Publications by authors named "Simon Bailey"

168 Publications

Combining multi-site magnetic resonance imaging with machine learning predicts survival in pediatric brain tumors.

Sci Rep 2021 Sep 23;11(1):18897. Epub 2021 Sep 23.

Institute of Cancer and Genomic Sciences, School of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Brain tumors represent the highest cause of mortality in the pediatric oncological population. Diagnosis is commonly performed with magnetic resonance imaging. Survival biomarkers are challenging to identify due to the relatively low numbers of individual tumor types. 69 children with biopsy-confirmed brain tumors were recruited into this study. All participants had perfusion and diffusion weighted imaging performed at diagnosis. Imaging data were processed using conventional methods, and a Bayesian survival analysis performed. Unsupervised and supervised machine learning were performed with the survival features, to determine novel sub-groups related to survival. Sub-group analysis was undertaken to understand differences in imaging features. Survival analysis showed that a combination of diffusion and perfusion imaging were able to determine two novel sub-groups of brain tumors with different survival characteristics (p < 0.01), which were subsequently classified with high accuracy (98%) by a neural network. Analysis of high-grade tumors showed a marked difference in survival (p = 0.029) between the two clusters with high risk and low risk imaging features. This study has developed a novel model of survival for pediatric brain tumors. Tumor perfusion plays a key role in determining survival and should be considered as a high priority for future imaging protocols.
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http://dx.doi.org/10.1038/s41598-021-96189-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460620PMC
September 2021

Perioperative corticosteroid use in paediatric neuro-oncology.

Childs Nerv Syst 2021 Sep 13. Epub 2021 Sep 13.

Department of Paediatric Oncology, Great North Children's Hospital, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

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http://dx.doi.org/10.1007/s00381-021-05354-xDOI Listing
September 2021

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.

Neuro Oncol 2021 Jul 17. Epub 2021 Jul 17.

Newcastle University Centre for Cancer, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK.

Background: <5% of medulloblastoma patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations suggested significant genetic divergence of the relapsed disease.

Methods: We undertook large-scale integrated characterization of the molecular features of rMB - molecular subgroup, novel subtypes, copy number variation (CNV) and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n=107), alongside an independent reference cohort sampled at diagnosis (n=282). rMB events were investigated for association with outcome post-relapse in clinically-annotated patients (n=54).

Results: Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. MBSHH Non-infant displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (e.g. CDK amplifications) and novel (e.g. USH2A mutations) events. Importantly, many hallmark features of medulloblastoma were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (e.g. SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (e.g. DNA damage-signaling) and specific events (e.g. 3p loss) predicted survival post-relapse.

Conclusions: rMB is defined by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
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http://dx.doi.org/10.1093/neuonc/noab178DOI Listing
July 2021

Droplet digital PCR-based detection of circulating tumor DNA from pediatric high grade and diffuse midline glioma patients.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab013. Epub 2021 Jan 27.

Division of Molecular Pathology, Institute of Cancer Research, London, UK.

Background: The use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory.

Methods: We optimized droplet digital PCR (ddPCR) assays for the detection of common somatic mutations observed in pediatric HGG/DMG, and applied them to liquid biopsies from plasma, serum, cerebrospinal fluid (CSF), and cystic fluid collected from 32 patients.

Results: Although detectable in all biomaterial types, ctDNA presented at significantly higher levels in CSF compared to plasma and/or serum. When applied to a cohort of 127 plasma specimens from 41 patients collected from 2011 to 2018 as part of a randomized clinical trial in pediatric non-brainstem HGG/DMG, ctDNA profiling by ddPCR was of limited use due to the small volumes (mean = 0.49 mL) available. In anecdotal cases where sufficient material was available, cfDNA concentration correlated with disease progression in two examples each of poor response in _K27M-mutant DMG, and longer survival times in hemispheric _V600E-mutant cases.

Conclusion: Tumor-specific DNA alterations are more readily detected in CSF than plasma. Although we demonstrate the potential of the approach to assessing tumor burden, our results highlight the necessity for adequate sample collection and approach to improve detection if plasma samples are to be used.
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http://dx.doi.org/10.1093/noajnl/vdab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218704PMC
January 2021

Acceptance and commitment therapy for young brain tumour survivors: study protocol for an acceptability and feasibility trial.

BMJ Open 2021 06 1;11(6):e051091. Epub 2021 Jun 1.

Nottingham University Hospitals NHS Trust, Nottingham, UK.

Introduction: Survivors of childhood brain tumours have the poorest health-related quality of life of all cancer survivors due to the multiple physical and psychological sequelae of brain tumours and their treatment. Remotely delivered acceptance and commitment therapy (ACT) may be a suitable and accessible psychological intervention to support young people who have survived brain tumours. This study aims to assess the feasibility and acceptability of remotely delivered ACT to improve quality of life among these young survivors.

Methods And Analysis: This study is a two-arm, parallel group, randomised controlled trial comparing ACT with waitlist control at 12-week follow-up as the primary endpoint. Seventy-two participants will be recruited, who are aged 11-24 and have completed brain tumour treatment. Participants will be randomised to receive 12 weeks of ACT either immediately or after a 12-week wait. The DNA-v model of ACT will be employed, which is a developmentally appropriate model for young people. Feasibility will be assessed using the proportion of those showing interest who consent to the trial and complete the intervention. Acceptability will be assessed using participant evaluations of the intervention, alongside qualitative interviews and treatment diaries analysed thematically. A range of clinical outcome measures will also assess physical and mental health, everyday functioning, quality of life and service usage at 12-week follow-up. The durability of treatment effects will be assessed by further follow-up assessments at 24 weeks, 36 weeks and 48 weeks.

Ethics And Dissemination: Ethical approval was given by East Midlands, Nottingham 1 Research Ethics Committee (Reference: 20/EM/0237). Study results will be disseminated in peer-reviewed journals, through public events and relevant third sector organisations.

Trial Registration: ISRCTN10903290; NCT04722237.
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http://dx.doi.org/10.1136/bmjopen-2021-051091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173289PMC
June 2021

Postprandial insulin responses to various feedstuffs differ in insulin dysregulated horses compared with non-insulin dysregulated controls.

Equine Vet J 2021 May 30. Epub 2021 May 30.

Department of Veterinary Science, M. H. Gluck Equine Research Center, University of Kentucky, Lexington, KY, USA.

Background: Controlling postprandial hyperinsulinaemia is important in insulin dysregulated (ID) horses to reduce the risk of laminitis.

Objectives: To evaluate postprandial insulin responses of ID versus non-insulin dysregulated (NID) horses to feedstuffs varying in nonstructural carbohydrate (NSC) and crude protein (CP).

Study Design: Randomised crossover.

Methods: Eighteen adult mixed-breed horses (13.3 ± 2.2 years; 621 ± 78.8 kg) were individually fed [~1 g/kg body weight (BW)] specific feedstuffs within two crossover studies. Eight ID and eight NID were used in Study A, and 11 ID and 5 NID in Study B. In Study A, all horses were randomly fed once: cracked corn (CC: ~74% NSC & ~9% CP), ration balancer with low protein (RB-LP: ~15% NSC & ~17% CP), ration balancer with high protein (RB-HP: ~14% NSC and ~37% CP) and 50:50 mixture of RB-LP:RB-HP (MIX-P). In Study B, horses were randomly fed once: CC, RB-HP, steam-flaked corn (SF: ~73% NSC & ~10% CP), oat groats (OG: ~64% NSC & ~14% CP) and a low NSC pellet (L-NSC: ~6% NSC & ~12% CP). Blood was collected for insulin determination [radioimmunoassay (RIA)] before and 30, 60, 75, 90, 105, 120, 150, 180, 210 and 240-minute post-feeding in Study A and at 60-minute in Study B. Data were analysed via analysis of variance (ANOVA) for repeated measures after any required transformations.

Results: ID horses had significantly greater insulin responses (AUCi) than NID for all diets in both studies (P < .001; ID 22 362 ± 10 298 µIU/mL/min & NID 6145 ± 1922 µIU/mL/min). No effect of diet on AUCi for NID (P = .2), but in ID, the CC (32 000 ± 13 960 µIU/mL/min) AUCi was higher than RB-LP (P = .01; 18 977 ± 6731 µIU/mL/min). ID insulin (T60) was lower for the L-NSC (57.8 ± 18.5 µIU/mL) versus all other diets (P < .02; 160.1 ± 91.5 µIU/mL).

Main Limitations: Small numbers of horses; no ponies.

Conclusions: NSC appears to be the main driver of the postprandial insulin response. ID horses respond disproportionately to feeding even small amounts of low/moderate NSC feedstuffs. Data on possible dietary thresholds for postprandial insulin responses cannot be extrapolated from NID horses.
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http://dx.doi.org/10.1111/evj.13474DOI Listing
May 2021

Validation of ROS1 by immunohistochemistry against fluorescent in situ hybridisation on cytology and small biopsy samples in a large teaching hospital.

Cytopathology 2021 Sep 15;32(5):621-630. Epub 2021 Jun 15.

Manchester Cytology Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Objective: Rearranged ROS1, present in 1%-2% of non-small cell lung cancer (NSCLC) patients, usually young, never or light smokers, is assessed by fluorescence in situ hybridization (FISH) to determine eligibility for tyrosine kinase inhibitors (TKI). Immunohistochemistry (IHC) for the protein product of ROS1 rearrangement, a cost-effective alternative, is validated on cytology and small biopsy samples.

Methods: From 1 March to 31 December 2019, cytology cell blocks and small biopsy samples from a selected cohort of NSCLC patients were concurrently tested for ROS1 gene rearrangement by Vysis 6q22 Break Apart FISH probe and IHC using Cell Signalling D4D6 antibody. Mismatch cases were tested by an RNA fusion next generation sequencing (NGS) panel.

Results: In a prospective population of 95 cases, 91 were negative and two were positive by both FISH and IHC. Both dual positive cases were female never smokers and benefited from TKI treatment. Another two cases were positive by FISH but negative by IHC and repeat by NGS showed one to be negative but one failed. Turnaround time for IHC was 0 to 8 days from request to authorisation, whilst that of FISH was 9 to 42 days at a cost of £51 and £159 respectively.

Conclusion: IHC to assess for the protein product of ROS1 gene rearrangement on cytology cell blocks and small biopsy samples in a routine setting is a promising screening method to assess eligibility for TKI treatment with positive and indeterminate cases confirmed by FISH or NGS as it has good negative predictive value, faster turnaround time and is cost effective, with proven technical and clinical validation.
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http://dx.doi.org/10.1111/cyt.12994DOI Listing
September 2021

Optimal postoperative management of perineal flaps in oncologic patients undergoing extralevator abdominoperineal excision: An introduction of a postoperative monitoring and flap management protocol.

J Perioper Pract 2021 May 6:1750458920959565. Epub 2021 May 6.

Queen Victoria Hospital, East Grinstead, UK.

There is extensive discussion regarding method of perineal defect closure extralevator abdominoperineal excision, but little consideration of optimal postoperative management of the flaps, or use of Enhanced Recovery After Surgery in flap reconstruction. Literature review revealed little discussion of optimum postoperative care of perineal flaps following extralevator abdominoperineal excision. We have developed a protocol for postoperative care of perineal flaps for use in conjunction with colorectal Enhanced Recovery After Surgery pathways, easily followed in units not specialising in plastic surgery. The protocol was developed using translatable evidence from guidelines for flap care from other subspecialties, as well as the experience of management of post-extralevator abdominoperineal excision perineal flaps in our trust, with the aim of enabling early detection of deterioration in this complex cohort, with a multidisciplinary enhanced recovery approach.
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http://dx.doi.org/10.1177/1750458920959565DOI Listing
May 2021

Advanced molecular pathology for rare tumours: A national feasibility study and model for centralised medulloblastoma diagnostics.

Neuropathol Appl Neurobiol 2021 10 2;47(6):736-747. Epub 2021 May 2.

Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Aims: Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co-ordinated real-time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA-seq/DNA methylation-array).

Methods: This nationwide trial in medulloblastoma (<80 UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin-fixed, paraffin-embedded tumour material were co-submitted from 135 patients (16 referral centres).

Results: Complete CPR diagnostics were successful for 88% (120/135). Inadequate sampling was the most common cause of failure; biomaterials were typically suitable for methylation-array (129/135, 94%), but frozen tissues commonly fell below RNA-seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results; fluorescent in-situ hybridisation most accurately identified high-risk MYC/MYCN amplification (20/135, 15%), while combined methods (CTNNB1/chr6 status, methylation-array subgrouping) best defined favourable-risk WNT tumours (14/135; 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk-status for 29% of patients.

Conclusion: National real-time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk-status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker-driven routine diagnostics and clinical/research studies.
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http://dx.doi.org/10.1111/nan.12716DOI Listing
October 2021

Exploring commissioners' understandings of early primary care network development: qualitative interview study.

Br J Gen Pract 2021 Sep 26;71(710):e711-e718. Epub 2021 Aug 26.

GP, Centre for Primary Care and Health Services Research, Division of Population Health, Health Service Research & Primary Care, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester.

Background: Primary care networks (PCNs) are financially incentivised groupings of general practices in the English NHS. Their purpose is to deliver a number of policy goals set out in . Clinical commissioning groups (CCGs) have a role in their establishment, support, and oversight.

Aim: To explore commissioners' perspectives on the early development of PCNs.

Design And Setting: Qualitative study of CCG staff using telephone interviews.

Method: Semi-structured interviews were carried out with 37 CCG employees involved in PCN establishment. Interviewees were asked about local PCNs' characteristics, factors shaping development and form, activities to date, challenges and benefits, and their CCGs' relationship with PCNs. Interviewee responses were summarised within a matrix and analysed thematically.

Results: Three meta-themes were identified: the multifaceted role of the commissioner, tensions between PCN policy and locally commissioned services, and engaging the broader system. Interviewees reported that the policy potentially favours those PCNs working from a 'blank slate' and does not sufficiently account for the fact some GP practices and wider system organisations have been doing similar work already. The prescriptive, contractual nature of the policy has led to local challenges, trying to ensure that local good practices are not lost during implementation. Interviewees also considered an important part of their work to be protecting PCNs from the weight of expectations placed on them.

Conclusion: CCGs are well placed to understand the complexities of local systems and to facilitate PCNs and working practices between wider system partners. It is important that this local role is not lost as CCGs continue to merge and cover larger geographical populations.
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http://dx.doi.org/10.3399/BJGP.2020.0917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252856PMC
September 2021

Classification of paediatric brain tumours by diffusion weighted imaging and machine learning.

Sci Rep 2021 02 4;11(1):2987. Epub 2021 Feb 4.

Institute of Cancer and Genomic Sciences, School of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10 mm s with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.
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http://dx.doi.org/10.1038/s41598-021-82214-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862387PMC
February 2021

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

J Med Chem 2021 01 24;64(1):644-661. Epub 2020 Dec 24.

La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate ( (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of .
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http://dx.doi.org/10.1021/acs.jmedchem.0c01652DOI Listing
January 2021

Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study.

Lancet Child Adolesc Health 2020 12 22;4(12):865-874. Epub 2020 Oct 22.

Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, UK. Electronic address:

Background: Disease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management.

Methods: In this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed patients who relapsed following standard upfront therapies, from 16 UK Children's Cancer and Leukaemia Group institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular features at diagnosis, including established and recently described molecular features, prognostic factors, and treatment at diagnosis and relapse.

Findings: 247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis 2000 [IQR 1995-2006]) were included in this study. 17 patients were later excluded from further analyses because they did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p<0·0001). In the non-irradiated group, craniospinal irradiation at relapse (hazard ratio [HR] 0·27, 95% CI 0·11-0·68) and desmoplastic/nodular histology (0·23, 0·07-0·77) were associated with prolonged time to death after relapse, MYC amplification was associated with a reduced overall survival (23·52, 4·85-114·05), and re-resection at relapse was associated with longer overall survival (0·17, 0·05-0·57). In the irradiated group, patients with MB tumours relapsed significantly more quickly than did patients with MB tumours (median 1·34 [0·99-1·89] years vs 2·04 [1·39-3·42 years; p=0·0043). Distant disease was prevalent in patients with MB (23 [92%] of 25 patients) and MB (56 [90%] of 62 patients) tumour relapses. Patients with distantly-relapsed MB and MB displayed both nodular and diffuse patterns of disease whereas isolated nodular relapses were rare in distantly-relapsed MB (1 [8%] of 12 distantly-relapsed MB were nodular alone compared with 26 [34%] of 77 distantly-relapsed MB and MB). In MB and MB, nodular disease was associated with a prolonged survival after relapse (HR 0·42, 0·21-0·81). Investigation of second-generation MB and MB molecular subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time to relapse and subtype II had a rapid time from relapse to death. Subtypes II, III, and VIII developed a significantly higher incidence of distant disease at relapse whereas subtypes V and VII did not (equivalent rates to diagnosis).

Interpretation: This study suggests that the nature and outcome of medulloblastoma relapse are biology and therapy-dependent, providing translational opportunities for improved disease management through biology-directed disease surveillance, post-relapse prognostication, and risk-stratified selection of second-line treatment strategies.

Funding: Cancer Research UK, Action Medical Research, The Tom Grahame Trust, The JGW Patterson Foundation, Star for Harris, The Institute of Child Health - Newcastle University - Institute of Child Health High-Risk Childhood Brain Tumour Network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).
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http://dx.doi.org/10.1016/S2352-4642(20)30246-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671998PMC
December 2020

The effect of serial administration of bicarbonate on plasma total CO concentrations in horses.

Drug Test Anal 2021 Feb 8;13(2):397-403. Epub 2020 Nov 8.

Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Werribee, Victoria, Australia.

The administration of alkalinising agents including bicarbonate is of concern to racing authorities because resultant alkalosis may enhance performance and interfere with the detection of drugs in post-race urine. A threshold for total carbon dioxide (TCO ) of 36.0 mmol/L in plasma (with action limit of 37.0 mmol/L) has been set. Serial dosing of sodium bicarbonate has gained popularity in human athletes but has not been studied in horses previously. Sodium bicarbonate (200 g per horse) and 60 g of an electrolyte-vitamin complex was administered in 2-L water via nasogastric intubation to five Standardbred horses for three consecutive days (total dose bicarbonate 0.42 ± 0.02 g/kg). Serial blood samples were taken over Days 1-5, with the final day (5) intended to simulate a 'clear day', and TCO was analysed. Following the first bicarbonate administration, plasma TCO peaked at 6 h (34.8 ± 1.3 mmol/L), returning to baseline by 23 h. On Day 2, four out of the five horses showed a peak greater than 36.0 mmol/L (mean 37.0 ± 2.1 mmol/L). With daily repeated dosing, plasma TCO peaked progressively earlier, and by Day 3, the peak occurred at 2 h and concentrations declined more rapidly. On Days 4 and 5, TCO levels remained low (<32.1 mmol/L on Day 4 and between 27.0-31.2 mmol/L on Day 5). These studies demonstrate that serial dosing of a 'split dose' of sodium bicarbonate on three consecutive days does not result in the accumulation or carry-over of plasma TCO levels beyond the levels observed following a single dose.
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http://dx.doi.org/10.1002/dta.2937DOI Listing
February 2021

Effects of an anti-IGF-1 receptor monoclonal antibody on laminitis induced by prolonged hyperinsulinaemia in Standardbred horses.

PLoS One 2020 29;15(9):e0239261. Epub 2020 Sep 29.

Biology and Environmental Sciences School, Queensland University of Technology, Brisbane, Queensland, Australia.

Currently, there are no registered veterinary drugs for the treatment of endocrinopathic equine laminitis, and although this form of the disease is known to be caused by prolonged hyperinsulinaemia, the mechanism of insulin toxicity is unclear. One possibility is that high concentrations of insulin activate IGF-1 receptors (IGF-1R) in lamellar tissue, leading to uncontrolled cell proliferation and epidermal lamellar dysregulation. An equinized version of a human anti-IGF-1R therapeutic monoclonal antibody (mAb11) was generated to test this theory, using a modification of the prolonged euglycaemic-hyperinsulinaemic clamp technique. Healthy Standardbred horses were infused for 48 h with 0.9% saline (negative-control, n = 6), a combination of insulin (4.5 mIU/kgBW/min) and a variable infusion of 50% glucose to maintain euglycaemia (positive-control, n = 6), or insulin and glucose, preceded by a low dose of mAb11 (20 mg), designed to treat one foot only and delivered by retrograde infusion into one forelimb (mAb-treated, n = 7). Maximum insulin concentrations were 502 ± 54.4 and 435 ± 30.4 μIU/mL in the positive-control and mAb11-treated groups, respectively (P = 0.33). While the control group remained healthy, all the insulin-treated horses developed laminitis within 30 h, as judged by clinical examination, foot radiographs and histological analysis. Some effects of insulin were not attenuated by the antibody, however, relative to the positive-control group, horses treated with mAb11 showed less sinking of the distal phalanx (P < 0.05) and milder histological changes, with markedly less elongation at the tips of the secondary epidermal lamellae (P < 0.05). These differences were apparent in both front feet and were statistically significant when the values for both feet were combined. The results confirm that IGF-1R may have a role in insulin-induced laminitis and suggest that mAb11 warrants further research as a potential agent to prevent or treat the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524003PMC
November 2020

Sympathetic nerves control bacterial clearance.

Sci Rep 2020 09 14;10(1):15009. Epub 2020 Sep 14.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection.
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http://dx.doi.org/10.1038/s41598-020-72008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490383PMC
September 2020

Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity.

Nat Commun 2020 08 28;11(1):4324. Epub 2020 Aug 28.

Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.
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http://dx.doi.org/10.1038/s41467-020-18070-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455736PMC
August 2020

SIOP PODC-adapted treatment guidelines for craniopharyngioma in low- and middle-income settings.

Pediatr Blood Cancer 2020 Aug 13:e28493. Epub 2020 Aug 13.

Department of Pediatric Oncology, Great North Children's Hospital, Newcastle upon Tyne, UK.

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage, and behavioral changes are among the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries where resources are variable. This report provides risk-stratified management guidelines for children diagnosed with craniopharyngioma in a resource-limited setting.
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http://dx.doi.org/10.1002/pbc.28493DOI Listing
August 2020

Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.

J Vet Intern Med 2020 Sep 23;34(5):2109-2116. Epub 2020 Jul 23.

Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia.

Background: Doramapimod, a p38 MAPK inhibitor, is a potent anti-inflammatory drug that decreases inflammatory cytokine production in equine whole blood in vitro. It may have benefits for treating systemic inflammation in horses.

Objective: To determine whether doramapimod is well tolerated when administered IV to horses, and whether it has anti-inflammatory effects in horses in a low-dose endotoxemia model.

Animals: Six Standardbred horses.

Methods: Tolerability study, followed by a blinded, randomized, placebo-controlled cross-over study. Horses were given doramapimod, and clinical and clinicopathological variables were monitored for 24 hours. Horses then were treated with doramapimod or placebo, followed by a low dose infusion of lipopolysaccharide (LPS). Clinical variables (heart rate, rectal temperature, noninvasive blood pressure), leukocyte count and tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) concentrations were measured at multiple time points until 6 hours post-LPS infusion.

Results: No adverse effects or clinicopathological changes were seen in the safety study. When treated with doramapimod as compared to placebo, horses had significantly lower heart rates (P = .03), rectal temperatures (P = .03), and cytokine concentrations (P = .03 for TNF-α and IL-1β), and a significantly higher white blood cell count (P = .03) after LPS infusion.

Conclusions And Clinical Importance: Doramapimod has clinically relevant anti-inflammatory effects in horses, likely mediated by a decrease in leukocyte activation and decrease in the release of pro-inflammatory cytokines. To evaluate its potential as a novel treatment for systemic inflammatory response syndrome in horses, clinical trials will be necessary to determine its efficacy in naturally occurring disease.
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http://dx.doi.org/10.1111/jvim.15847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517855PMC
September 2020

Exploring the multiple policy objectives for primary care networks: a qualitative interview study with national policy stakeholders.

BMJ Open 2020 07 5;10(7):e038398. Epub 2020 Jul 5.

Centre for Health Services Studies, University of Kent, Canterbury, Kent, UK.

Objectives: English general practice is suffering a workforce crisis, with general practitioners retiring early and trainees reluctant to enter the profession. To address this, additional funding has been offered, but only through participation in collaborations known as primary care networks (PCNs). This study explored national policy objectives underpinning PCNs and the mechanisms expected to help achieve these, from the perspective of those driving the policy.

Design: Qualitative semistructured interviews and policy document analysis.

Setting And Participants: National-level policy maker and stakeholder interviewees (n=16). Policy document analysis of the Network Contract Direct Enhanced Service draft service specifications.

Analysis: Interviews were transcribed, coded and organised thematically according to policy objectives and mechanisms. Thematic data were organised into a matrix so prominent elements can be identified and emphasised accordingly. Themes were considered alongside objectives embedded in PCN draft service delivery requirements.

Results: Three themes of policy objectives and associated mechanisms were identified: (1) supporting general practice, (2) place-based interorganisational collaboration and (3) primary care 'voice'. Interviewees emphasised and sequenced themes differently, suggesting meeting objectives for one was necessary to realise another. Interviewees most closely linked to primary care emphasised the importance of theme 1. The objectives embedded in draft service delivery requirements primarily emphasised theme 2.

Conclusions: These policy objectives are not mutually exclusive but may imply different approaches to prioritising investment or necessitate more explicit temporal sequencing, with the stabilisation of a struggling primary care sector probably needing to occur before meaningful engagement with other community service providers can be achieved or a 'collective voice' is agreed. Multiple objectives create space for stakeholders to feel dissatisfied when implementation details do not match expectations, as the negative reaction to draft service delivery requirements illustrates. Our study offers policy makers suggestions about how confidence in the policy might be restored by crafting delivery requirements so all groups see opportunities to meet favoured objectives.
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http://dx.doi.org/10.1136/bmjopen-2020-038398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337885PMC
July 2020

Validation of canine uterine and testicular arteries for the functional characterisation of receptor-mediated contraction as a replacement for laboratory animal tissues in teaching.

PLoS One 2020 26;15(5):e0230516. Epub 2020 May 26.

Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.

Teaching practicals for receptor physiology/pharmacology in medical and veterinary schools have involved the use of in vitro experiments using tissues from laboratory animals, which have been killed for isolated vascular strip or ring preparations. However, the use of scavenged tissues has been advocated to reduce animal use. Utilising discarded tissues from routine surgical procedures, such as canine neutering, has not previously been investigated. Canine testicular and uterine tissues (discarded tissues) were obtained from routine neutering procedures performed by the veterinary team at a local animal neutering clinic for stray dogs. Rings of uterine and testicular artery were dissected and mounted on a Mulvany-Halpern wire myograph in order to characterize the adrenergic and serotonergic receptors mediating vasoconstriction. Cumulative contractile concentration-response curves were constructed for the alpha adrenoceptor agonists epinephrine (α1 and α2 receptors), phenylephrine (α1 selective) and UK14304 (α2 selective). Pre-treatment with the α1-selective antagonist, prazosin, was also investigated. The response to serotonin (5-HT) receptor agonists were also investigated, including 5-HT (acting at both 5-HT1 and 5-HT2 receptors), 5-carboxamidotryptamine (5-CT; 5-HT1 selective) and α-methyl 5-HT (5-HT2 selective). A contractile response was observed in both canine uterine and testicular arteries to epinephrine and phenylephrine, and prazosin caused a dose-dependent parallel rightward shift in the phenylephrine dose-response curve (pA2 values of 7.97 and 8.39, respectively). UK14304 caused a contractile response in canine testicular arteries but very little appreciable contractile response in uterine arteries. The maximum responses produced by the uterine arteries to 5-HT was significantly lower than those of the testicular arteries. In the testicular artery, the 5-HT2 receptor selective agonist, α-methyl 5-HT, produced a similar contractile response to 5-HT but the administration of 5-CT failed to produce a response in either the testicular or uterine artery segments. These results validate the use of discarded tissue from routine canine neutering procedures as a useful source of vascular tissue for pharmacological teaching, for characterizing alpha and 5-HT receptor contractile responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250439PMC
July 2020

Outcome at the end of treatment of patients with common and curable childhood cancer types in Blantyre, Malawi.

Pediatr Blood Cancer 2020 07 11;67(7):e28322. Epub 2020 May 11.

Academy Outreach and Department of Solid Tumours, Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands.

Background: The WHO Global Initiative for Childhood Cancer aims to increase survival to at least 60% for all children with cancer globally, with initial focus on six common curable cancer types. Frequent causes of treatment failure in low income countries (LICs) are treatment abandonment and death during treatment. Here, we report on the outcome at the end of treatment of patients with newly diagnosed common and curable cancer types, admitted in the Queen Elizabeth Central Hospital, Blantyre, Malawi.

Procedure: Outcome at end of treatment was documented and analyzed retrospectively for all children with a working diagnosis of a common and curable cancer type (ALL, Hodgkin disease, Wilms tumor, retinoblastoma, and Burkitt lymphoma) admitted over a 2-year period. Patients with a misdiagnosis were excluded. Outcomes were categorized as alive without evidence of disease, treatment abandonment, death during treatment, or persistent disease.

Results: We included 264 patients. Seven patients with a misdiagnosis were excluded. At the end of treatment, 53% (139 of 264) of patients were alive without evidence of disease, 19% (49 of 264) had abandoned treatment, 23% (61 of 264) had died during treatment, and 6% (15 of 264) had persistent disease.

Conclusion: Survival of children with common and curable cancers is (significantly) below 50%. Almost half (42%) of the patients either abandoned treatment or died during treatment. Strategies to enable parents to complete treatment of their child and improved supportive care are needed. Such interventions may need to be given priority to improve the currently poor survival.
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http://dx.doi.org/10.1002/pbc.28322DOI Listing
July 2020

Managing death: navigating divergent logics in end-of-life care.

Sociol Health Illn 2020 Jul 6;42(6):1277-1295. Epub 2020 May 6.

University of Birmingham, Birmingham, UK.

Delivery of end-of-life care has gained prominence in the UK, driven by a focus upon the importance of patient choice. In practice choice is influenced by several factors, including the guidance and conduct of healthcare professionals, their different understandings of what constitutes 'a good death', and contested ideas of who is best placed to deliver this. We argue that the attempt to elicit and respond to patient choice is shaped in practice by a struggle between distinct 'institutional logics'. Drawing on qualitative data from a two-part study, we examine the tensions between different professional and organisational logics in the delivery of end-of-life care. Three broad clusters of logics are identified: finance, patient choice and professional authority. We find that the logic of finance shapes the meaning and practice of 'choice', intersecting with the logic of professional authority in order to shape choices that are in the 'best interest' of the patient. Different groups might be able to draw upon alternative forms of professionalism, and through these enact different versions of choice. However, this can resemble a struggle for ownership of patients at the end of life, and therefore, reinforce a conventional script of professional authority.
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http://dx.doi.org/10.1111/1467-9566.13095DOI Listing
July 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Cancer Discov 2020 07 1;10(7):942-963. Epub 2020 Apr 1.

Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313225PMC
July 2020

Distinguishing between paediatric brain tumour types using multi-parametric magnetic resonance imaging and machine learning: A multi-site study.

Neuroimage Clin 2020 23;25:102172. Epub 2020 Jan 23.

Institute of Cancer and Genomic Sciences, School of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Oncology, Birmingham Women's and Children's NHS foundation trust, Birmingham, United Kingdom. Electronic address:

The imaging and subsequent accurate diagnosis of paediatric brain tumours presents a radiological challenge, with magnetic resonance imaging playing a key role in providing tumour specific imaging information. Diffusion weighted and perfusion imaging are commonly used to aid the non-invasive diagnosis of children's brain tumours, but are usually evaluated by expert qualitative review. Quantitative studies are mainly single centre and single modality. The aim of this work was to combine multi-centre diffusion and perfusion imaging, with machine learning, to develop machine learning based classifiers to discriminate between three common paediatric tumour types. The results show that diffusion and perfusion weighted imaging of both the tumour and whole brain provide significant features which differ between tumour types, and that combining these features gives the optimal machine learning classifier with >80% predictive precision. This work represents a step forward to aid in the non-invasive diagnosis of paediatric brain tumours, using advanced clinical imaging.
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http://dx.doi.org/10.1016/j.nicl.2020.102172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005468PMC
January 2021

Translational genomics of malignant rhabdoid tumours: Current impact and future possibilities.

Semin Cancer Biol 2020 04 7;61:30-41. Epub 2020 Jan 7.

Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK. Electronic address:

Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.
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http://dx.doi.org/10.1016/j.semcancer.2019.12.017DOI Listing
April 2020

Anti-inflammatory effects of a p38 MAP kinase inhibitor, doramapimod, against bacterial cell wall toxins in equine whole blood.

Vet Immunol Immunopathol 2020 Feb 17;220:109994. Epub 2019 Dec 17.

Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia.

Doramapimod (BIRB-796-BS), is an anti-inflammatory compound, acting through p38 MAPK inhibition, but its anti-inflammatory effects have not previously been studied in the horse. Whole blood aliquots from healthy horses diluted 1:1 with cell culture medium were incubated for 21 h with 1 μg/ml of lipopolysaccharide (LPS), lipoteichoic acid (LTA) or peptidoglycan (PGN) in the presence of increasing concentrations of doramapimod (3 × 10 M to 10 M). Cell bioassays were used to measure TNF-α and IL-1β activity. Doramapimod significantly and potently inhibited TNF-α and IL-1β activity induced by all three bacterial toxins. There was no significant difference in IC or maximum inhibition of TNF-α or IL-1β production between any of the toxins. Maximum inhibition of IL-1β was higher than that of TNF-α for all toxins, and this difference was significant for LPS (P = 0.04). Doramapimod was a potent inhibitor of TNF-α and IL-1β for inflammation induced by LPS, LTA and PGN, with potency much greater than that of other drugs previously tested using similar methods.
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http://dx.doi.org/10.1016/j.vetimm.2019.109994DOI Listing
February 2020
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