased at concentrations where cytotoxicity was detected. With APAP, the most sensitive biomarkers were albumin in the Liver-Chips (EC 5.6 mM, day 1) and miR-122 and ATP in the liver spheroids (14-fold and EC 2.9 mM, respectively, day 3). With FIAU, the most sensitive biomarkers were albumin in the Liver-Chip (EC 126 µM) and miR-122 (15-fold) in the liver spheroids, both on day 7. In conclusion, both models exhibited integrated toxicity and metabolism, and broadly similar sensitivity to the hepatotoxicants at relevant clinical concentrations, demonstrating the utility of these models for improved hepatotoxicity risk assessment.
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http://dx.doi.org/10.1007/s00204-019-02427-4DOI Listing
April 2019

EED and EZH2 constitutive variants: A study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome.

Am J Med Genet A 2019 04 21;179(4):588-594. Epub 2019 Feb 21.

Department of Clinical Genetics, St George's University of London, London, United Kingdom.

Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
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http://dx.doi.org/10.1002/ajmg.a.61066DOI Listing
April 2019

Introducing an automated high content confocal imaging approach for Organs-on-Chips.

Lab Chip 2019 01;19(3):410-421

AstraZeneca IMED Biotech Unit, Discovery Sciences, Cambridge, UK.

Organ-Chips are micro-engineered systems that aim to recapitulate the organ microenvironment. Implementation of Organ-Chips within the pharmaceutical industry aims to improve the probability of success of drugs reaching late stage clinical trial by generating models for drug discovery that are of human origin and have disease relevance. We are adopting the use of Organ-Chips for enhancing pre-clinical efficacy and toxicity evaluation and prediction. Whilst capturing cellular phenotype via imaging in response to drug exposure is a useful readout in these models, application has been limited due to difficulties in imaging the chips at scale. Here we created an end-to-end, automated workflow to capture and analyse confocal images of multicellular Organ-Chips to assess detailed cellular phenotype across large batches of chips. By automating this process, we not only reduced acquisition time, but we also minimised process variability and user bias. This enabled us to establish, for the first time, a framework of statistical best practice for Organ-Chip imaging, creating the capability of using Organ-Chips and imaging for routine testing in drug discovery applications that rely on quantitative image data for decision making. We tested our approach using benzbromarone, whose mechanism of toxicity has been linked to mitochondrial damage with subsequent induction of apoptosis and necrosis, and staurosporine, a tool inducer of apoptosis. We also applied this workflow to assess the hepatotoxic effect of an active AstraZeneca drug candidate illustrating its applicability in drug safety assessment beyond testing tool compounds. Finally, we have demonstrated that this approach could be adapted to Organ-Chips of different shapes and sizes through application to a Kidney-Chip.
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http://dx.doi.org/10.1039/c8lc00829aDOI Listing
January 2019

The broiler chicken as a signal of a human reconfigured biosphere.

R Soc Open Sci 2018 Dec 12;5(12):180325. Epub 2018 Dec 12.

School of Agriculture Science, North West University, P Bag X 2046, Mmabatho 2735, South Africa.

Changing patterns of human resource use and food consumption have profoundly impacted the Earth's biosphere. Until now, no individual taxa have been suggested as distinct and characteristic new morphospecies representing this change. Here we show that the domestic broiler chicken is one such potential marker. Human-directed changes in breeding, diet and farming practices demonstrate at least a doubling in body size from the late medieval period to the present in domesticated chickens, and an up to fivefold increase in body mass since the mid-twentieth century. Moreover, the skeletal morphology, pathology, bone geochemistry and genetics of modern broilers are demonstrably different to those of their ancestors. Physical and numerical changes to chickens in the second half of the twentieth century, i.e. during the putative Anthropocene Epoch, have been the most dramatic, with large increases in individual bird growth rate and population sizes. Broiler chickens, now unable to survive without human intervention, have a combined mass exceeding that of all other birds on Earth; this novel morphotype symbolizes the unprecedented human reconfiguration of the Earth's biosphere.
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http://dx.doi.org/10.1098/rsos.180325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304135PMC
December 2018

Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.

Am J Med Genet A 2019 03 13;179(3):344-349. Epub 2019 Jan 13.

South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61024DOI Listing
March 2019

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Nat Rev Endocrinol 2018 04 29;14(4):229-249. Epub 2018 Jan 29.

South West Thames Regional Genetics Service and St George's University of London and Institute of Cancer Research, London, SW17 0RE, UK.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
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http://dx.doi.org/10.1038/nrendo.2017.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022848PMC
April 2018

Comparison of Hepatic 2D Sandwich Cultures and 3D Spheroids for Long-term Toxicity Applications: A Multicenter Study.

Toxicol Sci 2018 04;162(2):655-666

Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.

Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.
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http://dx.doi.org/10.1093/toxsci/kfx289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888952PMC
April 2018

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Arch Toxicol 2017 Aug 13;91(8):2849-2863. Epub 2017 Jun 13.

Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.

Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC values. Regardless of comparing IC values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.
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http://dx.doi.org/10.1007/s00204-017-2002-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515971PMC
August 2017

Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid.

Toxicol Res (Camb) 2017 Jan 9;6(1):81-88. Epub 2016 Nov 9.

Drug Safety Consultant , Macclesfield , UK . Email: ; Tel: +44 (0)1625432113.

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit no functional expression of hepatic cytochrome P450 (P450) when compared to wild type (WT) mice, but have normal hepatic and extrahepatic expression of other biotransformation enzymes. We have assessed the utility of HRN™ mice for investigation of the role of metabolic bioactivation in liver toxicity caused by the nonsteroidal anti-inflammatory drug (NSAID) fenclozic acid. studies revealed significant NADPH-dependent ( P450-mediated) covalent binding of [C]-fenclozic acid to liver microsomes from WT mice and HRN™ mice, whereas no covalent binding was observed in the presence of the UDP-glucuronyltransferase cofactor UDPGA. Oral fenclozic acid administration did not alter the liver histopathology or elevate the plasma liver enzyme activities of WT mice, or affect their hepatic miRNA contents. Livers from HRN™ mice exhibited abnormal liver histopathology (enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration, necrosis, inflammatory cell infiltration) and plasma clinical chemistry (elevated alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities). Modest apparent improvements in these abnormalities were observed when HRN™ mice were dosed orally with fenclozic acid for 7 days at 100 mg kg day. Previously we observed more marked effects on liver histopathology and integrity in HRN™ mice dosed orally with the NSAID diclofenac for 7 days at 30 mg kg day. We conclude that HRN™ mice are valuable for assessing P450-related hepatic drug biotransformation, but not for drug toxicity studies due to underlying liver dysfunction. Nonetheless, HRN™ mice may provide novel insights into the role of inflammation in liver injury, thereby aiding its treatment.
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http://dx.doi.org/10.1039/c6tx00376aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062145PMC
January 2017

Cytotoxicity evaluation using cryopreserved primary human hepatocytes in various culture formats.

Toxicol Lett 2016 Sep 27;258:207-215. Epub 2016 Jun 27.

Translational Safety, Drug Safety & Metabolism, AstraZeneca, Cambridge Science Park, Cambridge, UK. Electronic address:

Sixteen training compounds selected in the IMI MIP-DILI consortium, 12 drug-induced liver injury (DILI) positive compounds and 4 non-DILI compounds, were assessed in cryopreserved primary human hepatocytes. When a ten-fold safety margin threshold was applied, the non-DILI-compounds were correctly identified 2h following a single exposure to pooled human hepatocytes (n=13 donors) in suspension and 14-days following repeat dose exposure (3 treatments) to an established 3D-microtissue co-culture (3D-MT co-culture, n=1 donor) consisting of human hepatocytes co-cultured with non-parenchymal cells (NPC). In contrast, only 5/12 DILI-compounds were correctly identified 2h following a single exposure to pooled human hepatocytes in suspension. Exposure of the 2D-sandwich culture human hepatocyte monocultures (2D-sw) for 3days resulted in the correct identification of 11/12 DILI-positive compounds, whereas exposure of the human 3D-MT co-cultures for 14days resulted in identification of 9/12 DILI-compounds; in addition to ximelagatran (also not identified by 2D-sw monocultures, Sison-Young et al., 2016), the 3D-MT co-cultures failed to detect amiodarone and bosentan. The sensitivity of the 2D human hepatocytes co-cultured with NPC to ximelagatran was increased in the presence of lipopolysaccharide (LPS), but only at high concentrations, therefore preventing its classification as a DILI positive compound. In conclusion (1) despite suspension human hepatocytes having the greatest metabolic capacity in the short term, they are the least predictive of clinical DILI across the MIP-DILI test compounds, (2) longer exposure periods than 72h of human hepatocytes do not allow to increase DILI-prediction rate, (3) co-cultures of human hepatocytes with NPC, in the presence of LPS during the 72h exposure period allow the assessment of innate immune system involvement of a given drug.
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http://dx.doi.org/10.1016/j.toxlet.2016.06.1127DOI Listing
September 2016

CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.

Am J Med Genet A 2016 10 17;170(10):2681-93. Epub 2016 Jun 17.

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.

Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37800DOI Listing
October 2016

Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

Nat Neurosci 2016 Apr 14;19(4):571-7. Epub 2016 Mar 14.

MRC Centre for Neuropsychiatric Genetics &Genomics, Institute of Psychological Medicine &Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
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http://dx.doi.org/10.1038/nn.4267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689268PMC
April 2016

The health impact of selective breeding in poultry: A probable case of 'creeper' chicken (Gallus gallus) from 16th-century Chester, England.

Int J Paleopathol 2015 Jun 16;9:1-7. Epub 2014 Dec 16.

School of Archaeology and Ancient History, University of Leicester, University Road, Leicester LE1 7RH, UK.

Two articulating chicken bones from a feast deposit, dated to the 16th century, from Chester, exhibit lesions consistent with the skeletal disorder chondrodystrophy. While this form of dwarfism has many potential causes, it is also consistent with the presentation of the 'creeper' mutation. In this paper we describe and undertake a differential diagnosis of the two articulating chicken bones, and consider the wider significance of this find in 16th-century Britain. The appearance of these lesions, along with the widespread size increase in chickens, the rise of early modern publications concerning chicken husbandry, and contemporary observations that dwarf fowl were luxury foods, provide indirect support for this diagnosis and adds to the growing body of knowledge regarding the unintended health impact of selective breeding.
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http://dx.doi.org/10.1016/j.ijpp.2014.11.003DOI Listing
June 2015

Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.

J Clin Invest 2015 May 20;125(5):2151-60. Epub 2015 Apr 20.

Dyskeratosis congenita (DC) and related syndromes are inherited, life-threatening bone marrow (BM) failure disorders, and approximately 40% of cases are currently uncharacterized at the genetic level. Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. PARN is an extensively characterized exonuclease with deadenylation activity that controls mRNA stability in part and therefore regulates expression of a large number of genes. The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. Individuals with biallelic PARN mutations and PARN-depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC, DKC1, RTEL1, and TERF1. Moreover, PARN-deficient cells also possessed critically short telomeres. Collectively, these results identify a role for PARN in telomere maintenance and demonstrate that it is a disease-causing gene in a subset of patients with severe DC.
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http://dx.doi.org/10.1172/JCI78963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463202PMC
May 2015

Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice.

Arch Toxicol 2016 Apr 28;90(4):853-62. Epub 2015 Mar 28.

FRAME, Nottingham, UK.

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [(14)C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [(14)C]-diclofenac was incubated with HRN™ mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN™ mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN™ mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN™ mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN™ mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN™ mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.
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http://dx.doi.org/10.1007/s00204-015-1505-xDOI Listing
April 2016

Cortisol in mother's milk across lactation reflects maternal life history and predicts infant temperament.

Behav Ecol 2015 Jan-Feb;26(1):269-281. Epub 2014 Oct 31.

Brain, Mind, and Behavior Unit, California National Primate Research Center, University of Califoria, One Shields Avenue , Davis CA 95616 , USA , ; Department of Psychology, University of California Davis , One Shields Ave, Davis, CA, 95616 , USA.

The maternal environment exerts important influences on offspring mass/growth, metabolism, reproduction, neurobiology, immune function, and behavior among birds, insects, reptiles, fish, and mammals. For mammals, mother's milk is an important physiological pathway for nutrient transfer and glucocorticoid signaling that potentially influences offspring growth and behavioral phenotype. Glucocorticoids in mother's milk have been associated with offspring behavioral phenotype in several mammals, but studies have been handicapped by not simultaneously evaluating milk energy density and yield. This is problematic as milk glucocorticoids and nutrients likely have simultaneous effects on offspring phenotype. We investigated mother's milk and infant temperament and growth in a cohort of rhesus macaque () mother-infant dyads at the California National Primate Research Center ( = 108). Glucocorticoids in mother's milk, independent of available milk energy, predicted a more Nervous, less Confident temperament in both sons and daughters. We additionally found sex differences in the windows of sensitivity and the magnitude of sensitivity to maternal-origin glucocorticoids. Lower parity mothers produced milk with higher cortisol concentrations. Lastly, higher cortisol concentrations in milk were associated with greater infant weight gain across time. Taken together, these results suggest that mothers with fewer somatic resources, even in captivity, may be "programming" through cortisol signaling, behaviorally cautious offspring that prioritize growth. Glucocorticoids ingested through milk may importantly contribute to the assimilation of available milk energy, development of temperament, and orchestrate, in part, the allocation of maternal milk energy between growth and behavioral phenotype.
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http://dx.doi.org/10.1093/beheco/aru186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309982PMC
October 2014

Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists.

J Pharmacol Exp Ther 2015 Feb 2;352(2):281-90. Epub 2014 Dec 2.

Drug Safety Consultant, Macclesfield, Cheshire, United Kingdom (J.G.K.); DMPK (S.H.S.), Discovery Safety (J.A.E.), and Translational Safety (A.J.F.), Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; DMPK (L.C.A., J.B., C.S.E.), Regulatory Safety (M.B.), Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Mölndal, Sweden; and DMPK, Cardiovascular and Metabolic Diseases (M.E.), and Respiratory, Inflammation, and Autoimmunity (R.A.T.), iMED AstraZeneca R&D Mölndal, Mölndal, Sweden

Drug-induced liver injury has been observed in patients treated with the endothelin receptor antagonists sitaxentan and bosentan, but not following treatment with ambrisentan. The aim of our studies was to assess the possible role of multiple contributory mechanisms in this clinically relevant toxicity. Inhibition of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 was quantified using membrane vesicle assays. Inhibition of mitochondrial respiration in human liver-derived HuH-7 cells was determined using a Seahorse XF(e96) analyzer. Cytochrome P450 (P450)-independent and P450-mediated cell toxicity was assessed using transfected SV40-T-antigen-immortalized human liver epithelial (THLE) cell lines. Exposure-adjusted assay ratios were calculated by dividing the maximum human drug plasma concentrations by the IC50 or EC50 values obtained in vitro. Covalent binding (CVB) of radiolabeled drugs to human hepatocytes was quantified, and CVB body burdens were calculated by adjusting CVB values for fractional drug turnover in vitro and daily therapeutic dose. Sitaxentan exhibited positive exposure-adjusted signals in all five in vitro assays and a high CVB body burden. Bosentan exhibited a positive exposure-adjusted signal in one assay (BSEP inhibition) and a moderate CVB body burden. Ambrisentan exhibited no positive exposure-adjusted assay signals and a low CVB body burden. These data indicate that multiple mechanisms contribute to the rare, but potentially severe liver injury caused by sitaxentan in humans; provide a plausible rationale for the markedly lower propensity of bosentan to cause liver injury; and highlight the relative safety of ambrisentan.
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http://dx.doi.org/10.1124/jpet.114.220491DOI Listing
February 2015

A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice.

Biochem Pharmacol 2014 Dec 22;92(4):701-11. Epub 2014 Oct 22.

Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom; RIA iMed DMPK, AstraZeneca Sweden, Pepparedsleden 1, 43183, Mölndal, Sweden. Electronic address:

The hepatic cytochrome P450 reductase null (HRN) mouse, which has no functional hepatic Cyp P450s, may represent a useful model for examining extra-hepatic P450-related oxidative metabolism. Here the pharmacokinetics and metabolic fate of midazolam, a drug known to undergo such extra-hepatic metabolism, have been investigated in the HRN mouse and compared with a phenotypically normal strain (C57BL/6J). In addition, the effects of co-administration of the pan-P450 inhibitor 1'-aminobenzotriazole (ABT) on the metabolic profile have been compared in both strains. Significant pharmacokinetic differences for midazolam were observed between the two strains of mice with the HRN mice showing lower circulating concentrations of 1'-hydroxymidazolam but higher concentrations of 1'-hydroxymidazolam-O-glucuronide. A significant increase in midazolam exposure was seen upon ABT exposure for both strains of mice, but no differences in the area under the concentration time curves (AUC) for the monitored metabolites were observed. Although oxidative metabolism of midazolam was not abolished, significant decreases in 1'-hydroxymidazolam formation ratios were observed for both strains of mice exposed to ABT. Metabolite profiling of blood and bile showed a number of qualitative and quantitative differences between HRN and normal mice. These differences in midazolam metabolism between the two strains of mice clearly demonstrate the role that liver P450 enzymes play in the murine metabolism of midazolam. The fate of the compound in the HRN mice shows the importance of extrahepatic metabolism and also showed that these mice appear to be more capable of forming circulating phase II glucuronides than the normal strain.
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http://dx.doi.org/10.1016/j.bcp.2014.10.004DOI Listing
December 2014

Breast cancer and breast screening: perceptions of Chinese migrant women living in New Zealand.

J Prim Health Care 2014 Jun 1;6(2):135-42. Epub 2014 Jun 1.

Department of Primary Health Care and General Practice, University of Otago, Wellington, New Zealand.

Introduction: Migrant Chinese constitute a significant and increasing proportion of New Zealand women. They have lower rates of participation in breast cancer screening than other New Zealanders, but reasons for this are unknown. The aim of this study was to investigate factors affecting Chinese women's understanding of, and access to, breast health services, to better understand reasons for low participation in screening and their experiences of breast cancer clinic care.

Methods: The participants were 26 Chinese migrant women-19 recruited in the community and seven recruited from 17 eligible women attending a breast clinic between 2008 and 2010 in Wellington, New Zealand. The design was that of a qualitative study, using semi-structured interviews and thematic content analysis.

Findings: There were low levels of awareness about the national breast screening programme and limited engagement with preventive primary care services. Concerns about privacy and a range of communication difficulties were identified that related to oral language, lack of written information in Chinese, and limited understanding about Chinese perceptions of ill health and traditional Chinese medicine by New Zealand health professionals.

Conclusion: Addressing communication barriers for Chinese migrant women has the potential to raise awareness about breast cancer and breast health, and to increase successful participation in breast cancer screening. Greater efforts are needed to ensure this group has an understanding of, and is engaged with a primary care provider. Such efforts are key to improving health for this growing sector of the New Zealand population.
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June 2014

Evaluation of the use of imaging parameters for the detection of compound-induced hepatotoxicity in 384-well cultures of HepG2 cells and cryopreserved primary human hepatocytes.

Toxicol In Vitro 2014 Mar 1;28(2):171-81. Epub 2013 Nov 1.

Eurofins Panlabs Inc., USA.

Drug-induced liver injury (DILI) is a major cause of failed drug development, withdrawal and restricted usage. Therefore screening assays which aid selection of candidate drugs with reduced propensity to cause DILI are required. We have investigated the toxicity of 144 drugs, 108 of which caused DILI, using assays identified in the literature as having some predictivity for hepatotoxicity. The validated assays utilised either HepG2 cells, HepG2 cells in the presence of rat S9 fraction or isolated human hepatocytes. All parameters were quantified by multiplexed and automated high content fluorescence microscopy, at appropriate time points after compound administration (4, 24 or 48h). The individual endpoint which identified drugs that caused DILI with greatest precision was maximal fold induction in CM-H2DFFDA staining in hepatocytes after 24h (41% sensitivity, 86% specificity). However, hierarchical clustering analysis of all endpoints provided the most sensitive identification of drugs which caused DILI (58% sensitivity, 75% specificity). We conclude that multi-parametric high content cell toxicity assays can enable in vitro detection of drugs that have high propensity to cause DILI in vivo but that many DILI compounds exhibit few in vitro signals when evaluated using these assays.
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http://dx.doi.org/10.1016/j.tiv.2013.10.015DOI Listing
March 2014