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303 results on '"Dunne, Mark J."'

1. Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism

Author

Wakeling, Matthew N., Owens, Nick D. L., Hopkinson, Jessica R., Johnson, Matthew B., Houghton, Jayne A. L., Dastamani, Antonia, Flaxman, Christine S., Wyatt, Rebecca C., Hewat, Thomas I., Hopkins, Jasmin J., Laver, Thomas W., van Heugten, Rachel, Weedon, Michael N., De Franco, Elisa, Patel, Kashyap A., Ellard, Sian, Morgan, Noel G., Cheesman, Edmund, Banerjee, Indraneel, Hattersley, Andrew T., Dunne, Mark J., Richardson, Sarah J., and Flanagan, Sarah E.

Published
2022
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4. The behaviour change behind a successful pilot of hypoglycaemia reduction with HYPO-CHEAT

Author

Worth, Chris, Nutter, Paul W, Salomon-Estebanez, Maria, Auckburally, Sameera, Dunne, Mark J, Banerjee, Indraneel, Harper, Simon, Worth, Chris, Nutter, Paul W, Salomon-Estebanez, Maria, Auckburally, Sameera, Dunne, Mark J, Banerjee, Indraneel, and Harper, Simon

Abstract

Background: Children with hypoglycaemia disorders, such as congenital hyperinsulinism (CHI), are at constant risk of hypoglycaemia (low blood sugars) with the attendant risk of brain injury. Current approaches to hypoglycaemia detection and prevention vary from fingerprick glucose testing to the provision of continuous glucose monitoring (CGM) to machine learning (ML) driven glucose forecasting. Recent trends for ML have had limited success in preventing free-living hypoglycaemia, due to a focus on increasingly accurate glucose forecasts and a failure to acknowledge the human in the loop and the essential step of changing behaviour. The wealth of evidence from the fields of behaviour change and persuasive technology (PT) allows for the creation of a theory-informed and technologically considered approach. Objectives: We aimed to create a PT that would overcome the identified barriers to hypoglycaemia prevention for those with CHI to focus on proactive prevention rather than commonly used reactive approaches. Methods: We used the behaviour change technique taxonomy and persuasive systems design models to create HYPO-CHEAT (HYpoglycaemia-Prevention-thrOugh-Cgm-HEatmap-Assisted-Technology): a novel approach that presents aggregated CGM data in simple visualisations. The resultant ease of data interpretation is intended to facilitate behaviour change and subsequently reduce hypoglycaemia. Results: HYPO-CHEAT was piloted in 10 patients with CHI over 12 weeks and successfully identified weekly patterns of hypoglycaemia. These patterns consistently correlated with identifiable behaviours and were translated into both a change in proximal fingerprick behaviour and ultimately, a significant reduction in aggregated hypoglycaemia from 7.1% to 5.4% with four out of five patients showing clinically meaningful reductions in hypoglycaemia. Conclusions: We have provided pilot data of a new approach to hypoglycaemia prevention that focuses on proactive prevention and behaviour chang

Published
2023

8. Pancreatic ductal adenocarcinoma cells employ integrin α6β4 to form hemidesmosomes and regulate cell proliferation

Author

Humphries, Jonathan D., primary, Zha, Junzhe, additional, Burns, Jessica, additional, Askari, Janet A., additional, Below, Christopher R., additional, Chastney, Megan R., additional, Jones, Matthew C., additional, Mironov, Aleksandr, additional, Knight, David, additional, O'Reilly, Derek A., additional, Dunne, Mark J., additional, Garrod, David R., additional, Jorgensen, Claus, additional, and Humphries, Martin J., additional

Published
2022
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10. Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism—The UK Perspective

Author

Dastamani, Antonia, primary, Yau, Daphne, additional, Gilbert, Clare, additional, Morgan, Kate, additional, De Coppi, Paolo, additional, Craigie, Ross J, additional, Bomanji, Jamshed, additional, Biassoni, Lorenzo, additional, Sajjan, Rakesh, additional, Flanagan, Sarah E, additional, Houghton, Jayne A L, additional, Senniappan, Senthil, additional, Didi, Mohammed, additional, Dunne, Mark J, additional, Banerjee, Indraneel, additional, and Shah, Pratik, additional

Published
2022
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14. Altered Phenotype of β-Cells and Other Pancreatic Cell Lineages in Patients With Diffuse Congenital Hyperinsulinism in Infancy Caused by Mutations in the ATP-Sensitive K-Channel

Author

Salisbury, Rachel J., Han, Bing, Jennings, Rachel E., Berry, Andrew A., Stevens, Adam, Mohamed, Zainab, Sugden, Sarah A., De Krijger, Ronald, Cross, Sarah E., Johnson, Paul P.V., Newbould, Melanie, Cosgrove, Karen E., Hanley, Karen Piper, Banerjee, Indraneel, Dunne, Mark J., and Hanley, Neil A.

Published
2015
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17. Pancreatic ductal adenocarcinoma cells employ integrin α6β4 to form hemidesmosomes and regulate cell proliferation

Author

Humphries, Jonathan D., primary, Zha, Junzhe, additional, Burns, Jessica, additional, Askari, Janet A., additional, Below, Christopher R., additional, Chastney, Megan R., additional, Jones, Matthew C., additional, Mironov, Aleksandr, additional, Knight, David, additional, O’Reilly, Derek A., additional, Dunne, Mark J., additional, Garrod, David R., additional, Jorgensen, Claus, additional, and Humphries, Martin J., additional

Published
2021
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19. Hyperinsulinism in infancy: from basic science to clinical disease

Author

Dunne, Mark J., Cosgrove, Karen E., Shepherd, Ruth M., Aynsley-Green, Albert, and Lindley, Keith J.

Subjects
Children -- Diseases, Metabolic diseases -- Research -- Physiological aspects, Metabolic disorders in children -- Research -- Physiological aspects, Biological sciences, Health, Physiological aspects, Research
Abstract

Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered [...]

Published
2004

20. Non-coding variants disrupting a tissue-specific regulatory element in HK1cause congenital hyperinsulinism

Author

Wakeling, Matthew N., Owens, Nick D. L., Hopkinson, Jessica R., Johnson, Matthew B., Houghton, Jayne A. L., Dastamani, Antonia, Flaxman, Christine S., Wyatt, Rebecca C., Hewat, Thomas I., Hopkins, Jasmin J., Laver, Thomas W., van Heugten, Rachel, Weedon, Michael N., De Franco, Elisa, Patel, Kashyap A., Ellard, Sian, Morgan, Noel G., Cheesman, Edmund, Banerjee, Indraneel, Hattersley, Andrew T., Dunne, Mark J., Richardson, Sarah J., and Flanagan, Sarah E.

Abstract

Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.

Published
2022
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27. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor

Author

Dunne, Mark J., Kane, Charlotte, Shepherd, Ruth M., Sanchez, Jorge A., James, Roger F.L., Johnson, Paul R.V., Aynsley-Green, Albert, Lu, Shan, Clement, John P., IV, Lindley, Keith J., Seino, Susumu, and Aguilar-Bryan, Lydia

Subjects
Familial diseases -- Case studies, Hypoglycemia -- Case studies, Gene mutations -- Health aspects, Cell receptors -- Genetic aspects
Abstract

Patients with familial persistent hyperinsulinemic hypoglycemia may have a mutation in the gene for a potassium channel in the pancreatic beta cells. This hereditary form of hypoglycemia is caused by an excessive production of insulin. A baby born to an Arabic couple had the physical characteristics of hyperinsulinemia and no detectable blood glucose. After unsuccessful treatment with intravenous glucose, 99% of her pancreas was surgically removed. Genetic analysis revealed that she had a mutation in the sulfonylurea receptor, which is a subunit of the potassium channel in beta cells.

Published
1997

28. Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity

Author

Tornovsky, Sharona, Crane, Ana, Cosgrove, Karen E., Hussain, Khalid, Lavie, Judith, Heyman, Ma’ayan, Nesher, Yaron, Kuchinski, Na’ama, Ben-Shushan, Etti, Shatz, Olga, Nahari, Efrat, Potikha, Tamara, Zangen, David, Tenenbaum-Rakover, Yardena, de Vries, Liat, Argente, Jesús, Gracia, Ricardo, Landau, Heddy, Eliakim, Alon, Lindley, Keith, Dunne, Mark J., Aguilar-Bryan, Lydia, and Glaser, Benjamin

Published
2004

35. Extreme caution on the use of sirolimus for the congenital hyperinsulinism in infancy patient

Author

Banerjee, Indraneel, De Leon, Diva, and Dunne, Mark J.

Subjects
Sirolimus, Congenital hyperinsulinism in Infancy patient, islet, TOR Serine-Threonine Kinases, lcsh:R, Infant, Newborn, lcsh:Medicine, Hypoglycemia, Hyperinsulinism, mTOR, Animals, Humans, Congenital Hyperinsulinism, Letter to the Editor, hypoglycaemia
Abstract

We have recently published on the limited effectiveness of sirolimus as a treatment option for hypoglycaemia as a consequence of hyperinsulinism. Our data oppose the view that mTOR inhibitors provide new opportunities for the treatment of patients with hyperinsulinism. We are not convinced by the argument that any benefit for some patients outweighs the potential and later long-term problems that accompany mTOR inhibition in the neonate. We also express the opinion that caution must be taken when repurposing/repositioning therapies in the field of rare disease.

Published
2017

38. Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates with Histological Heterogeneity of Islet Cell Lesions

Author

Craigie, Ross J., Salomon-Estebanez, Maria, Yau, Daphne, Han, Bing, Mal, Walaa, Newbould, Melanie, Cheesman, Edmund, Bitetti, Stefania, Mohamed, Zainab, Sajjan, Rakesh, Padidela, Raja, Skae, Mars, Flanagan, Sarah, Ellard, Sian, Cosgrove, Karen E., Banerjee, Indraneel, and Dunne, Mark J.

Subjects
congenital hyperinsulinism, insulin, Endocrinology, positron emission tomography, islet, focal, Endocrinology, Diabetes and Metabolism, pancreas, β-cell, Original Research, hypoglycaemia
Abstract

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established.Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue.Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies.Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1–7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1–180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex.Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.

Published
2018

47. Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

Author

Salomon-Estebanez, Maria, Flanagan, Sarah E., Ellard, Sian, Rigby, Lindsey, Bowden, Louise, Mohamed, Zainab, Nicholson, Jacqueline, Skae, Mars, Hall, Caroline, Craigie, Ross, Padidela, Raja, Murphy, Nuala, Randell, Tabitha, Cosgrove, Karen E., Dunne, Mark J., and Banerjee, Indraneel

Subjects
Medicine(all), Male, Research, Diazoxide, Neurodevelopment, Infant, Newborn, Infant, Congenital hyperinsulinism, Octreotide, Child, Preschool, Mutation, Genetics, Insulin, Humans, Genetics(clinical), Pharmacology (medical), ATP-Binding Cassette Transporters, Female, Hypoglycaemia, Mutations
Abstract

Background Patients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy. Methods Twenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment. Results CHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [−0.1 (−1.2, 1.6) v −1.2 (−1.7, 0.03), p = 0.1]. Conclusions In K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0547-3) contains supplementary material, which is available to authorized users.

Published
2016

48. Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism.

Author

Houghton, Jayne AL, Banerjee, Indraneel, Shaikh, Guftar, Jabbar, Shamila, Laver, Thomas W, Cheesman, Edmund, Chinnoy, Amish, Yau, Daphne, Salomon‐Estebanez, Maria, Dunne, Mark J, and Flanagan, Sarah E

Subjects
ISLANDS of Langerhans, MOSAIC diseases, PANCREATIC diseases, MORPHOLOGY, SURGICAL excision, INSULIN aspart
Abstract

Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life‐threatening hypoglycaemia if not effectively managed. CHI can be sub‐classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic‐CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next‐generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease‐causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with β‐cell expansion in CHI. [ABSTRACT FROM AUTHOR]

Published
2020
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49. Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions

Author

Craigie, Ross J., primary, Salomon-Estebanez, Maria, additional, Yau, Daphne, additional, Han, Bing, additional, Mal, Walaa, additional, Newbould, Melanie, additional, Cheesman, Edmund, additional, Bitetti, Stefania, additional, Mohamed, Zainab, additional, Sajjan, Rakesh, additional, Padidela, Raja, additional, Skae, Mars, additional, Flanagan, Sarah, additional, Ellard, Sian, additional, Cosgrove, Karen E., additional, Banerjee, Indraneel, additional, and Dunne, Mark J., additional

Published
2018
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