Publications by authors named "Amy Campbell"

119 Publications

Metabolomic Biomarkers for the Detection of Obesity-Driven Endometrial Cancer.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 5th Floor Research, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥30kg/m and endometrioid endometrial cancer (cases, = 67) or histologically normal endometrium (controls, = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC > 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m.
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http://dx.doi.org/10.3390/cancers13040718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916512PMC
February 2021

Relational Quality of Registered Nurses and Nursing Assistants: Influence on Patient Safety Culture.

Healthcare (Basel) 2021 Feb 9;9(2). Epub 2021 Feb 9.

College of Nursing, East Carolina University, Greenville, NC 27858, USA.

Registered nurses (RNs) working within acute care hospitals have an incredible responsibility to provide safe care in a complex environment which requires trust, teamwork, and communication. Nursing assistants (NAs) play a critical role in working with RNs to meet these growing demands of inpatient care. Minimal evidence exists exploring the relational quality between RNs and NAs within hospitals. The aim of this study is to explore RN and NA behaviors and experiences that promote patient safety and teamwork and enhance communication between RNs and NAs within the hospital environment. Qualitative analysis was used, with two focus groups which included six participants within each group (three RNs and three NAs) from two separate inpatient units. Transcripts were reviewed and coded for themes. Collaborative teamwork and two-way communication were commonly reported as behaviors that promote patient safety. Trust between RNs and NAs was identified as a key component of positive relationships between RNs and NAs. Participants identified four common behaviors that build trust, which were accountability, effective conflict resolution, collaborative teamwork, and prioritizing patient needs. Finally, teamwork was identified as a common strategy to increase communication effectiveness between RNs and NAs. High relational quality (RQ) between the RN and NA is an important component of teamwork and patient safety culture.
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http://dx.doi.org/10.3390/healthcare9020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916158PMC
February 2021

Temporal modulation of the NF-κB RelA network in response to different types of DNA damage.

Biochem J 2021 Feb;478(3):533-551

Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.

Different types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to these DNA damage response pathways. However, we still lack understanding of the co-ordinated signalling mechanisms that permit different DNA damaging agents to induce distinct cellular outcomes through RelA. Here, we use label-free quantitative phosphoproteomics to examine the temporal effects of exposure of U2OS cells to either etoposide (ETO) or hydroxyurea (HU) by monitoring the phosphorylation status of RelA and its protein binding partners. Although few stimulus-specific differences were identified in the constituents of phosphorylated RelA interactome after exposure to these DNA damaging agents, we observed subtle, but significant, changes in their phosphorylation states, as a function of both type and duration of treatment. The DNA double strand break (DSB)-inducing ETO invoked more rapid, sustained responses than HU, with regulated targets primarily involved in transcription, cell division and canonical DSB repair. Kinase substrate prediction of ETO-regulated phosphosites suggest abrogation of CDK and ERK1 signalling, in addition to the known induction of ATM/ATR. In contrast, HU-induced replicative stress mediated temporally dynamic regulation, with phosphorylated RelA binding partners having roles in rRNA/mRNA processing and translational initiation, many of which contained a 14-3-3ε binding motif, and were putative substrates of the dual specificity kinase CLK1. Our data thus point to differential regulation of key cellular processes and the involvement of distinct signalling pathways in modulating DNA damage-specific functions of RelA.
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http://dx.doi.org/10.1042/BCJ20200627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886319PMC
February 2021

Cholera Risk: A Machine Learning Approach Applied to Essential Climate Variables.

Int J Environ Res Public Health 2020 12 15;17(24). Epub 2020 Dec 15.

Plymouth Marine Laboratory, Prospect Place, The Hoe, Plymouth PL1 3DH, UK.

Oceanic and coastal ecosystems have undergone complex environmental changes in recent years, amid a context of climate change. These changes are also reflected in the dynamics of water-borne diseases as some of the causative agents of these illnesses are ubiquitous in the aquatic environment and their survival rates are impacted by changes in climatic conditions. Previous studies have established strong relationships between essential climate variables and the coastal distribution and seasonal dynamics of the bacteria , pathogenic types of which are responsible for human cholera disease. In this study we provide a novel exploration of the potential of a machine learning approach to forecast environmental cholera risk in coastal India, home to more than 200 million inhabitants, utilising atmospheric, terrestrial and oceanic satellite-derived essential climate variables. A Random Forest classifier model is developed, trained and tested on a cholera outbreak dataset over the period 2010-2018 for districts along coastal India. The random forest classifier model has an Accuracy of 0.99, an F1 Score of 0.942 and a Sensitivity score of 0.895, meaning that 89.5% of outbreaks are correctly identified. Spatio-temporal patterns emerged in terms of the model's performance based on seasons and coastal locations. Further analysis of the specific contribution of each Essential Climate Variable to the model outputs shows that chlorophyll-a concentration, sea surface salinity and land surface temperature are the strongest predictors of the cholera outbreaks in the dataset used. The study reveals promising potential of the use of random forest classifiers and remotely-sensed essential climate variables for the development of environmental cholera-risk applications. Further exploration of the present random forest model and associated essential climate variables is encouraged on cholera surveillance datasets in other coastal areas affected by the disease to determine the model's transferability potential and applicative value for cholera forecasting systems.
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http://dx.doi.org/10.3390/ijerph17249378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765326PMC
December 2020

Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity.

Sci Signal 2020 07 7;13(639). Epub 2020 Jul 7.

Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.

Reactive oxygen species (ROS) are physiological mediators of cellular signaling and play potentially damaging roles in human diseases. In this study, we found that the catalytic activity of the Ser/Thr kinase Aurora A was inhibited by the oxidation of a conserved cysteine residue (Cys) that lies adjacent to Thr, a critical phosphorylation site in the activation segment. Cys is present at the equivalent position in ~100 human Ser/Thr kinases, a residue that we found was important not only for the activity of human Aurora A but also for that of fission yeast MAPK-activated kinase (Srk1) and PKA (Pka1). Moreover, the presence of this conserved Cys predicted biochemical redox sensitivity among a cohort of human CAMK, AGC, and AGC-like kinases. Thus, we predict that redox modulation of the conserved Cys of Aurora A may be an underappreciated regulatory mechanism that is widespread in eukaryotic Ser/Thr kinases. Given the key biological roles of these enzymes, these findings have implications for understanding physiological and pathological responses to ROS and highlight the importance of protein kinase regulation through multivalent modification of the activation segment.
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http://dx.doi.org/10.1126/scisignal.aax2713DOI Listing
July 2020

Long-term athletic training does not alter age-associated reductions of left-ventricular mid-diastolic lengthening or expansion at rest.

Eur J Appl Physiol 2020 Sep 4;120(9):2059-2073. Epub 2020 Jul 4.

Institute of Clinical Exercise and Health Sciences, School of Science and Sport, University of the West of Scotland, Stephenson Place, Hamilton International Technology Park Blantyre, Glasgow, UK.

Purpose: The interaction of ageing and exercise training status on left-ventricular (LV) peak strain is unclear. Additionally, strain analysis across the entire cardiac cycle facilitates a more detailed assessment of deformation, yet this has not been implemented to characterize the ageing LV and in association with training status. This study investigated healthy ageing and training status on LV systolic and diastolic strain utilizing novel echocardiographic applications.

Methods: Forty healthy males were included and allocated into four groups; young recreationally active (Y n = 9; 28 ± 5 years), old recreationally active (O, n = 10; 68 ± 6), young trained (Y n = 10; 27 ± 6 years), and old trained (O, n = 11, 64 ± 4 years) groups. Two-dimensional speckle-tracking echocardiography was performed to ascertain peak LV longitudinal and circumferential strain (base and apex) strain within each myocardial layer and at 5% increments across the cardiac cycle.

Results: Older groups had lower diastolic longitudinal lengthening and circumferential expansion between 40-85% mid-diastole, regardless of training status (P < 0.05). Whereas, strain throughout systole was similar between groups (P > 0.05). Longitudinal and circumferential (base and apex) peak and layer-specific strain did not differ between groups (P > 0.05).

Conclusion: Novel applications of diastolic strain revealed lower age-associated LV longitudinal lengthening and circumferential expansion in older age. Yet, diastolic strain profiles did not differ based on chronic habits of exercise training and, thus, older trained men did not demonstrate an attenuation of age-associated differences in mid-diastolic LV strain.
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http://dx.doi.org/10.1007/s00421-020-04418-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419356PMC
September 2020

Interventions to promote teamwork, delegation and communication among registered nurses and nursing assistants: An integrative review.

J Nurs Manag 2020 Oct 3;28(7):1465-1472. Epub 2020 Sep 3.

College of Nursing, East Carolina University, Greenville, NC, USA.

Aims: To understand the strategies to influence patient outcomes by synthesizing existing evidence on effective interventions for teamwork, delegation and communication between registered nurses and nursing assistants.

Background: Three-quarters of deaths in hospitals are related to breakdowns in teamwork and communication. Acute care systems utilize teams of registered nurses and nursing assistants for primary delivery of nursing care. Research has been conducted to improve the partnership between the dyad. Literature reviews are needed to synthesize the effectiveness of delegation and communication interventions between registered nurses and nursing assistants on patient outcomes.

Methods: The authors applied Whittemore and Knafl's integrative review methodology to conduct an integrative review of the literature. Databases searched included Cumulative Index to Nursing and Allied Health Literature, MEDLINE and PubMed along with reference searches. Included articles were intervention studies related to teamwork, delegation or communication between registered nurses and nursing assistants, and published from 2000 to 2019. Methodological quality was assessed utilizing the Mixed Methods Appraisal Tool. The Systems Engineering Initiative for Patient Safety model 2.0 was applied as a guiding framework to analyse the findings.

Results: Seven articles met the inclusion criteria. The interventions in these articles focused on building a foundation of trust and respect through simulation, education and mindful communication. Four of the seven articles measured patient outcomes including patient falls, hospital-acquired pressure injuries and patient satisfaction. Three articles reported decreased patient falls, two articles reported increased patient satisfaction, while one article reported a reduction in pressure injury. Five of the studies reported improved teamwork and/or communication, and two studies reported improved job satisfaction.

Conclusions: There has been limited research on the impact of the registered nurse-nursing assistant relationship on patient safety and care outcomes. The existing research demonstrates a need for interventions to foster a dynamic and effective relationship between registered nurses and nursing assistants. There is a need for more interventional studies linking improved teamwork, delegation and communication between the registered nurse and nursing assistant to patient outcomes such as falls and hospital-acquired pressure injury.

Implications For Nursing Management: Several interventions exist to improve teamwork and communication between the registered nurse-nursing assistant dyad. Leaders need to assess their own culture and develop interventions to build and maintain high-functioning teams. Future research is necessary to develop interventions aimed at improving delegation from registered nurses to nursing assistants for applicable activities.
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http://dx.doi.org/10.1111/jonm.13083DOI Listing
October 2020

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics.

Biochem J 2020 07;477(13):2451-2475

Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.

Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signalling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilisation. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely 'non-canonical' substrates. Surprisingly, sequence interrogation of ∼300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signalling.
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http://dx.doi.org/10.1042/BCJ20200309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338032PMC
July 2020

Electrocardiogram-Based Timings Cause Systematic Errors in Vascular Strain Measures: A Method for Error Correction and Estimation of Pulse Transit Time.

J Am Soc Echocardiogr 2020 05 12;33(5):636-638. Epub 2020 Mar 12.

School of Sport, York St John University, York, United Kingdom.

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http://dx.doi.org/10.1016/j.echo.2020.02.002DOI Listing
May 2020

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies.

Hum Mol Genet 2020 04;29(6):1030-1043

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.
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http://dx.doi.org/10.1093/hmg/ddaa031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158378PMC
April 2020

complex infection complicating long-term urethral catheterisation.

BMJ Case Rep 2019 Nov 14;12(11). Epub 2019 Nov 14.

Department of Medicine of the Elderly, Borders General Hospital, Melrose, Scotland, UK

This report describes a 79-year-old Caucasian man with a history of syringomyelia, paraplegia and a long-term urethral catheter, presenting with recurrent catheter-related or catheter-associated urinary tract infections (CAUTIs) and persistent delirium. On one occasion, urine cultured bacteria from the complex (BCC). This organism is recognised as being a coloniser of fluid or aquatic settings. However, in certain circumstances (eg, immunosuppression, immunocompromise, multimorbidity), BCC has been recognised to cause infection, that is, rather than merely contamination or colonisation. In this unwell older patient, treatment of the BCC CAUTI was guided by antibiotic sensitivities and microbiology advice. The report incorporates a brief discussion of some relevant microbiological terminology, and refers to associations and commoner sites of BCC-related infection. The report concludes by exploring how three philosophical concepts (Occam's razor, Hickam's dictum and Crabtree's bludgeon) proved relevant in supporting clinical decision-making in this case.
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http://dx.doi.org/10.1136/bcr-2019-230342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887370PMC
November 2019

DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD.

Hum Mol Genet 2019 12;28(23):3997-4011

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

The DUX4 transcription factor is normally expressed in the cleavage-stage embryo and regulates genes involved in embryonic genome activation. Misexpression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the activation of the double-stranded RNA (dsRNA) response pathway and the accumulation of intranuclear dsRNA foci. Here, we determined the composition of DUX4-induced dsRNAs. We found that a subset of DUX4-induced dsRNAs originate from inverted Alu repeats embedded within the introns of DUX4-induced transcripts and from DUX4-induced dsRNA-forming intergenic transcripts enriched for endogenous retroviruses, Alu and LINE-1 elements. However, these repeat classes were also represented in dsRNAs from cells not expressing DUX4. In contrast, pericentric human satellite II (HSATII) repeats formed a class of dsRNA specific to the DUX4 expressing cells. Further investigation revealed that DUX4 can initiate the bidirectional transcription of normally heterochromatin-silenced HSATII repeats. DUX4-induced HSATII RNAs co-localized with DUX4-induced nuclear dsRNA foci and with intranuclear aggregation of EIF4A3 and ADAR1. Finally, gapmer-mediated knockdown of HSATII transcripts depleted DUX4-induced intranuclear ribonucleoprotein aggregates and decreased DUX4-induced cell death, suggesting that HSATII-formed dsRNAs contribute to DUX4 toxicity.
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http://dx.doi.org/10.1093/hmg/ddz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342170PMC
December 2019

Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation.

EMBO J 2019 10 21;38(21):e100847. Epub 2019 Aug 21.

Centre for Proteome Research, Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.

Phosphorylation is a key regulator of protein function under (patho)physiological conditions, and defining site-specific phosphorylation is essential to understand basic and disease biology. In vertebrates, the investigative focus has primarily been on serine, threonine and tyrosine phosphorylation, but mounting evidence suggests that phosphorylation of other "non-canonical" amino acids also regulates critical aspects of cell biology. However, standard methods of phosphoprotein characterisation are largely unsuitable for the analysis of non-canonical phosphorylation due to their relative instability under acidic conditions and/or elevated temperature. Consequently, the complete landscape of phosphorylation remains unexplored. Here, we report an unbiased phosphopeptide enrichment strategy based on strong anion exchange (SAX) chromatography (UPAX), which permits identification of histidine (His), arginine (Arg), lysine (Lys), aspartate (Asp), glutamate (Glu) and cysteine (Cys) phosphorylation sites on human proteins by mass spectrometry-based phosphoproteomics. Remarkably, under basal conditions, and having accounted for false site localisation probabilities, the number of unique non-canonical phosphosites is approximately one-third of the number of observed canonical phosphosites. Our resource reveals the previously unappreciated diversity of protein phosphorylation in human cells, and opens up avenues for high-throughput exploration of non-canonical phosphorylation in all organisms.
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http://dx.doi.org/10.15252/embj.2018100847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826212PMC
October 2019

DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockade.

Dev Cell 2019 09 18;50(5):658-671.e7. Epub 2019 Jul 18.

Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

Advances in cancer immunotherapies make it critical to identify genes that modulate antigen presentation and tumor-immune interactions. We report that DUX4, an early embryonic transcription factor that is normally silenced in somatic tissues, is re-expressed in diverse solid cancers. Both cis-acting inherited genetic variation and somatically acquired mutations in trans-acting repressors contribute to DUX4 re-expression in cancer. Although many DUX4 target genes encode self-antigens, DUX4-expressing cancers were paradoxically characterized by reduced markers of anti-tumor cytolytic activity and lower major histocompatibility complex (MHC) class I gene expression. We demonstrate that DUX4 expression blocks interferon-γ-mediated induction of MHC class I, implicating suppressed antigen presentation in DUX4-mediated immune evasion. Clinical data in metastatic melanoma confirmed that DUX4 expression was associated with significantly reduced progression-free and overall survival in response to anti-CTLA-4. Our results demonstrate that cancers can escape immune surveillance by reactivating a normal developmental pathway and identify a therapeutically relevant mechanism of cell-intrinsic immune evasion.
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http://dx.doi.org/10.1016/j.devcel.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736738PMC
September 2019

A genome-wide association study implicates that the gene is associated with diabetic maculopathy with decreased visual acuity.

Ophthalmic Genet 2019 06 2;40(3):252-258. Epub 2019 Jul 2.

a Division of Population Health and Genomics , Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee , Dundee , UK.

: Diabetic maculopathy is a form of diabetic retinopathy. The visual acuity of one third of patients with diabetic maculopathy will be affected. The purpose of this study was to identify genetic contributors of diabetic maculopathy with decreased visual acuity based on a genome-wide association approach using a well-defined Scottish diabetic cohort. : We used linked e-health records of diabetic patients to define our cases and controls. The cases in this study were defined as type 2 diabetic patients who had ever been recorded in the linked e-health records as having maculopathy (observable or referable) in at least one eye and whose visual acuity of the eye was recorded to have decreased between the first and the last visual acuity record of that eye in the longitudinal e-health records. The controls were defined as a type 2 diabetic individual who had never been diagnosed with maculopathy or retinopathy in the linked e-health records. Anyone who had laser photocoagulation treatment was also excluded from the controls. A standard genome-wide association approach was applied. : Overall, we identified 469 cases and 1,374 controls within the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. We found that the value of rs9966620 in the gene was 4.13x10, which reached genome-wide significance. : We suggest that the gene is associated with diabetic maculopathy with decreased visual acuity. This needs to be confirmed by further replication studies and functional studies.
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http://dx.doi.org/10.1080/13816810.2019.1633549DOI Listing
June 2019

Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.

J Pharmacol Exp Ther 2019 08 12;370(2):219-230. Epub 2019 Jun 12.

Departments of Biochemistry and Molecular Biology (J.O., A.R., N.M., F.M.S.) and Chemistry (M.J.M.), Saint Louis University, St. Louis, Missouri; Ultragenyx Pharmaceutical Inc., Novato, California (S.G.); Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington (A.E.C., J.W.Z., S.J.T.); Department of Neurology, University of Rochester Medical Center, Rochester, New York (R.T.); and Department of Neurology, University of Washington, Seattle, Washington (S.J.T.)

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the -2 adrenergic receptor suppress expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38 and p38 isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.
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http://dx.doi.org/10.1124/jpet.119.259663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652132PMC
August 2019

Microscopic colitis impacts quality of life in older people.

BMJ Case Rep 2019 Jun 6;12(6). Epub 2019 Jun 6.

Department of Medicine of the Elderly, Royal Infirmary of Edinburgh, Edinburgh, UK.

This report describes a frail 92-year-old woman with dementia who presented with a year's history of chronic watery non-bloody diarrhoea. She had abdominal bloating, weight loss, faecal urgency, nocturnal stools and developed faecal incontinence. Her serum C reactive peptide and faecal calprotectin were elevated. Flexible sigmoidoscopy was macroscopically normal, but demonstrated histological features of microscopic colitis (MC) in sigmoid colon and rectal biopsies. Polypharmacy was reviewed for possible medication-induced MC. Ranitidine, donepezil and simvastatin were discontinued. She was started on oral budesonide with improvement in the abdominal and bowel symptoms. Stool frequency and consistency normalised, and the faecal incontinence resolved with treatment. The outcomes were an improved quality of life, reduced functional dependency, reduced carer strain and avoidance of premature transition from her home into a long-term/institutional care setting. We briefly review terminology, basic epidemiology, notable associations, the importance of establishing a diagnosis and some treatment considerations for MC.
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http://dx.doi.org/10.1136/bcr-2018-228092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557315PMC
June 2019

Wexler Tribute Issue: Editorial.

Int J Law Psychiatry 2019 Mar - Apr;63:1-2

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http://dx.doi.org/10.1016/j.ijlp.2019.03.003DOI Listing
January 2020

Long-Term Aerobic Exercise Improves Vascular Function Into Old Age: A Systematic Review, Meta-Analysis and Meta Regression of Observational and Interventional Studies.

Front Physiol 2019 26;10:31. Epub 2019 Feb 26.

School of Health and Life Sciences, Institute of Clinical Exercise and Health Sciences, University of the West of Scotland, Hamilton, United Kingdom.

There is an emerging body of literature relating to the effectiveness of frequent aerobic exercise as a prophylactic for age-associated dysfunction of large arteries, yet systematic evaluation and precise estimate of this effect is unknown. We conducted a systematic review and meta-analysis of controlled studies examining flow mediated dilatation (FMD) of athletic older persons and otherwise healthy sedentary counterparts to (i) compare FMD as a determinant of endothelial function between athletes and sedentary individuals and, (ii) summarize the effect of exercise training on FMD in studies of sedentary aging persons. Studies were identified from systematic search of major electronic databases from inception to January 2018. Study quality was assessed before conducting a random effects meta-analysis to calculate a pooled ES (mean difference) with 95% CI's. Thirteen studies [4 interventional ( = 125); 10 cross-sectional [including one study from the interventional analysis; ( = 485)] with age ranges from 62 to 75 years underwent quantitative pooling of data. The majority of study participants were male. Older athletes had more favorable FMD compared with sedentary controls (2.1%; CI: 1.4, 2.8%; < 0.001). There was no significant improvement in the vascular function of sedentary cohorts following a period of exercise training (0.7%; CI: -0.675, 2.09%; = 0.316). However, there was a significant increase in baseline diameter from pre to post intervention (0.1 mm; CI: 0.07, 0.13 mm; < 0.001). In addition, there was no significant difference in endothelial independent vasodilation between the trained and sedentary older adults (1.57%; CI: -0.13, 3.27%; = 0.07), or from pre to post exercise intervention (1.48%; CI: -1.34, 4.3%; = 0.3). In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults.
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http://dx.doi.org/10.3389/fphys.2019.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399418PMC
February 2019

Aerobic Training Protects Cardiac Function During Advancing Age: A Meta-Analysis of Four Decades of Controlled Studies.

Sports Med 2019 Feb;49(2):199-219

School of Health and Life Science, Institute of Clinical Exercise and Health Science, University of the West of Scotland, Glasgow, UK.

Background: In contrast to younger athletes, there is comparatively less literature examining cardiac structure and function in older athletes. However, a progressive accumulation of studies during the past four decades offers a body of literature worthy of systematic scrutiny.

Objectives: We conducted a systematic review, meta-analysis and meta-regression of controlled echocardiography studies comparing left ventricular (LV) structure and function in aerobically trained older athletes (> 45 years) with age-matched untrained controls, in addition to investigating the influence of chronological age.

Methods: Electronic databases were searched from inception to January 2018 before conducting a random-effects meta-analysis to calculate pooled differences in means, effect size and 95% confidence intervals (CIs). Study heterogeneity was reported using Cochran's Q and I statistic.

Results: Overall, 32 studies (644 athletes; 582 controls) were included. Athletes had greater LV end-diastolic diameter (3.65 mm, 95% CI 2.66-4.64), interventricular septal thickness (1.23 mm, 95% CI 0.85-1.60), posterior wall thickness (1.20 mm, 95% CI 0.83-1.56), LV mass (72 g, 95% CI 46-98), LV mass index (28.17 g·m, 95% CI 19.84-36.49) and stroke volume (13.59 mL, 95% CI 7.20-19.98) (all p < 0.01). Athletes had superior global diastolic function [ratio of early (E) to late (A) mitral inflow velocity (E/A) 0.18, 95% CI 0.13-0.24, p < 0.01; ratio of early (e') to late (a') diastolic annular tissue velocity (e'/a') 0.23, 95% CI 0.06-0.40, p = 0.01], lower A (-8.20 cm·s, 95% CI -11.90 to -4.51, p < 0.01) and a' (-0.72 cm·s, 95% CI -1.31 to -0.12, p = 0.02), and more rapid e' (0.96 cm·s, 95% CI 0.05-1.86, p = 0.04). Meta-regression for chronological age identified that athlete-control differences, in the main, are maintained during advancing age.

Conclusions: Athletic older men have larger cardiac dimensions and enjoy more favourable cardiac function than healthy, non-athletic counterparts. Notably, the athlete groups maintain these effects during chronological ageing.
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http://dx.doi.org/10.1007/s40279-018-1004-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513799PMC
February 2019

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD.

Hum Mol Genet 2019 02;28(3):476-486

Neuromuscular Unit, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.
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http://dx.doi.org/10.1093/hmg/ddy364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337697PMC
February 2019

Neuromyelitis optica spectrum disorder presenting in an octogenarian.

BMJ Case Rep 2018 Sep 8;2018. Epub 2018 Sep 8.

Medicine of the Elderly Department, Royal Infirmary of Edinburgh, Edinburgh, UK.

This case describes an 81-year-old woman with a history of Sjögren's syndrome presenting with recurrent falls and poor balance. She subsequently developed new and rapidly evolving neurology including hyperaesthesia, spastic paraplegia and sphincteric dysfunction. Following serial clinical reviews and detailed investigations, MRI (brainstem and cervicothoracic spine) and a seropositive result for aquaporin 4 IgG, a diagnosis of neuromyelitis optica spectrum disorder (NMOSD) was made. This case describes the clinical course of this index patient with an unusual late age of onset. The report also includes a discussion on NMOSD. We review aspects of terminology, brief epidemiology, pathogenesis, notable autoimmune associations, variance in clinical presentation and current diagnostic criteria. We also review the importance of distinguishing NMOSD from multiple sclerosis in view of the significant implications for treatment and prognosis.
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http://dx.doi.org/10.1136/bcr-2018-225601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129075PMC
September 2018

Neurovasculature of high and low tie ligation of the inferior mesenteric artery.

Surg Radiol Anat 2018 Dec 1;40(12):1343-1348. Epub 2018 Sep 1.

Laboratory of Human Anatomy, School of Life Sciences, University of Glasgow, Glasgow, UK.

Purpose: Controversy exists as to whether a high or low tie ligation of the inferior mesenteric artery (IMA) is the preferred technique in surgeries of the left colon and rectum. This study aims to contribute to the discussion as to which is the more beneficial technique by investigating the neurovasculature at each site.

Methods: Ten embalmed cadaveric donors underwent division of the inferior mesenteric artery at the level of the low tie. The artery was subsequently ligated at the root to render a section of tissue for histological analysis of the proximal (high tie), mid and distal (low tie) segments.

Results: Ganglia observed in the proximal end of seven specimens in the sample imply that there would be disruption to the innervation in a high tie procedure.

Conclusion: This study suggests that a high tie should be avoided if the low tie is oncologically viable.
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http://dx.doi.org/10.1007/s00276-018-2092-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244984PMC
December 2018

A case study for applying therapeutic jurisprudence to policymaking: Assembling a policy toolbox to achieve a trauma-informed early care and learning system.

Authors:
Amy T Campbell

Int J Law Psychiatry 2019 Mar - Apr;63:45-55. Epub 2018 Jun 29.

University of Memphis School of Law, 1 North Front Street, Memphis, Tennessee 38103, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijlp.2018.06.005DOI Listing
January 2020

Using Real-Time Data to Warn Nurses of Medication Administration Errors Using a Nurse Situational Awareness Dashboard.

Stud Health Technol Inform 2018 ;250:140-141

School of Computing, University of South Alabama, Mobile, Alabama, USA.

Electronic Health Records (EHR) are constantly gathering an exponential amount healthcare data. Historical data is often studied to identify trends and determine the effectiveness of interventions, but rarely is Real-time data utilized to positively influence the nurse at the Point of Care. A dashboard allowing nurses to visualize their individual Near-Miss (MN) medication error risk as the needs and subsequent workload of the patients they served changed was created and piloted for 30- days. Implementation of the dashboard resulted in a 15.6% reduction of NMs.
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October 2018

Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle.

Hum Mol Genet 2018 08;27(R2):R153-R162

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Facioscapulohumeral dystrophy (FSHD) is the third most prevalent muscular dystrophy. A progressive disease, it presents clinically as weakness and wasting of the face, shoulder and upper arm muscles, with later involvement of the trunk and lower extremities. FSHD develops through complex genetic and epigenetic events that converge on a common mechanism of toxicity with mis-expression of the transcription factor double homeobox 4 (DUX4). There is currently no treatment available for FSHD. However, the consensus that ectopic DUX4 expression in skeletal muscle is the root cause of FSHD pathophysiology has allowed research efforts to turn toward cultivating a deeper understanding of DUX4 biology and the pathways that underlie FSHD muscle pathology, and to translational studies aimed at developing targeted therapeutics using ever more sophisticated cell and animal-based models of FSHD. This review summarizes recent advances in our understanding of FSHD, including the regulation and activity of DUX4 in its normal developmental roles as well as its pathological contexts. We highlight how these advances raise new questions and challenges for the field as it moves into the next decade of FSHD research.
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http://dx.doi.org/10.1093/hmg/ddy162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061842PMC
August 2018

Meal Replacements Are They for You?

Authors:
Amy Campbell

Diabetes Self Manag 2017 May;34(3):66-69

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May 2017

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators.

J Biol Chem 2018 05 22;293(19):7160-7175. Epub 2018 Mar 22.

From the School of Life and Environmental Sciences, University of Sydney New South Wales 2006, Australia,

Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4, and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease, and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET family proteins regulate gene expression are not well defined. In particular, the functions of the other domains such as the ET domain have been less extensively studied. Here, we examine the properties of the ET domain of BRD3 as a protein/protein interaction module. Using a combination of pulldown and biophysical assays, we demonstrate that BRD3 binds to a range of chromatin-remodeling complexes, including the NuRD, BAF, and INO80 complexes, via a short linear "KIKL" motif in one of the complex subunits. NMR-based structural analysis revealed that, surprisingly, this mode of interaction is shared by the AF9 and ENL transcriptional coregulators that contain an acetyl-lysine-binding YEATS domain and regulate transcriptional elongation. This observation establishes a functional commonality between these two families of cancer-related transcriptional regulators. In summary, our data provide insight into the mechanisms by which BET family proteins might link chromatin acetylation to transcriptional outcomes and uncover an unexpected functional similarity between BET and YEATS family proteins.
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http://dx.doi.org/10.1074/jbc.RA117.000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949996PMC
May 2018

NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins.

Elife 2018 03 13;7. Epub 2018 Mar 13.

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.

The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells.
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http://dx.doi.org/10.7554/eLife.31023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849414PMC
March 2018

Value of Information Analysis of Multiparameter Tests for Chemotherapy in Early Breast Cancer: The OPTIMA Prelim Trial.

Value Health 2017 12 11;20(10):1311-1318. Epub 2017 Jul 11.

University of Alberta, Edmonton, Alberta, Canada.

Background: Precision medicine is heralded as offering more effective treatments to smaller targeted patient populations. In breast cancer, adjuvant chemotherapy is standard for patients considered as high-risk after surgery. Molecular tests may identify patients who can safely avoid chemotherapy.

Objectives: To use economic analysis before a large-scale clinical trial of molecular testing to confirm the value of the trial and help prioritize between candidate tests as randomized comparators.

Methods: Women with surgically treated breast cancer (estrogen receptor-positive and lymph node-positive or tumor size ≥30 mm) were randomized to standard care (chemotherapy for all) or test-directed care using Oncotype DX™. Additional testing was undertaken using alternative tests: MammaPrint, PAM-50 (Prosigna), MammaTyper, IHC4, and IHC4-AQUA™ (NexCourse Breast™). A probabilistic decision model assessed the cost-effectiveness of all tests from a UK perspective. Value of information analysis determined the most efficient publicly funded ongoing trial design in the United Kingdom.

Results: There was an 86% probability of molecular testing being cost-effective, with most tests producing cost savings (range -£1892 to £195) and quality-adjusted life-year gains (range 0.17-0.20). There were only small differences in costs and quality-adjusted life-years between tests. Uncertainty was driven by long-term outcomes. Value of information demonstrated value of further research into all tests, with Prosigna currently being the highest priority for further research.

Conclusions: Molecular tests are likely to be cost-effective, but an optimal test is yet to be identified. Health economics modeling to inform the design of a randomized controlled trial looking at diagnostic technology has been demonstrated to be feasible as a method for improving research efficiency.
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http://dx.doi.org/10.1016/j.jval.2017.04.021DOI Listing
December 2017