Publications by authors named "Paul Murray"

176 Publications

Comparison of characteristics and outcomes of patients admitted to hospital with COVID-19 during wave 1 and wave 2 of the current pandemic.

Intern Emerg Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Endocrinology, Ashford and St Peter's Hospitals NHS Foundation Trust, Guildford Road, Chertsey, Surrey, KT16 0PZ, UK.

In this study of patients admitted with COVID-19, we examined differences between the two waves in patient characteristics and outcomes. Data were collected from the first COVID-19 admission to the end of study (01/03/2020-31/03/2021). Data were adjusted for age and sex and presented as odds ratios (OR) with 95% confidence intervals (CI). Among 12,471 admissions, 1452 (11.6%) patients were diagnosed with COVID-19. On admission, the mean (± SD) age of patients with other causes was 68.3 years (± 19.8) and those with COVID-19 in wave 1 was 69.4 years (± 18.0) and wave 2 was 66.2 years (± 18.4). Corresponding ages at discharge were 67.5 years (± 19.7), 63.9 years (± 18.0) and 62.4 years (± 18.0). The highest proportion of total admissions was among the oldest group (≥ 80 years) in wave 1 (35.0%). When compared with patients admitted with other causes, those admitted with COVID-19 in wave 1 and in wave 2 were more frequent in the 40-59 year band: 20.8, 24.6 and 30.0%; consisted of more male patients: 47.5, 57.6 and 58.8%; and a high LACE (Length of stay, Acuity of admission, Comorbidity and Emergency department visits) index (score ≥ 10): 39.4, 61.3 and 50.3%. Compared to wave-2 patients, those admitted in wave 1 had greater risk of death in hospital: OR = 1.58 (1.18-2.12) and within 30 days of discharge: OR = 2.91 (1.40-6.04). Survivors of COVID-19 in wave 1 stayed longer in hospital (median = 6.5 days; interquartile range = 2.9-12.0) as compared to survivors from wave 2 (4.5 days; interquartile range = 1.9-8.7). Patient characteristics differed significantly between the two waves of COVID-19 pandemic. There was an improvement in outcomes in wave 2, including shorter length of stay in hospital and reduction of mortality.
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http://dx.doi.org/10.1007/s11739-021-02842-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505475PMC
October 2021

The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery.

iScience 2021 Oct 2:103215. Epub 2021 Oct 2.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, UK.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-α . We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.
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http://dx.doi.org/10.1016/j.isci.2021.103215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487319PMC
October 2021

Calcium-dependent signalling in B-cell lymphomas.

Oncogene 2021 Oct 8. Epub 2021 Oct 8.

Health Research Institute, University of Limerick, Castletroy, Limerick, V94 T9PX, Ireland.

Induced waves of calcium fluxes initiate multiple signalling pathways that play an important role in the differentiation and maturation of B-cells. Finely tuned transient Ca fluxes from the endoplasmic reticulum in response to B-cell receptor (BCR) or chemokine receptor activation are followed by more sustained calcium influxes from the extracellular environment and contribute to the mechanisms responsible for the proliferation of B-cells, their migration within lymphoid organs and their differentiation. Dysregulation of these well-balanced mechanisms in B-cell lymphomas results in uncontrolled cell proliferation and resistance to apoptosis. Consequently, several cytotoxic drugs (and anti-proliferative compounds) used in standard chemotherapy regimens for the treatment of people with lymphoma target calcium-dependent pathways. Furthermore, ~10% of lymphoma associated mutations are found in genes with functions in calcium-dependent signalling, including those affecting B-cell receptor signalling pathways. In this review, we provide an overview of the Ca-dependent signalling network and outline the contribution of its key components to B cell lymphomagenesis. We also consider how the oncogenic Epstein-Barr virus, which is causally linked to the pathogenesis of a number of B-cell lymphomas, can modify Ca-dependent signalling.
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http://dx.doi.org/10.1038/s41388-021-02025-8DOI Listing
October 2021

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers.

Cancers (Basel) 2021 Aug 3;13(15). Epub 2021 Aug 3.

Health Research Institute, University of Limerick, V94 T9PX Limerick, Ireland.

EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.
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http://dx.doi.org/10.3390/cancers13153909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345394PMC
August 2021

Changes in cortisol levels by continuous positive airway pressure in patients with obstructive sleep apnoea: Meta-analysis of 637 individuals.

Clin Endocrinol (Oxf) 2021 Jul 29. Epub 2021 Jul 29.

Institute of Cardiovascular Research, Royal Holloway, University of London, Surrey, UK.

Background: Obesity, obstructive sleep apnoea (OSA) and hypertension frequently coexist and are associated with elevated cortisol levels. Identification and treatment of such patients is important when investigating for suspected Cushing's syndrome and hypertension. Studies of the impact of continuous positive airway pressure (CPAP) on cortisol and blood pressure are limited by the small sample size and show conflicting findings. We conducted a meta-analysis to document changes in the levels of cortisol and blood pressure in response to CPAP treatment of OSA.

Methods: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean difference (SMD) for catecholamines and mean difference for systolic (SBP) and diastolic blood pressure (DBP). The quality of the studies was evaluated using standard tools for assessing the risk of bias.

Results: A total of 22 studies met our search criteria; they consisted of 16 prospective cohort studies (PCS) that recruited 385 participants and six randomized control trials (RCT) totalling 252 participants. The range of mean age was 41-62 years and BMI 27.2-35.1 kg/m . CPAP treatment reduced plasma cortisol levels in PCS: SMD = -0.28 [95% confidence interval (95% CI) = -0.45 to -0.12], I  = 0%, p = .79 and in RCT: SMD = -0.39 (95% CI = -0.75 to -0.03), I  = 28.3%, p = .25. CPAP treatment reduced SBP by 5.4 mmHg (95% CI = 1.7-9.1) and DBP by 3.3 mmHg (95% CI = 1.0-5.7). Interstudy heterogeneity was low for all studies. Bias in most RCT arose from the lack of blinding of participants and personnel.

Conclusion: CPAP treatment in individuals with OSA reduces cortisol levels and blood pressure.
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http://dx.doi.org/10.1111/cen.14573DOI Listing
July 2021

Editorial: Molecular Mechanisms of Pathogen-Driven Infectious and Neoplastic Diseases.

Front Cell Dev Biol 2021 31;9:696152. Epub 2021 May 31.

Division of Cancer Epidemiology & Genetics Infections and Immunoepidemiology Branch, National Cancer Institute, Bethesda, MD, United States.

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http://dx.doi.org/10.3389/fcell.2021.696152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202500PMC
May 2021

Embedded product authentication codes in additive manufactured parts: Imaging and image processing for improved scan ability.

Addit Manuf 2020 Oct;35

Composite Materials and Mechanics Laboratory, Mechanical and Aerospace Engineering Department, Tandon School of Engineering, New York University, Brooklyn, NY 11201 USA.

The layer-by-layer printing process of additive manufacturing methods provides new opportunities to embed identification codes inside parts during manufacture. These embedded codes can be used for product authentication and identification of counterfeits. The availability of reverse engineering tools has increased the risk of counterfeit part production and new authentication technologies such as the one proposed in this paper are required for many applications including aerospace components and medical implants and devices. The embedded codes are read by imaging techniques such as micro-Computed Tomography (micro-CT) scanners or radiography. The work presented in this paper is focused on developing methods that can improve the quality of the recovered micro-CT scanned code images such that they can be interpreted by standard code reader technology. Inherent low contrast and the presence of imaging artifacts are the main challenges that need to be addressed. Image processing methods are developed to address these challenges using titanium and aluminum alloy specimens containing embedded quick response (QR) codes. The proposed techniques for recovering the embedded codes are based on a combination of Mathematical Morphology and an innovative de-noising algorithm based on optimal image filtering techniques. The results show that the proposed methods are successful in making the codes scannable using readily available smartphone apps.
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http://dx.doi.org/10.1016/j.addma.2020.101319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017490PMC
October 2020

Early emergency readmission frequency as an indicator of short-, medium- and long-term mortality post-discharge from hospital.

Intern Emerg Med 2021 09 26;16(6):1497-1505. Epub 2020 Dec 26.

Department of Endocrinology, Ashford and St Peter's Hospitals NHS Foundation Trust, Guildford Road, Chertsey, Surrey, KT16 0PZ, UK.

Frequent emergency readmissions, an indicator of quality of care, has been rising in England but the underlying reasons remain unclear. We examined the association of early readmissions with subsequent mortality in adults, taking into account the underlying presenting diagnoses and hospital length of stay (LOS). Data of alive-discharge episodes were prospectively collected between 01/04/2017 and 31/03/2019 in an National Health Service hospital, comprising 32,270 patients (46.1% men) aged 18-107 years (mean = 64.0, ± SD = 20.5 years). The associations of readmission frequency within 28 days of discharge and mortality within 30 days and 6 months of hospital discharge, and over a 2-year period were evaluated, adjusted for presenting diagnoses, LOS, age and sex during the first admission. Analysis of all patients 18-107 years (reference: no readmission) showed mortality within 30 days was increased for 1 readmission: event rate = 9.2%, odds ratio (OR) = 3.4 (95% confidence interval (CI) = 2.9-4.0), and ≥ 2 readmissions: event rate = 10.0%, OR = 2.6 (95%CI = 2.0-3.3), and within 6 months for 1 readmission: event rate = 19.6%, OR = 3.0 (95%CI = 2.7-3.4), and ≥ 2 readmissions: event rate = 27.4%, OR = 3.4 (95%CI = 2.9-4.0), and over a 2-year period for 1 readmission: event rate = 25.5%, hazard ratio = 2.2 (95%CI = 2.0-2.4), and ≥ 2 readmissions: event rate = 36.1%, hazard ratio = 2.5 (95%CI = 2.2-2.8). Within the age groups 18-49, 50-59, 60-69, 70-79 and ≥ 80 years, readmissions were also associated with increased risk of mortality within 3 months and 6 months of discharge, and over 2-year period. In conclusion, early hospital readmission predicts short-, medium- and long-term mortality post-discharge from hospital in adults aged 18-107 years, independent of underlying presenting conditions, LOS, age and sex. Further research focussing on safe discharge and follow-up patient care may help reduce preventable readmissions and post-discharge mortality.
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http://dx.doi.org/10.1007/s11739-020-02599-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354916PMC
September 2021

Advanced Symptom Management System for Patients with Malignant Pleural Mesothelioma (ASyMSmeso): Mixed Methods Study.

J Med Internet Res 2020 11 12;22(11):e19180. Epub 2020 Nov 12.

Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom.

Background: Patients with malignant pleural mesothelioma (MPM) have a life-limiting illness and short prognosis and experience many debilitating symptoms from early in the illness. Innovations such as remote symptom monitoring are needed to enable patients to maintain wellbeing and manage symptoms in a proactive and timely manner. The Advanced Symptom Management System (ASyMS) has been successfully used to monitor symptoms associated with cancer.

Objective: This study aimed to determine the feasibility and acceptability of using an ASyMS adapted for use by patients with MPM, called ASyMSmeso, enabling the remote monitoring of symptoms using a smartphone.

Methods: This was a convergent mixed methods study using patient-reported outcome measures (PROMs) at key time points over a period of 2-3 months with 18 patients. The Sheffield Profile for Assessment and Referral for Care (SPARC), Technology Acceptance Model (TAM) measure for eHealth, and Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) were the PROMs used in the study. Patients were also asked to complete a daily symptom questionnaire on a smartphone throughout the study. At the end of the study, semistructured interviews with 11 health professionals, 8 patients, and 3 carers were conducted to collect their experience with using ASyMSmeso.

Results: Eighteen patients with MPM agreed to participate in the study (33.3% response rate). The completion rates of study PROMs were high (97.2%-100%), and completion rates of the daily symptom questionnaire were also high, at 88.5%. There were no significant changes in quality of life, as measured by LCSS-Meso. There were statistically significant improvements in the SPARC psychological need domain (P=.049) and in the "Usefulness" domain of the TAM (P=.022). End-of-study interviews identified that both patients and clinicians found the system quick and easy to use. For patients, in particular, the system provided reassurance about symptom experience and the feeling of being listened to. The clinicians largely viewed the system as feasible and acceptable, and areas that were mentioned included the early management of symptoms and connectivity between patients and clinicians, leading to enhanced communication.

Conclusions: This study demonstrates that remote monitoring and management of symptoms of people with MPM using a mobile phone are feasible and acceptable. The evidence supports future trials using remote symptom monitoring to support patients with MPM at home.
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http://dx.doi.org/10.2196/19180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691092PMC
November 2020

Compact multispectral pushframe camera for nanosatellites.

Appl Opt 2020 Sep;59(27):8511-8518

In this paper we present an evolution of the single-pixel camera architecture, called "pushframe," which addresses the limitations of pushbroom cameras in space-based applications. In particular, it is well-suited to observing fast-moving scenes while retaining high spatial resolution and sensitivity. We show that the system is capable of producing color images with good fidelity and scalable resolution performance. The principle of our design broadens the choice of spectral ranges that can be captured, making it suitable for wide spectral ranges of infrared imaging.
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http://dx.doi.org/10.1364/AO.399227DOI Listing
September 2020

Design of 2D Sparse Array Transducers for Anomaly Detection in Medical Phantoms.

Sensors (Basel) 2020 Sep 19;20(18). Epub 2020 Sep 19.

Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow G1 1XW, UK.

Aperiodic sparse 2D ultrasonic array configurations, including random array, log spiral array, and sunflower array, have been considered for their potential as conformable transducers able to image within a focal range of 30-80 mm, at an operating frequency of 2 MHz. Optimisation of the imaging performance of potential array patterns has been undertaken based on their simulated far field directivity functions. Two evaluation criteria, peak sidelobe level (PSL) and integrated sidelobe ratio (ISLR), are used to access the performance of each array configuration. Subsequently, a log spiral array pattern with -19.33 dB PSL and 2.71 dB ISLR has been selected as the overall optimal design. Two prototype transducers with the selected log spiral array pattern have been fabricated and characterised, one using a fibre composite element composite array transducer (CECAT) structure, the other using a conventional 1-3 composite (C1-3) structure. The CECAT device demonstrates improved coupling coefficient (0.64 to 0.59), reduced mechanical cross-talk between neighbouring array elements (by 10 dB) and improved operational bandwidth (by 16.5%), while the C1-3 device performs better in terms of sensitivity (~50%). Image processing algorithms, such as Hough transform and morphological opening, have been implemented to automatically detect and dimension particles located within a fluid-filled tube structure, in a variety of experimental scenarios, including bespoke phantoms using tissue mimicking material. Experiments using the fabricated CECAT log spiral 2D array transducer demonstrated that this algorithmic approach was able to detect the walls of the tube structure and stationary anomalies within the tube with a precision of ~0.1 mm.
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http://dx.doi.org/10.3390/s20185370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570994PMC
September 2020

LACE index predicts age-specific unplanned readmissions and mortality after hospital discharge.

Aging Clin Exp Res 2021 Apr 5;33(4):1041-1048. Epub 2020 Jun 5.

Department of Endocrinology, Ashford and St Peter's Hospitals NHS Foundation Trust, Guildford Road, Chertsey, KT16 0PZ, Surrey, UK.

Background: The LACE index scoring tool (Length of stay, Acuity of admission, Co-morbidities and Emergency department visits) has been designed to predict hospital readmissions. We evaluated the ability of the LACE index to predict age-specific frequent admissions and mortality.

Methods: Analysis of prospectively collected data of alive-discharge episodes between 01/04/2017 and 31/03/2019 in an NHS hospital. Data on 14,878 men and 17,392 women of mean age 64.0 years, SD = 20.5, range 18.0-106.7 years were analysed. The association of the LACE index with frequency of all-cause readmissions within 28 days of discharge and over a 2-year period, and with all-cause mortality within 30 days or within 6 months after discharge from hospital were evaluated.

Results: Within LACE index scores of 0-4, 5-9 or ≥ 10, the proportions of readmission ≥ 2 times within 28 days of discharge were 0.1, 1.3 and 9.2% (χ = 3070, p < 0.001) and over a 2-year period were 1.7, 4.8 and 19.1% (χ = 3364, p < 0.001). Compared with a LACE index score of 0-4, a score ≥ 10 increased the risk (adjusted for age, sex and frequency of admissions) of death within 6 months of discharge by 6.8-fold (5.1-9.0, p < 0.001) among all ages, and most strongly in youngest individuals (18.0-49.9 years): adjusted odds ratio = 16.1 (5.7-45.8, p < 0.001). For those aged 50-59.9, 60-69.9, 70-79.9 and ≥ 80 years, odds ratios reduced progressively to 9.6, 7.7, 5.1 and 2.3, respectively. Similar patterns were observed for the association of LACE index with mortality within 30 days of hospital discharge.

Conclusions: The LACE index predicts short-term and long-term frequent admissions and short-term and medium-term mortality, most pronounced among younger individuals, after hospital discharge.
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http://dx.doi.org/10.1007/s40520-020-01609-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084827PMC
April 2021

Comparing nanoparticles for drug delivery: The effect of physiological dispersion media on nanoparticle properties.

Mater Sci Eng C Mater Biol Appl 2020 Aug 23;113:110985. Epub 2020 Apr 23.

BioScience and Bioengineering Research (BioSciBer), Bernal Biomaterials, Bernal Institute, University of Limerick, Limerick, Ireland; School of Engineering, University of Limerick, Limerick, Ireland; Health Research Institute, (HRI), University of Limerick, Limerick, Ireland. Electronic address:

Delivering therapeutics to disease sites is a challenge facing modern medicine. Nanoparticle delivery systems are of considerable interest to overcome this challenge, but these systems suffer from poor clinical translation. It is believed this is, in part, due to incomplete understanding of nanoparticle physico-chemical properties in vivo. To understand how nanoparticle properties could change following intravenous delivery, Au, Ag, FeO, TiO, and ZnO nanoparticles of 5, 20, and 50 nm were characterised in water and physiological fluids. The effects of the dispersion medium, concentration, and incubation time on size, dispersion, and zeta potential were measured. Properties varied significantly depending on material type, size, and concentration over 24 h. Gold and silver nanoparticles were generally the most stable. Meanwhile, 20 nm nanoparticles appeared to be the least stable size, across materials. These results could have important implications for selecting nanoparticles for drug delivery that will elicit the desired physiological response.
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http://dx.doi.org/10.1016/j.msec.2020.110985DOI Listing
August 2020

Dihydropyridine calcium channel blockers and obstructive sleep apnea: Two underrecognized causes of nocturia?

Neurourol Urodyn 2020 06 21;39(5):1612-1614. Epub 2020 Apr 21.

Ashford and St. Peter's Hospitals NHS Foundation Trust, Chertsey, UK.

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http://dx.doi.org/10.1002/nau.24359DOI Listing
June 2020

Monoamine oxidase A is down-regulated in EBV-associated nasopharyngeal carcinoma.

Sci Rep 2020 04 9;10(1):6115. Epub 2020 Apr 9.

Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.

Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.
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http://dx.doi.org/10.1038/s41598-020-63150-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145851PMC
April 2020

Low-cost hyper-spectral imaging system using a linear variable bandpass filter for agritech applications.

Appl Opt 2020 Feb;59(5):A167-A175

Hyperspectral imaging for agricultural applications provides a solution for non-destructive, large-area crop monitoring. However, current products are bulky and expensive due to complicated optics and electronics. A linear variable filter was developed for implementation into a prototype hyperspectral imaging camera that demonstrates good spectral performance between 450 and 900 nm. Equipped with a feature extraction and classification algorithm, the proposed system can be used to determine potato plant health with ∼88 accuracy. This algorithm was also capable of species identification and is demonstrated as being capable of differentiating between rocket, lettuce, and spinach. Results are promising for an entry-level, low-cost hyperspectral imaging solution for agriculture applications.
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http://dx.doi.org/10.1364/AO.378269DOI Listing
February 2020

Non-uniform Expansion of Epstein-Barr Virus-Specific T-Cells Following Donor Lymphocyte Infusion for Post-transplant Lymphoproliferative Disease.

Front Immunol 2019 29;10:2489. Epub 2019 Oct 29.

Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of T-lymphocyte deplete allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients with PTLD refractory to Rituximab, donor lymphocyte infusion (DLI) is established as a successful option for salvage therapy. However, although lymphocyte expansion has been correlated with good clinical outcome following DLI, the specificity and functional characteristics of EBV-specific T-cell responses remain poorly characterized. Here we describe two patients with Rituximab-refractory PTLD complicating T-cell deplete allo-HSCT, both of whom were successfully rescued with 1 × 10/Kg unselected stem cell donor-derived DLI. Prospective analyses revealed that complete clinical and radiological responses were associated with expansion of T and NK cells. Furthermore, EBV MHC tetramer, and interferon gamma analyses revealed a marked increase in EBV-specific T-cell frequency from 4 weeks after DLI. Reactivity was demonstrated against a range of EBV latent and lytic antigens, including those detected in tumor biopsy material. The immunodominant EBV-specific T cell response expanding following infusion matched the dominant response present in the DLI preparations prior to administration. Furthermore, differences in the repertoire of subdominant antigen-specific T-cells were also detected, suggesting that antigen-encounter can shape the immune response. These results demonstrate the value of prospectively studying T-cell responses, by facilitating the identification of important specificities required for clinical efficacy. Applying this approach on a larger scale promises to yield data which may be essential for the optimization of future adoptive immunotherapeutic strategies for PTLD.
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http://dx.doi.org/10.3389/fimmu.2019.02489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828838PMC
October 2020

Collagen Induces a More Proliferative, Migratory and Chemoresistant Phenotype in Head and Neck Cancer via DDR1.

Cancers (Basel) 2019 Nov 9;11(11). Epub 2019 Nov 9.

Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, and showed that it is over-expressed in HNSCC tissues. Further, we demonstrated that collagen promoted the proliferation and migration of HNSCC cells and attenuated the apoptotic response to cisplatin. Knockdown of DDR1 in HNSCC cells demonstrated that these tumour-promoting effects of collagen are mediated by DDR1. Our data suggest that specific inhibitors of DDR1 might provide novel therapeutic opportunities to treat HNSCC.
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http://dx.doi.org/10.3390/cancers11111766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896141PMC
November 2019

Treatment patterns in patients with a new diagnosis of epilepsy and psychiatric comorbidities.

Epilepsy Behav 2019 10 2;99:106405. Epub 2019 Sep 2.

UCB Pharma, Cheltenham, Gloucestershire, UK. Electronic address:

Objective: The objective of this study was to describe antiepileptic drug (AED) treatment patterns in patients with epilepsy, with and without psychiatric comorbidities.

Methods: This was a retrospective claims-based cohort study using Truven Health MarketScan databases (Commercial and supplemental Medicare, calendar years 2012-2017; Medicaid, 2012-2016). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (<1 year for persons of 1 to <2 years of age; none for persons <1 year), and continuous medical and pharmacy enrolment without epilepsy/seizure diagnosis or AED prescription during baseline. Based on presence/absence of psychiatric diagnosis codes in the baseline period, persons were classified into two cohorts: with or without psychiatric comorbidities. Outcomes included percentage of treated persons (AED prescription), type, duration, and outcome of first-line AED treatment.

Results: There were 18,062 persons in each cohort with and without psychiatric comorbidities, matched by age, sex, and insurance type, who met selection (or inclusion) criteria. More patients with psychiatric comorbidities were prescribed an AED after diagnosis (57.6% vs. 52.8%), and had at least two AEDs prescribed during follow-up (16.7% vs. 11.4%) than patients without psychiatric comorbidities. Most patients with and without psychiatric comorbidities prescribed AED monotherapy as first-line treatment (73.0% vs. 78.7%). Levetiracetam was the most common AED prescribed less frequently in patients with than without psychiatric comorbidities (40.8% vs. 56.7%). More patients with psychiatric comorbidities changed first-line AED treatment than patients without psychiatric comorbidities.

Conclusion: The presence of psychiatric comorbidities may impact treatment decisions in newly diagnosed persons with epilepsy to optimize patient outcomes.
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http://dx.doi.org/10.1016/j.yebeh.2019.07.006DOI Listing
October 2019

An etiological role for the Epstein-Barr virus in the pathogenesis of classical Hodgkin lymphoma.

Blood 2019 08 11;134(7):591-596. Epub 2019 Jun 11.

Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Although a pathogenic role for the Epstein-Barr virus (EBV) is largely undisputed for tumors that are consistently EBV genome positive (eg, nasopharyngeal carcinoma, endemic Burkitt lymphoma), this is not the case for classical Hodgkin lymphoma (cHL), a tumor with only a variable EBV association. In light of recent developments in immunotherapeutics and small molecules targeting EBV, we believe it is now timely to reevaluate the role of EBV in cHL pathogenesis.
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http://dx.doi.org/10.1182/blood.2019000568DOI Listing
August 2019

Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma.

Leukemia 2019 12 16;33(12):2884-2897. Epub 2019 May 16.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.
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http://dx.doi.org/10.1038/s41375-019-0478-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887546PMC
December 2019

Low Expression and Promoter Hypermethylation of the Tumour Suppressor SLIT2, are Associated with Adverse Patient Outcomes in Diffuse Large B Cell Lymphoma.

Pathol Oncol Res 2019 Jul 9;25(3):1223-1231. Epub 2019 Feb 9.

Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, Birmingham, B15 2TT, UK.

SLIT2 has been classified as a major tumour suppressor gene due to its frequent inactivation in different cancer types. However, alterations of SLIT2 expression and relation to patient outcomes in diffuse large B cell lymphoma (DLBCL) remain undefined. The aim of this study was to investigate the expression and the methylation status of SLIT2 gene as well as its relation to patient outcomes in DLBCL. Immunohistochemical (IHC) staining was carried out to detect the expression of SLIT2 in a series of 108 DLBCL cases. Re-analysis of previously published dataset (GSE10846) that measured gene expression in DLBCL patients who had received CHOP or R-CHOP therapy was performed to identify associations between SLIT2 and patients survival. Laser capture microdissection was performed to isolate GC B cells and DLBCL primary tumor cells. Bisulfite treatment and methylation-specific PCR (MSP) analysis were done to assess SLIT2 promotor methylation status. We report that the expression of SLIT2 protein was reduced in a subset of DLBCL cases and this was significantly correlated with advanced clinical stage (p = 0.041) and was an independent predictor of worse overall survival (OS) (p = 0.012). Re-analysis of published gene expression data showed that reduced SLIT2 mRNA expression was significantly correlated with worse OS in R-CHOP-treated ABC DLBCL patients (p = <0.01). Hypermethylation of the SLIT2 promotor was significantly correlated with low SLIT2 expression (p = 0.009). Our results provide a novel evidence of reduced expression of SLIT2 that is associated with promoter hypermethylation and adverse outcomes in patients with DLBCL.
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http://dx.doi.org/10.1007/s12253-019-00600-9DOI Listing
July 2019

Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma.

J Pathol 2019 06 22;248(2):142-154. Epub 2019 Mar 22.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5237DOI Listing
June 2019

A water-cooled monochromator for the B16 Test beamline at the Diamond Light Source: capabilities and performance characterization.

J Synchrotron Radiat 2019 Jan 1;26(Pt 1):253-262. Epub 2019 Jan 1.

Instrument Design Technology Ltd, Unit 2 Turnstone Business Park, Mulberry Avenue, Widnes WA8 0WN, UK.

Systematic studies of the performance of a water-cooled X-ray monochromator, designed and built for the B16 Test beamline at the Diamond Light Source, UK, are presented. A technical description of the monochromator is given and the results of commissioning measurements are discussed. Overall, the monochromator satisfies the original specifications well and meets all the major requirements of the versatile beamline. Following its successful implementation on B16, the basic monochromator design has been reproduced and adapted on other Diamond Light Source beamlines, including B18 and B21.
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http://dx.doi.org/10.1107/S1600577518014662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337885PMC
January 2019

Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma.

Head Neck 2019 04 23;41(4):993-1006. Epub 2018 Dec 23.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

Background: Head and neck squamous cell carcinoma (HNSCC) is more prevalent in men than women and this disparity cannot be fully explained by known risk factors. Recent studies have shown that loss of Y chromosome (LoY) confers an increased risk of solid cancer and reduces life expectancy in men.

Methods: Using publicly available data from The Cancer Genome Atlas, we investigated the prevalence of LoY and its association with clinicopathological features in male HNSCC.

Results: LoY was detectable in around 25% of male HNSCC. Men with human papillomavirus-negative tumors exhibiting LoY experienced significantly worse overall survival than those with no LoY. Moreover, LoY tumors exhibited overexpression of genes involved in redox processes, including genes previously implicated in resistance to both radiotherapy and cisplatin-based chemotherapeutics.

Conclusion: LoY may be an indicator of poor prognosis in male HNSCC that is linked to the overexpression of genes associated with resistance to standard care therapies.
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http://dx.doi.org/10.1002/hed.25537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492017PMC
April 2019

The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.

PLoS Biol 2018 09 4;16(9):e2005046. Epub 2018 Sep 4.

Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.

The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node-derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue-based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs.
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http://dx.doi.org/10.1371/journal.pbio.2005046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122729PMC
September 2018

Co-Expression of the Epstein-Barr Virus-Encoded Latent Membrane Proteins and the Pathogenesis of Classic Hodgkin Lymphoma.

Cancers (Basel) 2018 Aug 24;10(9). Epub 2018 Aug 24.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis.
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http://dx.doi.org/10.3390/cancers10090285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162670PMC
August 2018

Predicting Ligand-Free Cell Attachment on Next-Generation Cellulose-Chitosan Hydrogels.

ACS Omega 2018 Jan 25;3(1):937-945. Epub 2018 Jan 25.

Department of Chemical Engineering, Centre for Sustainable Chemical Technologies, and Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.

There is a growing appreciation that engineered biointerfaces can regulate cell behaviors, or functions. Most systems aim to mimic the cell-friendly extracellular matrix environment and incorporate protein ligands; however, the understanding of how a ligand-free system can achieve this is limited. Cell scaffold materials comprised of interfused chitosan-cellulose hydrogels promote cell attachment in ligand-free systems, and we demonstrate the role of cellulose molecular weight, MW, and chitosan content and MW in controlling material properties and thus regulating cell attachment. Semi-interpenetrating network (SIPN) gels, generated from cellulose/ionic liquid/cosolvent solutions, using chitosan solutions as phase inversion solvents, were stable and obviated the need for chemical coupling. Interface properties, including surface zeta-potential, dielectric constant, surface roughness, and shear modulus, were modified by varying the chitosan degree of polymerization and solution concentration, as well as the source of cellulose, creating a family of cellulose-chitosan SIPN materials. These features, in turn, affect cell attachment onto the hydrogels and the utility of this ligand-free approach is extended by forecasting cell attachment using regression modeling to isolate the effects of individual parameters in an initially complex system. We demonstrate that increasing the charge density, and/or shear modulus, of the hydrogel results in increased cell attachment.
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http://dx.doi.org/10.1021/acsomega.7b01583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045362PMC
January 2018

Epstein-Barr Virus-Induced Epigenetic Pathogenesis of Viral-Associated Lymphoepithelioma-Like Carcinomas and Natural Killer/T-Cell Lymphomas.

Pathogens 2018 Jul 18;7(3). Epub 2018 Jul 18.

Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It is known now that epigenetic alterations play a critical role in the pathogenesis of EBV-associated tumors. As an oncogenic virus, EBV establishes its latent and lytic infections in B-lymphoid and epithelial cells, utilizing hijacked cellular epigenetic machinery. EBV-encoded oncoproteins modulate cellular epigenetic machinery to reprogram viral and host epigenomes, especially in the early stage of infection, using host epigenetic regulators. The genome-wide epigenetic alterations further inactivate a series of tumor suppressor genes (TSG) and disrupt key cellular signaling pathways, contributing to EBV-associated cancer initiation and progression. Profiling of genome-wide CpG methylation changes (CpG methylome) have revealed a unique epigenotype of global high-grade methylation of TSGs in EBV-associated tumors. Here, we have summarized recent advances of epigenetic alterations in EBV-associated tumors (LELCs and NKTCL), highlighting the importance of epigenetic etiology in EBV-associated tumorigenesis. Epigenetic study of these EBV-associated tumors will discover valuable biomarkers for their early detection and prognosis prediction, and also develop effective epigenetic therapeutics for these cancers.
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http://dx.doi.org/10.3390/pathogens7030063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161003PMC
July 2018

Contribution of Epstein⁻Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma.

Pathogens 2018 Jun 27;7(3). Epub 2018 Jun 27.

Institute for Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK.

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein⁻Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.
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http://dx.doi.org/10.3390/pathogens7030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161176PMC
June 2018
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