30 results on '"John Willan"'
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2. P1640: REAL-WORLD SUPPORTIVE EVIDENCE FOR THE 4D-DVT ALGORITHM: ADJUSTING D-DIMER THRESHOLDS FOR INITIAL AND FOLLOW-UP IMAGING OF PATIENTS WITH SUSPECTED DEEP VEIN THROMBOSIS BY CLINICAL PROBABILITY
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John Willan, Gaurav Agarwal, Tara Varghese, Karen Cairns, Peter Baker, and Nicola Curry
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Neutrophilic erythrophagocytosis in a child with paroxysmal cold hamoglobinuria
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Omer Pervaiz, Eleni Louka, and John Willan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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4. The Maestro (Mro) gene is dispensable for normal sexual development and fertility in mice.
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Lee Smith, John Willan, Nick Warr, Frances A Brook, Michael Cheeseman, Richard Sharpe, Pam Siggers, and Andy Greenfield
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Medicine ,Science - Abstract
The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microarrays to screen for novel genes controlling the developmental fate of the indifferent embryonic mouse gonad. Maestro (Mro), which encodes a HEAT-repeat protein, was originally identified as a gene exhibiting sexually dimorphic expression during mouse gonad development. Wholemount in situ hybridisation analysis revealed Mro to be expressed in the embryonic male gonad from approximately 11.5 days post coitum, prior to overt sexual differentiation. No significant expression was detected in female gonads at the same developmental stage. In order to address its physiological function, we have generated mice lacking Maestro using gene targeting. Male and female mice homozygous for a Mro null allele are viable and fertile. We examined gonad development in homozygous male embryos in detail and observed no differences when compared to wild-type controls. Immunohistochemical analysis of homozygous mutant testes of adult mice revealed no overt abnormalities. Expression profiling using DNA microarrays also indicated no significant differences between homozygote embryonic male gonads and controls. We conclude that Maestro is dispensable for normal male sexual development and fertility in laboratory mice; however, the Mro locus itself does have utility as a site for insertion of transgenes for future studies in the fields of sexual development and Sertoli cell function.
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- 2008
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5. Planning for the emergence of vaccine-resistant SARS-CoV-2: addressing revaccination delivery bottlenecks
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Lorenz Kemper, Claire Bayntun, Katie Jeffery, Andrew J. King, John Willan, and Robbie Scott
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2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Vaccination Coverage ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Drug Resistance ,Immunization, Secondary ,COVID-19 ,General Medicine ,Virology ,Health Planning ,Medicine ,Humans ,Health Workforce ,business ,Delivery of Health Care - Published
- 2024
6. Mortality and burden of <scp>post‐COVID</scp> ‐19 syndrome have reduced with time across <scp>SARS‐CoV</scp> ‐2 variants in haematology patients
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John Willan, Gaurav Agarwal, and Nicola Bienz
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Hematology - Published
- 2023
7. Diagnosis of deep vein thrombosis using an adjusted clinical probability scoring: supportive evidence for a change in clinical practices
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John Willan, Gaurav Agarwal, Tara Varghese, Karen Cairns, Peter Baker, and Nicola Curry
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Hematology - Published
- 2023
8. Spontaneous splenic rupture as initial presentation of diffuse large B-cell lymphoma
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Gaurav Agarwal, Simon Moule, Alexandra Cope, David Maudgil, and John Willan
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Hematology - Published
- 2022
9. Investigation and management of severe thrombocytopaenia in a patient with cavitating lung disease
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Kate Brackenborough, Jasmine Ming Gan, Aya M Abbas, Safoora Rehman, Sarah Menzies, and John Willan
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Lung Diseases ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Respiratory infection ,Emergency department ,medicine.disease ,Thrombocytopenia ,Lobe ,03 medical and health sciences ,Pneumonia ,Lethargy ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Coronal plane ,medicine ,Humans ,Outpatient clinic ,Medical history ,030212 general & internal medicine ,Radiology ,business ,Lung - Abstract
A 44-year-old Polish man attended the emergency department complaining of cough and pleuritic chest pain. He had a fever of 38.6°C and his oxygen saturation (SpO2) was 97%. His medical history included childhood asthma. He took no medication or over-the-counter remedies. He was a smoker with a 60-pack year history and consumed 200 units of alcohol a week for 16 years, but reported he stopped drinking 1 month ago. He migrated from Poland 15 years ago and worked as a manual labourer. He denied any recent foreign travel. A chest X-ray (CXR) showed a cavitating lung lesion, and a subsequent urgent CT scan of the chest performed to rule out malignancy demonstrated a cavitating consolidation in the left posterior upper lobe and consolidation of the right lateral middle lobe (figures 1–4). Cavitating pneumonia in those with alcohol excess usually occurs in the posterior segments of the upper lobes. He was prescribed a 1-week course of co-amoxiclav for suspected bacterial pneumonia and was referred to the respiratory outpatient clinic to investigate these lesions further. At that time, his full blood count was normal. Figure 1 Coronal CT chest image showing cavitating consolidation in the left posterior upper lobe. Figure 2 Coronal CT chest image showing consolidation in the right lateral middle lobe. Figure 3 Axial CT chest image showing cavitating consolidation in the left posterior upper lobe. Figure 4 Axial CT chest image showing consolidation in the right lateral middle lobe. We met this patient 1 month later when he re-presented to the emergency department, with a 1-day history of moderate-volume haemoptysis and epistaxis on a background of left lateral chest pain, dry cough and exertional dyspnoea. He was apyrexic and his SpO2 was 95% at rest. He reported loss of appetite and 40 kg weight loss over the past year. Weighing 93 kg on admission with new onset lethargy …
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- 2021
10. Post‐COVID‐19 syndrome in patients with haematological disorders who have survived infection with severe acute respiratory syndrome coronavirus‐2
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John Willan, Lidice Hernandez, Harley Katz, Nicola Gray, and Nicola Bienz
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Post-Acute COVID-19 Syndrome ,Pregnancy ,SARS-CoV-2 ,COVID-19 ,Humans ,Female ,Hematology ,Pregnancy Complications, Infectious - Published
- 2021
11. Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm
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Sebastian Francis, Jaymathi Dhanapal, Lee Bond, Beth Psaila, Louise Wallis, Jennifer O'Sullivan, Anna L. Godfrey, Natalia Curto-Garcia, Andrew J. Innes, Richard Szydlo, Andrew McGregor, Laura Munro, Pratap Neelakantan, Siamak Arami, Rebecca Frewin, Adam J. Mead, Hayder Hussein, Frances Wadelin, James Russell, Steven Knapper, Peter Dyer, John Willan, Chun Huat Teh, Richard A. Salisbury, Mallika Sekhar, Manish Jain, Claire N. Harrison, Tim C. P. Somervaille, Shivani Joshi, C Cargo, Paolo Polzella, Mamta Garg, Andrew S Duncombe, Sarah Burns, Mary Frances McMullin, Dragana Milojkovic, Frederick Chen, Salisbury, Richard A [0000-0002-3500-3215], Willan, John [0000-0001-8700-2073], McMullin, Mary Frances [0000-0002-0773-0204], Mead, Adam J [0000-0001-8522-1002], Innes, Andrew J [0000-0003-0918-8882], and Apollo - University of Cambridge Repository
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Adult ,Male ,Cancer Research ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Letter ,Coronavirus disease 2019 (COVID-19) ,Epidemiology ,Disease-free survival ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,MEDLINE ,Myeloproliferative disease ,SDG 3 - Good Health and Well-being ,Internal medicine ,Medicine ,Humans ,1112 Oncology and Carcinogenesis ,In patient ,Myeloproliferative neoplasm ,Aged ,Aged, 80 and over ,Science & Technology ,Myeloproliferative Disorders ,business.industry ,SARS-CoV-2 ,COVID-19 ,Disease Management ,1103 Clinical Sciences ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,United Kingdom ,Risk factors ,Oncology ,Female ,business ,Life Sciences & Biomedicine - Abstract
Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272
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- 2021
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12. Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma
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Joanna M Oladipo, Hannah Plaschkes, Paul Fields, Arief Gunawan, Amy A Kirkwood, John Willan, Bing Tseu, Catherine Hildyard, Tim Ebsworth, Lucia Chen, Usman Khan, Robert Lown, Joe Browning, Adam Gibb, Patrick Horgan, Julia Wolf, Kim Linton, Jaimal Kothari, Dominic Gordon-Walker, Nimish Shah, Claire Higham, Graham P. Collins, Stephen Booth, and Toby A. Eyre
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medicine.medical_specialty ,Vincristine/adverse effects ,Osteoporosis ,Cyclophosphamide/adverse effects ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Rituximab/adverse effects ,medicine ,Humans ,Cyclophosphamide ,Aged ,Retrospective Studies ,030203 arthritis & rheumatology ,Lymphoid Neoplasia ,Manchester Cancer Research Centre ,business.industry ,Incidence (epidemiology) ,Antineoplastic Combined Chemotherapy Protocols/adverse effects ,ResearchInstitutes_Networks_Beacons/mcrc ,Retrospective cohort study ,Hematology ,medicine.disease ,Osteopenia ,Lymphoma, Large B-Cell, Diffuse/drug therapy ,Doxorubicin ,Vincristine ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Prednisolone ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,Doxorubicin/adverse effects ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if
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- 2020
13. Regional outcomes of severe acute respiratory syndrome coronavirus 2 infection in hospitalised patients with haematological malignancy
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John Willan, Steven Prideaux, Graham P. Collins, Lucia Chen, Stephen Booth, Moez Dungarwalla, Toby A. Eyre, Alicia Hunter, Alex Sternberg, Joe Browning, Rachel Farnell, Elissa K. Dhillon, Dalia Khan, Paolo Polzella, Henna Wong, David Dutton, Andy Peniket, Nicola S. Gray, Pratap Neelakantan, and Harley Katz
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Male ,medicine.medical_specialty ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Population ,Antineoplastic Agents ,SARS‐CoV‐2 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Case fatality rate ,medicine ,Humans ,In patient ,Prospective Studies ,education ,Pandemics ,Aged ,Aged, 80 and over ,Immunosuppression Therapy ,education.field_of_study ,Cytotoxins ,SARS-CoV-2 ,business.industry ,Mortality rate ,Risk of infection ,COVID-19 ,Original Articles ,Haematological malignancy ,Hematology ,General Medicine ,Middle Aged ,United Kingdom ,Hospitalization ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Female ,Original Article ,Active treatment ,business ,030215 immunology - Abstract
Objectives We sought to characterise the outcomes of patients with haematological malignancy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospital in our regional network of 7 hospitals. Methods Consecutive hospitalised patients with haematological malignancy and SARS-CoV-2 infection were identified from 01/03/2020 to 06/05/2020. Outcomes were categorised as death, resolved or ongoing. The primary outcome was preliminary case fatality rate (pCFR), defined as the number of cases resulting in death as a proportion of all diagnosed cases. Analysis was primarily descriptive. Results 66 Patients were included, overall pCFR was 51.5%. Patients ≥ 70 years accounted for the majority of hospitalised cases (42, 63%) and fatalities (25, 74%). Mortality was similar between females (52%) and males (51%). Immunosuppressive or cytotoxic treatment within 3 months of the diagnosis of SARS-CoV-2 infection was associated with a significantly higher pCFR of 70%, compared with 28% in those not on active treatment (P = .0013, 2 proportions z test). Conclusions Mortality rates in patients with haematological malignancy and SARS-CoV-2 infection in hospital are high supporting measures to minimise the risk of infection in this population.
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- 2020
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14. Assessing the impact of lockdown: Fresh challenges for the care of haematology patients in the COVID‐19 pandemic
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Graham P. Collins, Gareth D. H. Turner, John Willan, Andrew J. King, Andy Peniket, Sue Pavord, Faouzi Djebbari, and Daniel J. Royston
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Male ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,COVID-19 ,Hematologic Neoplasms ,Hematology ,medicine.disease ,Betacoronavirus ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,Pandemic ,medicine ,Viral therapy ,Humans ,Female ,Medical emergency ,business ,Coronavirus Infections ,Pandemics - Published
- 2020
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15. Challenges for NHS hospitals during covid-19 epidemic
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John Willan, Andrew J. King, Katie Jeffery, and Nicola Bienz
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2019-20 coronavirus outbreak ,Critical Care ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,COVID-19 ,General Medicine ,medicine.disease ,Hospitals ,State Medicine ,United Kingdom ,Betacoronavirus ,Humans ,Medicine ,Health Workforce ,Medical emergency ,Coronavirus Infections ,Epidemics ,business ,Delivery of Health Care ,Equipment and Supplies, Hospital - Published
- 2020
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16. Care of haematology patients in a COVID‐19 epidemic
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Andrew J. King, Graham P. Collins, John Willan, Andrew Peniket, and Sandy Hayes
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Adult ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,MEDLINE ,Comorbidity ,Betacoronavirus ,Internal medicine ,Correspondence ,medicine ,Humans ,Epidemics ,Pandemics ,Aged ,Covid‐19 ,Aged, 80 and over ,Hematology ,biology ,SARS-CoV-2 ,business.industry ,Viral Epidemiology ,Age Factors ,COVID-19 ,Middle Aged ,biology.organism_classification ,medicine.disease ,Hematologic Diseases ,Pneumonia ,Practice Guidelines as Topic ,Coronavirus Infections ,business - Published
- 2020
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17. DPACE-based chemotherapy in the era of myeloma novel agents: A UK multicentre study
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Toby A. Eyre, Kanchana De abrew, Jaimal Kothari, Supratik Basu, Faouzi Djebbari, John Willan, Matthew W Jenner, Karthik Ramasamy, Imran Hossain, Beena Salhan, and Fotios Panitsas
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Hematology ,General Medicine ,Prognosis ,United Kingdom ,Treatment Outcome ,Novel agents ,Doxorubicin ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Multicenter Studies as Topic ,Cisplatin ,business ,Multiple Myeloma ,Cyclophosphamide ,Etoposide - Published
- 2020
18. Care of haematology patients in an overwhelmed healthcare system
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John Willan, Nicola Bienz, Andrew J. King, and Graham P. Collins
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Reino unido ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Hematology ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Vaccination ,COVID-19 ,Guidelines as Topic ,Vulnerable Populations ,United Kingdom ,Disease Outbreaks ,Hospitalization ,Hospital Bed Capacity ,Internal medicine ,medicine ,Humans ,Intensive care medicine ,business ,Delivery of Health Care ,Healthcare system - Published
- 2021
19. Coronavirus disease 2019: achieving good mental health during social isolation
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Rowan Diamond and John Willan
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Economic growth ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Pneumonia, Viral ,information technologies ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Political science ,Pandemic ,medicine ,Humans ,030212 general & internal medicine ,Social isolation ,Pandemics ,Social functioning ,SARS-CoV-2 ,Social distance ,COVID-19 ,Mental health ,social deprivation ,030227 psychiatry ,Psychiatry and Mental health ,Mental Health ,Editorial ,social functioning ,Social deprivation ,Social Isolation ,Quarantine ,medicine.symptom ,Coronavirus Infections ,Psychosocial interventions ,depressive disorders - Abstract
SummaryThe coronavirus disease 2019 pandemic has led to unprecedented disruption to the normal way of life for people around the globe. Social distancing, self-isolation or shielding have been strongly advised or mandated in most countries. We suggest evidence-based ways that people can maintain or even strengthen their mental health during this crisis.
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- 2020
20. A HaemSTAR-led, UK-wide ‘flash-mob’ audit of intravenous immunoglobulin use in immune thrombocytopenia
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Arunodaya Mohan, Mairi Walker, Luke Carter-Brzezinski, Chris Peet, Yezenash Ayalew, Israa Kaddam, Rita Perry, David Tucker, Mac Macheta, Hayder Hussein, Suriya Kirkpatrick, Julia Wolf, Cristina Crossette-Thambiah, Sarah Wharin, Dianne Plews, Melek Akay, Graham McIlroy, Alexandros Rampotas, Lydia Wilson, Sarah Davis, Jesca Boot, Regina Nolan, Akila Danga, Dan Mei Xu, Tina T. Biss, Dominique Chan-Lam, Jennifer Swieton, Tanya Freeman, Claire Burney, Keir Pickard, Sheila Jen, Chloe Knott, Alvin Katumba, Sam Ackroyd, Edward Blacker, Beena Salhan, Richard Buka, Duncan Murray, Charlotte Bradbury, Sally Chown, Quentin A. Hill, Mohd Sharin Mohd Noh, Chira Mustafa, Nicola Crosbie, Surenthini Suntharalingam, Katja Kimberger, Rory McCulloch, Thomas Skinner, Naoimh Herlihy, Daire Quinn, Abbas Zaidi, Haroon Miah, Louise Garth, Eleana Loizou, Robert Dunk, Dan Halperin, Michael J R Desborough, Nithya Prasannan, Rupert Hipkins, Holly Gibson, Christopher McDermott, Amelia Fisher, Yogesh Upadhye, Sarah Wexler, Hina Peter, Sarah Jaafar, Sine Janum, Andrew J. Doyle, John Willan, Sree Sreedhara, Han Wang, Jonathan Kerr, Laura Aiken, Tom Bull, Seda Cakmak, Jennifer Darlow, Martin Besser, Michael Joffe, Benjamin Bailiff, Susan Robinson, Charlotte Wilding, Atiqa Miah, Jorge Cartier, Ryan Mullally, Miroslab Kmonicek, Samuel Harrison, Marquita Camillieri, Vickie MacDonald, Jane Graham, Ayesha Ejaz, Ipek Cakmak, Upekha Badaguma, Michelle Melly, Christopher Bailey, Belen Sevillano, Francesca Crolla, Frances Seymour, Indrani Venkatadasari, Laura Magill, Claire Lentaigne, Pamela Oshinyemi, Katherine Leighton, Maipelo Kgologolo, Zara Sayar, Elissa K. Dhillon, Lindsay McLeod-Kennedy, Sophie Hanina, Alice Thorpe, David Wright, Andrew Hastings, Caroline Shrubsole, Gillian C. Lowe, Nichola Cooper, Shivali Walia, Gulnaz Shah, Abi Martin, David Sharpe, Anna Dillon, Georgina Talbot, Imogen Swart-Rimmer, Phillip L R Nicolson, Paul Greaves, Olivia Kreze, Gemma Scott, Amir Shenouda, Edmund Watson, Shereef Elmoamly, Roochi Trikha, Wayne Thomas, Rebecca Pryor, Hafiz Qureshi, Laura Batey, Abigail Atkin, Dimitris Tsitsikas, Suthesh Sivapalaratnam, and Hajer Oun
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Response rate (survey) ,biology ,business.industry ,Research ,General Medicine ,030204 cardiovascular system & hematology ,Immune thrombocytopenia ,03 medical and health sciences ,Flash (photography) ,0302 clinical medicine ,hemic and lymphatic diseases ,Immunology ,biology.protein ,Medicine ,030212 general & internal medicine ,Antibody ,business - Abstract
Intravenous immunoglobulin (IVIg) is a common therapy for patients with immune thrombocytopenia (ITP). The initial response rate for IVIg is 80%[1][1] and is typically rapid, with some patients responding in 24 hours, although usually in 2–4 days.[2][2] When IVIg is used alone, the response is
- Published
- 2019
21. The use of artificial neural network analysis can improve the risk-stratification of patients presenting with suspected deep vein thrombosis
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John Willan, David Keeling, and Harley Katz
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Adult ,Male ,medicine.medical_specialty ,Proof of Concept Study ,Risk Assessment ,Fibrin Fibrinogen Degradation Products ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Medical imaging ,Medicine ,Blood test ,Humans ,False Negative Reactions ,Retrospective Studies ,Ultrasonography ,Venous Thrombosis ,Training set ,Artificial neural network ,medicine.diagnostic_test ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Venous thrombosis ,030220 oncology & carcinogenesis ,Suspected deep vein thrombosis ,Risk stratification ,Emergency medicine ,Female ,Neural Networks, Computer ,business ,Risk assessment ,Algorithms ,Biomarkers ,030215 immunology - Abstract
Artificial neural networks are machine-learning algorithms designed to analyse data without a pre-existing hypothesis as to any associations that may exist. This technique has not previously been applied to the risk stratification of patients referred with suspected deep vein thrombosis (DVT). Current assessment is usually with a points-based clinical score, which may be combined with a D-dimer blood test. A neural network was trained to risk-stratify patients presenting with suspected DVT and its performance compared with existing tools. Data from 11 490 cases of suspected DVT presenting consecutively between 1 January 2011 and 31 December 2017 were analysed, and 7080 for whom all components of the Wells' score, a D-dimer and an ultrasound result were available were included in the analysis. The data were broken into a training set of 5270 patients, used to develop the algorithm, and a testing set of 1810 patients to assess performance of the trained algorithm. This network was able to exclude DVT without the need for ultrasound in significantly more patients than existing risk assessment scores, whilst retaining very low false negatives rates. More generally, this approach may improve the analysis of complex data to support decision-making in other areas of clinical medicine.
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- 2018
22. Risk of Fracture Following Front Line R-CHOP Immunochemotherapy in Older Patients with Diffuse Large B Cell Lymphoma Is Common
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John Willan, Catherine Hildyard, Adam Gibb, Claire Higham, Arief Gunawan, Toby A. Eyre, Julia Wolf, Graham P. Collins, Joseph Andrew Browning, Patrick Horgan, Amy A Kirkwood, Joanna M Oladipo, Stephen Booth, Usman Khan, Paul Fields, Kim Linton, Jaimal Kothari, and Hannah Plaschkes
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,Front line ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Older patients ,Internal medicine ,Compact bone ,Medicine ,business ,Diffuse large B-cell lymphoma ,Diagnostic radiologic examination - Abstract
Introduction Diffuse large B cell lymphoma (DLBCL) and osteoporotic fracture are commoner in older patients (pts). Steroids and chemotherapy are recognised as a risk factor (RF) for fragility-related fracture and its associated morbidity. A small randomised trial (RCT) (Westin 2013) showed bisphosphonates stabilize bone mineral density (including all ages / histologies) in NHL pts. Despite this, there is a lack of data defining the specific incidence and fracture risk in older DLBCL pts post R-CHOP. We aimed to better define this risk in this specific cohort. Methods Data on consecutive DLBCL pts ≥70 years (y) treated with R-CHOP were retrospectively collected across 7 UK centres (2009-2019). Follow up was censored in 07/2019. All pts had untreated, de novo DLBCL or untreated transformed (to DLBCL) indolent B cell NHL. PTLD, HIV and pre-treated NHL pts were excluded. All pts received 1-9 cycles of full or attenuated R-CHOP with curative intent. Pts were excluded if they had progressive disease (PD) or died < 6 months (m) of cycle 1 R-CHOP (RCHOP1). A detailed anonymised database included ECOG performance status (PS), body mass index (BMI), history of osteoporosis / osteopenia, documented steroid pre-phase, vitamin D supplementation, calcium and alkaline phosphatase levels, and sites of bone DLBCL involvement. Fractures at diagnosis (DLBCL-related/unrelated) and pre diagnosis were collected. Fractures (including bone site) occurring during 18m from RCHOP1 were identified from radiology records. Pts were followed for a minimum of 6m and censored at 18m from RCHOP1, or at their last follow up if < 18m or at PD or death if between 6-18m. Baseline pt characteristics were descriptive. Survival analyses were performed using Kaplan Meier methods and Cox regression with comparisons between categories using the log-rank test. Time to event analyses were measured from RCHOP1 until fracture event. Primary end point was 18m cumulative fracture incidence censoring pts at death or relapse. Univariable and multivariable analyses (UVA; MVA) of potential influencing RFs for fracture was assessed by Cox regression (Final stepwise model; p=0.1 for inclusion). Results Of 589 pts identified, 92 pts had PD or died prior to 6m and were excluded. 20 pts were excluded due to short follow up. Across 477 pts, the median age was 77 (range 70-93) y. 66% had an ECOG PS 0-1. The median cycles given was 6 (range 1-9). 27.3% received pre-phase steroids. The median BMI was 25.5 (range 14.2-48.1). 8.1% had a fracture prior to DLBCL, and 9.1% had a history of osteopenia or osteoporosis. 5.7% were current smokers, 3% had rheumatoid arthritis, 13.5% had type (T) 2 diabetes (DM), and 4.5% had a history of excess alcohol. At baseline, 25.2% had PET or CT-assessed cortical bone involvement. Overall, there were 52 fractures, including 50 within 18m follow up. Cumulative fracture incidence was 6.3% (95% confidence interval (CI) 4.4 - 8.9) at 6m, 9.5% (95% CI 7.1 - 12.6) at 12m and 11.5% (95% CI 8.8 - 14.9) at 18m (Fig A). 6 pts had multiple fracture sites (2; n=5, 3; n=1). 32 (62%) had vertebral fracture(s). Thoracic (34% 20/59) and lumbar vertebral (27% 16/59) were dominant sites (Fig C). 7/52 fractures were at the site of DLBCL involvement, 17/52 were at a different site from initial bone DLBCL involvement, 27/52 were in pts without bone involvement and 1/52 was unknown. Univariable RFs included female sex (hazard ratio (HR) 1.89 (95% CI 1.05 - 3.28)), known osteopenia or osteoporosis (HR 2.64 (95% CI 1.32 - 5.29)), DLBCL-related fracture at diagnosis (HR 4.05 (95% CI 2.07 - 7.92) (Fig B). Initial bone involvement was only associated with an increased risk in pts with a DLBCL-related baseline fracture (95% CI HR 4.56 (2.27 - 9.17)) (Table 1). MVA showed that DLBCL-related baseline fracture (HR 4.32 (1.97 - 9.47)) was the only significant independent RF for fracture with low BMI (p=0.051) and smoking history (p=0.052) of borderline significance (Table 2). Conclusions This is the largest series to date to show there is a clinically relevant fracture risk in older DLBCL pts specifically receiving R-CHOP in early follow up. Our data have limitations inherent to a retrospective study including the potential for unknown confounders, missing data, and medical record misinterpretation. Prospective data is required to validate RFs identified which could enable targeting a high-risk population. An RCT is needed to determine the value of prophylactic intervention(s) in high risk pts. Figure Disclosures Gibb: Takeda: Research Funding. Collins:Gilead: Consultancy, Honoraria. Eyre:Janssen: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Roche: Honoraria.
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- 2019
23. Ibrutinib at First Relapse for Mantle Cell Lymphoma: A United Kingdom Real World Analysis of Outcomes in 169 Patients
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Harshita Goradia, Rory McCulloch, Helen Parry, Graham McIlroy, Andrew Robinson, Wendy Osborne, Alexander Langridge, Thomas Creasey, Jonathan Lambert, Neil Phillips, Nicola Crosbie, Deborah Turner, David Tucker, David J. Lewis, Simon Bolam, Shankara Paneesha, David Dutton, Helen McCarthy, Oliver Miles, Michelle Furtado, Simon Rule, Adam Bond, Mark Bishton, Nimish Shah, Gavin Campbell, Amir Shenouda, John Willan, Matthew R. Wilson, Toby A. Eyre, Luke Attwell, Samuel Harrison, Pamela McKay, and Annabel McMillan
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0301 basic medicine ,medicine.medical_specialty ,Univariate analysis ,business.industry ,Proportional hazards model ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Clinical trial ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,chemistry ,Median follow-up ,Internal medicine ,Ibrutinib ,Medicine ,Mantle cell lymphoma ,business ,Progressive disease ,030215 immunology - Abstract
Background: Ibrutinib has transformed the clinical approach to relapsed mantle cell lymphoma (MCL) with those receiving ibrutinib at first relapse obtaining the greatest benefit encouraging use earlier in the treatment algorithm (Rule et al, 2019). However, the general applicability of clinical trial findings is not established and concerns regarding ibrutinib tolerability persist, especially in non-trial populations enriched for frailer patients with multiple co-morbidities. In the United Kingdom, ibrutinib is funded as standard of care at first relapse. This study has analysed the clinical effectiveness and tolerability of this approach in a non-clinical trial real world population. Method: 23 centres across the United Kingdom contributed data from consecutive patients treated with ibrutinib for MCL at first relapse. Patients received standard dose 560 mg OD, unless documented, and commenced treatment between August 2014 and April 2019. Response to therapy was defined as per Lugano classification (Cheson et al, 2014), although CR assessment by bone marrow biopsy was not always undertaken. Data was collected on baseline characteristics, including response to prior therapy, and MIPI at time of relapse. The study primary outcome was PFS. Predictors of progression were determined using univariate Cox regression. Results: 169 patients were included in the study. Median age at start of ibrutinib was 72 years (range 33 to 97) and 122 (72.2%) were male. At diagnosis 13.5% had blastoid histology; 59.3% Ki67 ≥30%; 32.0% received cytarabine based induction and 27.8% HSCT consolidation; 11.2% received low intensity frontline therapy (i.e. not fit for R-CHOP) due to frailty. Median PFS following frontline therapy was 21.4 months (95% CI 14.6 to 28.3) and 52.1% progressed within 2 years. At start of ibrutinib 52.2% were MIPI high risk; 23.9% were ECOG 2 or higher and 2.4% had CNS involvement. Overall response rate (ORR) to ibrutinib was 71.6% with 30.4% achieving CR/CRu. Estimated median PFS from start of ibrutinib was 16.5 months (95% CI 11.5 to 21.5) and estimated OS 23.9 months (95% CI 13.0 to 34.8), with median follow up 26 months. Median PFS for patients with early relapse to frontline therapy (progression of disease 1 were also negative predictors of PFS (see table 1 for univariate analysis). 10 patients (5.9%) received attenuated dose from start of therapy due to frailty and 20 patients (11.8%) underwent dose reductions while on therapy due to drug toxicity. Of 109 patients to discontinue ibrutinib 72 (66.1%) were due to progressive disease, 15 for consolidation alloHSCT (13.8%), 13 due to medical co-morbidities and unrelated death (11.9%), and 9 due to drug toxicity (8.3%), including 1 bleed. Only 5.3% of all patients stopped therapy due to drug toxicity. Patients ≥80 yrs were more likely to stop therapy early for reasons other than progressive disease or alloHSCT (OR 2.92, p=0.02), but frailer patients who received low intensity frontline therapy also showed a trend for more durable response with second-line ibrutinib (PFS 10.0 months versus 4.0 months, p=0.36) justifying use in this patient group. Conclusion: This study population is enriched for several recognised adverse prognostic markers, including older age and poor performance status, which is likely to explain differences in PFS relative to clinical trial data. Despite these features response rates were similar, and it is notable that 46.7% of evaluable pts achieved longer PFS with ibrutinib than preceding front-line therapy. It is reassuring that the proportion of patients stopping ibrutinib due to toxicity was similar to trial data and bleeding events that required alterations to therapy were rare (3 cases, 1.8%). Although ibrutinib represents a significant breakthrough with clear benefit to most patients the results also highlight that outcome for many remains poor. 40% of patients progressed within 1 year of starting ibrutinib and median OS post ibrutinib was only 3.6 months. 35.2% of patients died within 1 month of documented relapse suggesting many, predominantly older patients, were not fit for further therapy. Of the 53 pts surviving beyond 1 month median OS was 7.5 months and 21.9% lived beyond 1 year. Improved treatment strategies in the post-ibrutinib setting remains a priority. Disclosures Rule: Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. Eyre:Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Furtado:Abbvie: Honoraria. Shah:ABBVIE: Consultancy. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. McKay:Epizyme: Consultancy, Honoraria. Osborne:Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy. Bishton:Takeda: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: Travel support, Research Funding. Crosbie:Janssen: Honoraria.
- Published
- 2019
24. Reducing the need for diagnostic imaging in suspected cases of deep vein thrombosis
- Author
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David Keeling and John Willan
- Subjects
Male ,Venous Thrombosis ,medicine.medical_specialty ,business.industry ,Deep vein ,Ultrasound ,Hematology ,Middle Aged ,medicine.disease ,Thrombosis ,Fibrin Fibrinogen Degradation Products ,medicine.anatomical_structure ,Predictive Value of Tests ,D-dimer ,Medical imaging ,Medicine ,Humans ,Female ,Radiology ,business ,Wells score ,Aged ,Retrospective Studies ,Ultrasonography - Published
- 2018
25. Multiple myeloma in the very elderly patient: challenges and solutions
- Author
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Andrew J. King, Caroline Watson, John Willan, Toby A. Eyre, Karthik Ramasamy, and Faye Sharpley
- Subjects
medicine.medical_specialty ,diagnosis ,media_common.quotation_subject ,Frail Elderly ,Comorbidity ,Review ,elderly ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Quality (business) ,Intensive care medicine ,Resilience (network) ,Elderly patient ,Multiple myeloma ,media_common ,Aged ,Randomized Controlled Trials as Topic ,Terminal Care ,Evidence-Based Medicine ,treatment ,business.industry ,Combination chemotherapy ,General Medicine ,Evidence-based medicine ,medicine.disease ,3. Good health ,myeloma ,030220 oncology & carcinogenesis ,Physical therapy ,Geriatrics and Gerontology ,business ,Multiple Myeloma ,End-of-life care ,030215 immunology - Abstract
Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life.
- Published
- 2016
26. A gene-driven ENU-based approach to generating an allelic series in any gene
- Author
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David Edwards, Lucie Vizor, Shelly Fuller, Emma Horner, Saffron Brady, Nicholas J. Parkinson, David I. Campbell, Emma L. Coghill, Richard McKeone, Zuzanna Lalanne, Steve D.M. Brown, Roger D. Cox, Pete Glenister, Ann F. C. Roberts, Susan Rodger, David A. Keays, Andy Greenfield, Nigel K. Spurr, Jessica Weedon, Alison Hugill, Mohamed M. Quwailid, Sara Wells, Ian C. Gray, Paul Woodman, Samuel G. Cox, John Willan, Jackie Hunter, Hamish McMath, Neil Dear, and Joanne Carey
- Subjects
Genetics ,Alkylating Agents ,Mutation rate ,DNA Mutational Analysis ,Mutagenesis (molecular biology technique) ,Biology ,Genome ,Phenotype ,Human genetics ,Mice ,chemistry.chemical_compound ,chemistry ,Ethylnitrosourea ,Mutation ,Animals ,Allele ,Gene ,Alleles ,Chromatography, High Pressure Liquid ,DNA - Abstract
N-ethyl-N-nitrosourea (ENU) introduces mutations throughout the mouse genome at relatively high efficiency. Successful high-throughput phenotype screens have been reported and alternative screens using sequence-based approaches have been proposed. For the purpose of generating an allelic series in selected genes by a sequence-based approach, we have constructed an archive of over 4000 DNA samples from individual F1 ENU-mutagenized mice paralleled by frozen sperm samples. Together with our previously reported archive, the total size now exceeds 6000 individuals. A gene-based screen of 27.4 Mbp of DNA, carried out using denaturing high-performance liquid chromatography (DHPLC), found a mutation rate of 1 in 1.01 Mbp of which 1 in 1.82 Mbp were potentially functional. Screening of whole or selected regions of genes on subsets of the archive has allowed us to identify 15 new alleles from 9 genes out of 15 tested. This is a powerful adjunct to conventional mutagenesis strategies and has the advantage of generating a variety of alleles with potentially different phenotypic outcomes that facilitate the investigation of gene function. It is now available to academic collaborators as a community resource.
- Published
- 2004
27. Candidate testis-determining gene, Maestro (Mro), encodes a novel HEAT repeat protein
- Author
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Pam Siggers, Gonzalo Blanco, Ruby Banerjee, Nick Van Hateren, Paul Denny, Rosario Romero, Chris P. Ponting, John Willan, Andy Greenfield, Lee B. Smith, and James Walsh
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Male ,Sex Differentiation ,Gonad ,Molecular Sequence Data ,Biology ,Mice ,Transcription (biology) ,Complementary DNA ,Gene expression ,medicine ,Animals ,Amino Acid Sequence ,Gonads ,Gene ,In Situ Hybridization, Fluorescence ,DNA Primers ,Oligonucleotide Array Sequence Analysis ,Radiation Hybrid Mapping ,Base Sequence ,Gonadal ridge ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Gene Expression Regulation, Developmental ,Sequence Analysis, DNA ,Sex reversal ,Molecular biology ,Testis determining factor ,medicine.anatomical_structure ,Sequence Alignment ,Cell Nucleolus ,Developmental Biology - Abstract
Mammalian sex determination depends on the presence or absence of SRY transcripts in the embryonic gonad. Expression of SRY initiates a pathway of gene expression resulting in testis development. Here, we describe a novel gene potentially functioning in this pathway using a cDNA microarray screen for genes exhibiting sexually dimorphic expression during murine gonad development. Maestro (Mro) transcripts are first detected in the developing male gonad before overt testis differentiation. By 12.5 days postcoitus (dpc), Mro transcription is restricted to the developing testis cords and its expression is not germ cell-dependent. No expression is observed in female gonads between 10.5 and 14.5 dpc. Maestro encodes a protein containing HEAT-like repeats that localizes to the nucleolus in cell transfection assays. Maestro maps to a region of mouse chromosome 18 containing a genetic modifier of XX sex reversal. We discuss the possible function of Maestro in light of these data. Developmental Dynamics 227:600–607, 2003. © 2003 Wiley-Liss, Inc.
- Published
- 2003
28. The Maestro (Mro) gene is dispensable for normal sexual development and fertility in mice
- Author
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John Willan, Richard M. Sharpe, Pam Siggers, Lee B. Smith, F. A. Brook, Nick Warr, Michael Cheeseman, and Andy Greenfield
- Subjects
Male ,Sex Differentiation ,Developmental Biology/Germ Cells ,Developmental Biology/Molecular Development ,Mice ,Testis ,Developmental Biology/Embryology ,Developmental Biology/Organogenesis ,Medicine(all) ,Genetics ,Multidisciplinary ,Agricultural and Biological Sciences(all) ,Developmental Biology/Morphogenesis and Cell Biology ,Genetics and Genomics/Functional Genomics ,Homozygote ,Days post coitum ,Gene Expression Regulation, Developmental ,Gene targeting ,Genetics and Genomics/Gene Expression ,Embryo ,Immunohistochemistry ,Null allele ,Genetics and Genomics/Gene Function ,medicine.anatomical_structure ,Medicine ,Female ,Research Article ,endocrine system ,Gonad ,Genetics and Genomics/Animal Genetics ,Science ,Biology ,Andrology ,medicine ,Animals ,Gonads ,Sertoli Cells ,Sexual differentiation ,Models, Genetic ,Biochemistry, Genetics and Molecular Biology(all) ,Embryo, Mammalian ,Mice, Inbred C57BL ,Sexual dimorphism ,Gene expression profiling ,Fertility ,Mutation ,Developmental Biology - Abstract
The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microarrays to screen for novel genes controlling the developmental fate of the indifferent embryonic mouse gonad. Maestro (Mro), which encodes a HEAT-repeat protein, was originally identified as a gene exhibiting sexually dimorphic expression during mouse gonad development. Wholemount in situ hybridisation analysis revealed Mro to be expressed in the embryonic male gonad from approximately 11.5 days post coitum, prior to overt sexual differentiation. No significant expression was detected in female gonads at the same developmental stage. In order to address its physiological function, we have generated mice lacking Maestro using gene targeting. Male and female mice homozygous for a Mro null allele are viable and fertile. We examined gonad development in homozygous male embryos in detail and observed no differences when compared to wild-type controls. Immunohistochemical analysis of homozygous mutant testes of adult mice revealed no overt abnormalities. Expression profiling using DNA microarrays also indicated no significant differences between homozygote embryonic male gonads and controls. We conclude that Maestro is dispensable for normal male sexual development and fertility in laboratory mice; however, the Mro locus itself does have utility as a site for insertion of transgenes for future studies in the fields of sexual development and Sertoli cell function.
- Published
- 2008
29. Candidate testis-determining gene, Maestro (Mro), encodes a novel HEAT repeat protein.
- Author
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Lee Smith, Nick Van Hateren, John Willan, Rosario Romero, Gonzalo Blanco, Pam Siggers, James Walsh, Ruby Banerjee, Paul Denny, Chris Ponting, and Andy Greenfield
- Published
- 2003
30. Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination
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Carole Oddoux, Andrew Friedman, Charles Farmer, Andrew H. Crosby, Johnny Loke, Nicholas Warr, Alexander Pearlman, Eric D. Brooks, Andy Greenfield, Lisa Chin, Shahin Shajahan, David Brauer, Jenny J. Couper, Tessa Homfray, Bridget Riley, Cédric Le Caignec, Albert David, John Willan, Harry Ostrer, Andrew H. Sinclair, Giovanna Camerino, and Stefan J. White
- Subjects
Male ,Gonad ,MAP Kinase Kinase Kinase 1 ,Gonadal dysgenesis ,Locus (genetics) ,Biology ,Report ,Testis ,WNT4 ,medicine ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Amino Acid Sequence ,Disorders of sex development ,Phosphorylation ,RSPO1 ,Gene ,Genetics (clinical) ,Disorder of Sex Development, 46,XY ,Sequence Homology, Amino Acid ,medicine.disease ,Molecular biology ,Pedigree ,medicine.anatomical_structure ,Testis determining factor ,Mutation ,Female ,Signal Transduction - Abstract
Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)—18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.
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