44 results on '"Graeme Black"'
Search Results
2. Cohort profile: rationale and methods of UK Biobank repeat imaging study eye measures to study dementia
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Martin McKibbin, Tariq Aslam, Sarah Barman, Jenny Barrett, Paul Bishop, Roxana Carare, Usha Chakravarthy, Michelle Chan, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John Gallacher, Jane Gibson, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Anthony Khawaja, Gerassimos Lascaratos, Andrew Lotery, Phil Luthert, Tom Macgillivray, Sarah Mackie, Bernadette Mcguinness, Gareth Mckay, Tony Moore, James Morgan, Eoin O’sullivan, Chris Owen, Praveen Patel, Euan Paterson, Axel Petzold, Alicja Rudnicka, Paul J Foster, Naomi Allen, Peng Tee Khaw, Praveen J Patel, Konstantinos Balaskas, Richard Oram, Robert Luben, Tasanee Braithwaite, Graeme Black, Christopher G Owen, Zihan Sun, David Garway-Heath, Thomas Littlejohns, Simon Sheard, Sharon Chua, Pearse Keane, Denize Atan, Savita Madhusudhan, and Alexander Doney
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Medicine - Abstract
Purpose The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40–69 enrolled in 2006–2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022–2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia.
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- 2023
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3. Genetic testing and diagnosis of inherited retinal diseases
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Byron L. Lam, Bart P. Leroy, Graeme Black, Tuyen Ong, Dan Yoon, and Karmen Trzupek
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Inherited retinal disease ,Ophthalmology ,Molecular diagnosis ,Genetic testing ,Genetic counseling ,Case studies ,Medicine - Abstract
Abstract Inherited retinal diseases (IRDs) are a diverse group of degenerative diseases of the retina that can lead to significant reduction in vision and blindness. Because of the considerable phenotypic overlap among IRDs, genetic testing is a critical step in obtaining a definitive diagnosis for affected individuals and enabling access to emerging gene therapy–based treatments and ongoing clinical studies. While advances in molecular diagnostic technologies have significantly improved the understanding of IRDs and identification of disease-causing variants, training in genetic diagnostics among ophthalmologists is limited. In this review, we will provide ophthalmologists with an overview of genetic testing for IRDs, including the types of available testing, variant interpretation, and genetic counseling. Additionally, we will discuss the clinical applications of genetic testing in the molecular diagnosis of IRDs through case studies.
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- 2021
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4. Unique Case of Bilateral Exudative Retinal Detachment following Creatine Supplementation in a Patient with Autosomal Dominant Bestrophinopathy
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Konstantinos Kopsidas, Hedayat Javidi, Simon P. Kelly, Tariq Aslam, Graeme Black, and Sajjad Mahmood
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creatine ,retina ,retinal dystrophy ,retinal detachment ,bestrophinopathy ,Ophthalmology ,RE1-994 - Abstract
We report a case of bilateral serous retinal detachment in a patient with rod-cone dystrophy caused by mutation of BEST1. This followed creatine monohydrate use as a dietary supplement. A 39-year-old male with rod-cone dystrophy and low hyperopia developed extensive bilateral exudative retinal detachment following creatine monohydrate diet supplementation. Five days after stopping creatine use, the bilateral retinal detachments resolved completely. This may indicate a causative relation of creatine supplementation to development of serous retinal detachment in a susceptible patient with pre-existing retinal dystrophy.
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- 2019
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5. LASER PROPHYLAXIS IN STICKLER SYNDROME
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Emma Linton, Assad Jalil, Panagiotis Sergouniotis, George Moussa, Graeme Black, Stephen Charles, and Tsveta Ivanova
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Ophthalmology ,General Medicine - Abstract
Patients with Stickler syndrome are at high risk of giant retinal tears (GRTs) and detachments. Vitreoretinal interventions can reduce this risk but there is presently no consensus about the optimal prophylactic approach. The aim of our study was to determine whether 360° laser prophylaxis is a safe and effective procedure to prevent GRT detachments in Stickler syndrome patients.Study subjects were recruited retrospectively through the databases of the vitreoretinal and ophthalmic genetic tertiary services in Manchester, UK. Clinical data were collected including on prophylactic intervention, the occurrence of retinal detachment and the presence/type of retinal breaks.113 eyes from 63 patients with Stickler syndrome were studied; 72.6% (82/113) of these eyes received 360° laser prophylaxis. Of these 9% had a retinal detachment, but no GRTs occurred. Among the 27.4% (31/113) of eyes that had no prophylactic treatment, 23% suffered a retinal detachment and 42.9% of these were associated with a GRT.Patients who underwent laser prophylaxis had fewer retinal detachments and no GRTs during an average of 6.1 years follow-up (median 5 years), suggesting that this is a safe and effective approach for individuals with Stickler syndrome.
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- 2023
6. Response to letter to editor regarding our recently published paper 'Laser Prophylaxis in Stickler Syndrome: The Manchester Protocol'
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Emma Linton, Assad Jalil, Panagiotis Sergouniotis, George Moussa, Graeme Black, Stephen Charles, and Tsveta Ivanova
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Ophthalmology ,General Medicine - Published
- 2023
7. A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration
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Rosie Clark, Samantha Sze-Yee Lee, Ran Du, Yining Wang, Sander C.M. Kneepkens, Jason Charng, Yu Huang, Michael L. Hunter, Chen Jiang, J.Willem L. Tideman, Ronald B. Melles, Caroline C.W. Klaver, David A. Mackey, Cathy Williams, Hélène Choquet, Kyoko Ohno-Matsui, Jeremy A. Guggenheim, Joan E. Bailey-Wilson, Paul N. Baird, Veluchamy A. Barathi, Ginevra Biino, Kathryn P. Burdon, Harry Campbell, Li Jia Chen, Ching-Yu Cheng, Emily Y. Chew, Jamie E. Craig, Margaret M. Deangelis, Cécile Delcourt, Xiaohu Ding, Qiao Fan, Maurizio Fossarello, Paul J. Foster, Puya Gharahkhani, Xiaobo Guo, Annechien E.G. Haarman, Toomas Haller, Christopher J. Hammond, Xikun Han, Caroline Hayward, Mingguang He, Alex W. Hewitt, Quan Hoang, Pirro G. Hysi, Adriana I. Iglesias, Robert P. Igo, Sudha K. Iyengar, Jost B. Jonas, Mika Kähönen, Jaakko Kaprio, Anthony P. Khawaja, Barbara E. Klein, Jonathan H. Lass, Kris Lee, Terho Lehtimäki, Deyana Lewis, Qing Li, Shi-Ming Li, Leo-Pekka Lyytikäinen, Stuart MacGregor, Nicholas G. Martin, Akira Meguro, Andres Metspalu, Candace Middlebrooks, Masahiro Miyake, Nobuhisa Mizuki, Anthony Musolf, Stefan Nickels, Konrad Oexle, Chi Pui Pang, Olavi Pärssinen, Andrew D. Paterson, Norbert Pfeiffer, Ozren Polasek, Jugnoo S. Rahi, Olli Raitakari, Igor Rudan, Srujana Sahebjada, Seang-Mei Saw, Claire L. Simpson, Dwight Stambolian, E-Shyong Tai, Milly S. Tedja, J. Willem L. Tideman, Akitaka Tsujikawa, Cornelia M. van Duijn, Virginie J.M. Verhoeven, Veronique Vitart, Ningli Wang, Ya Xing Wang, Juho Wedenoja, Wen Bin Wei, Katie M. Williams, James F. Wilson, Robert Wojciechowski, Jason C.S. Yam, Kenji Yamashiro, Maurice K.H. Yap, Seyhan Yazar, Shea Ping Yip, Terri L. Young, Xiangtian Zhou, Naomi Allen, Tariq Aslam, Denize Atan, Sarah Barman, Jenny Barrett, Paul Bishop, Graeme Black, Catey Bunce, Roxana Carare, Usha Chakravarthy, Michelle Chan, Sharon Chua, Valentina Cipriani, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Alexander Doney, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John Gallacher, David Garway-Heath, Jane Gibson, Dan Gore, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Pearse A. Keane, Peng Tee Khaw, Anthony Khawaja, Gerassimos Lascaratos, Thomas Littlejohns, Andrew Lotery, Phil Luthert, Tom MacGillivray, Sarah Mackie, Bernadette McGuinness, Gareth McKay, Martin McKibbin, Danny Mitry, Tony Moore, James Morgan, Zaynah Muthy, Eoin O'Sullivan, Chris Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Nikolas Pontikos, Jugnoo Rahi, Alicja Rudnicka, Jay Self, Panagiotis Sergouniotis, Sobha Sivaprasad, David Steel, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Robyn Tapp, Caroline Thaung, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Stephen Vernon, Ananth Viswanathan, Katie Williams, Jayne Woodside, Max Yates, Jennifer Yip, Yalin Zheng, Neurology, Ophthalmology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Epidemiology, Clinical Genetics, and Erasmus MC other
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All institutes and research themes of the Radboud University Medical Center ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] - Abstract
Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).
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- 2023
8. Supplementary Data from Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Robin L. Jones, Stanley R. Riddell, Robert H. Pierce, Cassian Yee, Brian A. Van Tine, Lee D. Cranmer, Venu G. Pillarisetty, Qianchuan He, Sydney M. Spadinger, Lu Yao, R. Graeme Black, Karan Kohli, and Shihong Zhang
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Supplementary Tables 1-3 and Supplementary Tables 1-6
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- 2023
9. Data from Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Robin L. Jones, Stanley R. Riddell, Robert H. Pierce, Cassian Yee, Brian A. Van Tine, Lee D. Cranmer, Venu G. Pillarisetty, Qianchuan He, Sydney M. Spadinger, Lu Yao, R. Graeme Black, Karan Kohli, and Shihong Zhang
- Abstract
Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.
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- 2023
10. Data from B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model
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Seth M. Pollack, Beverly Torok-Storb, Peter F. Moore, Stephen Gottschalk, Michael C. Jensen, Stanley R. Riddell, Alexander I. Salter, Bernard Seguin, Himaly Shinglot, Juliana Chi Kei Ng, Weiqing Jing, Ali Zhang, Amy B. Heimberger, Borislav A. Alexiev, Brian C. Schulte, Kraig Abrams, Brett A. Schroeder, Amanda Koehne, Cassandra Miller, Brian J. Hayes, Karan Kohli, R. Graeme Black, and Shihong Zhang
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One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy.Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed.In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.
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- 2023
11. Supplementary Figure from B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model
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Seth M. Pollack, Beverly Torok-Storb, Peter F. Moore, Stephen Gottschalk, Michael C. Jensen, Stanley R. Riddell, Alexander I. Salter, Bernard Seguin, Himaly Shinglot, Juliana Chi Kei Ng, Weiqing Jing, Ali Zhang, Amy B. Heimberger, Borislav A. Alexiev, Brian C. Schulte, Kraig Abrams, Brett A. Schroeder, Amanda Koehne, Cassandra Miller, Brian J. Hayes, Karan Kohli, R. Graeme Black, and Shihong Zhang
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Supplementary Figure from B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model
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- 2023
12. B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model
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Shihong Zhang, R. Graeme Black, Karan Kohli, Brian J. Hayes, Cassandra Miller, Amanda Koehne, Brett A. Schroeder, Kraig Abrams, Brian C. Schulte, Borislav A. Alexiev, Amy B. Heimberger, Ali Zhang, Weiqing Jing, Juliana Chi Kei Ng, Himaly Shinglot, Bernard Seguin, Alexander I. Salter, Stanley R. Riddell, Michael C. Jensen, Stephen Gottschalk, Peter F. Moore, Beverly Torok-Storb, and Seth M. Pollack
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Cancer Research ,B7 Antigens ,Dogs ,Receptors, Chimeric Antigen ,Oncology ,Cell Line, Tumor ,T-Lymphocytes ,Animals ,Humans ,Sarcoma ,Xenograft Model Antitumor Assays - Abstract
One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.
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- 2022
13. Supplementary Data from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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Seth M. Pollack, Robin L. Jones, Qianchuan He, Kimberly S. Smythe, Lauri Aicher, Pedro Hermida de Viveiros, Roxanne Moore, Rylee Johnson, Shannon Maxwell, Sabrina McDonnell, Graeme Black, Elizabeth T. Loggers, Lee D. Cranmer, Yuzheng Zhang, and Michael J. Wagner
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Supplementary Data from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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- 2023
14. Supplementary Figure from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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Seth M. Pollack, Robin L. Jones, Qianchuan He, Kimberly S. Smythe, Lauri Aicher, Pedro Hermida de Viveiros, Roxanne Moore, Rylee Johnson, Shannon Maxwell, Sabrina McDonnell, Graeme Black, Elizabeth T. Loggers, Lee D. Cranmer, Yuzheng Zhang, and Michael J. Wagner
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Supplementary Figure from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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- 2023
15. Data from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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Seth M. Pollack, Robin L. Jones, Qianchuan He, Kimberly S. Smythe, Lauri Aicher, Pedro Hermida de Viveiros, Roxanne Moore, Rylee Johnson, Shannon Maxwell, Sabrina McDonnell, Graeme Black, Elizabeth T. Loggers, Lee D. Cranmer, Yuzheng Zhang, and Michael J. Wagner
- Abstract
Purpose:Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti–PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma.Patients and Methods:A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression.Results:33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01).Conclusions:Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
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- 2023
16. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies
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Malena Daich Varela, James Bellingham, Fabiana Motta, Neringa Jurkute, Jamie M Ellingford, Mathieu Quinodoz, Kathryn Oprych, Michael Niblock, Lucas Janeschitz-Kriegl, Karolina Kaminska, Francesca Cancellieri, Hendrik P N Scholl, Eva Lenassi, Elena Schiff, Hannah Knight, Graeme Black, Carlo Rivolta, Michael E Cheetham, Michel Michaelides, Omar A Mahroo, Anthony T Moore, Andrew R Webster, and Gavin Arno
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Patient Care Team ,Genetics & Heredity ,Whole Genome Sequencing ,DNA Mutational Analysis ,Human Genome ,Membrane Proteins ,Nerve Tissue Proteins ,General Medicine ,Biological Sciences ,Medical and Health Sciences ,Pedigree ,Clinical Research ,Mutation ,Retinal Dystrophies ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Eye Proteins ,Molecular Biology ,Genetics (clinical) - Abstract
The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.
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- 2023
17. The Association of Alcohol Consumption with Glaucoma and Related Traits
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Kelsey V. Stuart, Robert N. Luben, Alasdair N. Warwick, Kian M. Madjedi, Praveen J. Patel, Mahantesh I. Biradar, Zihan Sun, Mark A. Chia, Louis R. Pasquale, Janey L. Wiggs, Jae H. Kang, Jihye Kim, Hugues Aschard, Jessica H. Tran, Marleen A.H. Lentjes, Paul J. Foster, Anthony P. Khawaja, Mark Chia, Sharon Chua, Ron Do, Paul Foster, Jae Kang, Alan Kastner, Anthony Khawaja, Marleen Lentjes, Robert Luben, Kian Madjedi, Giovanni Montesano, Louis Pasquale, Kelsey Stuart, Alasdair Warwick, Janey Wiggs, Naomi Allen, Tariq Aslam, Denize Atan, Sarah Barman, Jenny Barrett, Paul Bishop, Graeme Black, Tasanee Braithwaite, Roxana Carare, Usha Chakravarthy, Michelle Chan, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Alexander Doney, Cathy Egan, Sarah Ennis, Marcus Fruttiger, John Gallacher, David (Ted) Garway-Heath, Jane Gibson, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Pearse Keane, Peng Tee Khaw, Gerassimos Lascaratos, Thomas Littlejohns, Andrew Lotery, Phil Luthert, Tom MacGillivray, Sarah Mackie, Bernadette McGuinness, Gareth McKay, Martin McKibbin, Tony Moore, James Morgan, Eoin O'Sullivan, Richard Oram, Chris Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Nikolas Pontikos, Jugnoo Rahi, Alicja Rudnicka, Naveed Sattar, Jay Self, Panagiotis Sergouniotis, Sobha Sivaprasad, David Steel, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Robyn Tapp, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Ananth Viswanathan, Veronique Vitart, Mike Weedon, Katie Williams, Cathy Williams, Jayne Woodside, Max Yates, Jennifer Yip, Yalin Zheng, Tin Aung, Kathryn Burdon, Li Chen, Ching-Yu Cheng, Jamie Craig, Angela Cree, Victor de Vries, Sjoerd Driessen, John Fingert, Puya Gharahkhani, Christopher Hammond, Caroline Hayward, Alex Hewitt, Nomdo Jansonius, Fridbert Jonansson, Jost Jonas, Michael Kass, Chiea Khor, Caroline Klaver, Jacyline Koh, Stuart MacGregor, David Mackey, Paul Mitchell, Calvin Pang, Francesca Pasutto, Norbert Pfeiffer, Ozren Polašek, Wishal Ramdas, Alexander Schuster, Ayellet Segrè, Einer Stefansson, Kári Stefánsson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Cornelia van Duijn, Joëlle Vergroesen, Eranga Vithana, James Wilson, Robert Wojciechowski, Tien Wong, and Terri Young
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General Medicine - Published
- 2022
18. 93 PCR assay to identify woodchuck hepatitis virus posttranscriptional regulatory element in CAR-T and TCR-T cells for fresh and formalin-fixed samples
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Shalini Pullarkat, Jocelyn Wright, David Woolston, Erik Kimble, Bo Lee, Alexandre Hirayama, Aude Chapuis, Denise Buenrostro, Graeme Black, Marie Bleakley, Brandon Seaton, Jennifer Specht, Cameron Turtle, and Cecilia Yeung
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- 2022
19. The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
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Tomas Fitzgerald, Ewan Birney, Panos Sergouniotis, Graeme Black, and Benoit Arveiler
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.
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- 2022
20. Enlarged Vestibular Aqueduct: Disease Characterization and Exploration of Potential Prognostic Factors for Cochlear Implantation
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Haroon S. Saeed, Azita Rajai, Robert Nash, Shakeel R. Saeed, Stavros M. Stivaros, Graeme Black, and Iain A. Bruce
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Male ,Hearing Loss, Sensorineural ,Deafness ,Prognosis ,Cochlear Implantation ,Sensory Systems ,Vestibular Aqueduct ,Otorhinolaryngology ,Child, Preschool ,Humans ,Female ,Neurology (clinical) ,Hearing Loss ,Retrospective Studies - Abstract
There is an unmet need to match the anticipated natural history of hearing loss (HL) in enlarged vestibular aqueduct (EVA) with clinical management strategies. The objectives of this study are therefore to provide a detailed case characterization of an EVA cohort and explore the relationship between candidate prognostic factors and timing of cochlear implant (CI) surgery.A multicenter retrospective review of patients diagnosed with EVA.Patient data recruitment across three CI centers in the UK.One hundred fifty patients with a radiological diagnosis of EVA from January 1995 to January 2021.Age at audiological candidacy for CI and age at first implant surgery.EVA was predominately a bilateral condition (144/ 150) with increased prevalence in women (M:F, 64:86). 51.7% of patients failed new-born hearing screening, with 65.7% having HL diagnosed by 1 year. Initial moderate to severe and severe to profound HL were reported most frequently. In 123 patients, median age that audiological candidacy for CI was met for at least one ear was 2.75 years. Median age at first CI was 5 years (140/150).Pendred syndrome (confirmed in 73 patients) and ethnicity, were not significantly associated with earlier CI surgery. Multivariate linear regression demonstrated that male patients have first CI surgery significantly earlier than females (coefficient -0.43, 95% CI [-0.82, -0.05), p-value = 0.028).This large UK EVA cohort provides evidence that patients should be closely monitored for CI candidacy within the first 3 years of life. Significantly, male gender is emerging as an independent prognostic factor for earlier assessment and first CI surgery.
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- 2022
21. A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
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Michael J. Wagner, Yuzheng Zhang, Lee D. Cranmer, Elizabeth T. Loggers, Graeme Black, Sabrina McDonnell, Shannon Maxwell, Rylee Johnson, Roxanne Moore, Pedro Hermida de Viveiros, Lauri Aicher, Kimberly S. Smythe, Qianchuan He, Robin L. Jones, and Seth M. Pollack
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Leiomyosarcoma ,Cancer Research ,Oncology ,Leukocytes, Mononuclear ,Humans ,Liposarcoma ,Antibodies, Monoclonal, Humanized ,Antineoplastic Agents, Alkylating ,B7-H1 Antigen ,Article ,Trabectedin - Abstract
Purpose: Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti–PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. Patients and Methods: A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. Results: 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01). Conclusions: Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
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- 2022
22. DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration
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Anjali Vig, James A. Poulter, Daniele Ottaviani, Erika Tavares, Katerina Toropova, Anna Maria Tracewska, Antonio Mollica, Jasmine Kang, Oshini Kehelwathugoda, Tara Paton, Jason T. Maynes, Gabrielle Wheway, Gavin Arno, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, C. Patch, D. Perez-Gil, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Kamron N. Khan, Martin McKibbin, Carmel Toomes, Manir Ali, Matteo Di Scipio, Shuning Li, Jamie Ellingford, Graeme Black, Andrew Webster, Małgorzata Rydzanicz, Piotr Stawiński, Rafał Płoski, Ajoy Vincent, Michael E. Cheetham, Chris F. Inglehearn, Anthony Roberts, and Elise Heon
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0301 basic medicine ,Proband ,Retinal degeneration ,intraflagellar transport (IFT) ,Cytoplasmic Dyneins ,Ellis-Van Creveld Syndrome ,030105 genetics & heredity ,Biology ,Article ,Retina ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,primary cilia ,medicine ,Organoid ,Missense mutation ,Humans ,Induced pluripotent stem cell ,Genetics (clinical) ,Exome sequencing ,Retinal Degeneration ,Retinal ,Exons ,DYNC2H1 ,medicine.disease ,Molecular biology ,retinitis pigmentosa (RP) ,Pedigree ,inherited retinal disease (IRD) ,030104 developmental biology ,chemistry ,Mutation - Abstract
Purpose Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Methods Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). Conclusion The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
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- 2020
23. Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen
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Rachel L. Taylor, James A. Poulter, Susan M. Downes, Martin McKibbin, Kamron N. Khan, Chris F. Inglehearn, Andrew R. Webster, Alison J. Hardcastle, Michel Michaelides, Paul N. Bishop, Simon J. Clark, Graeme C. Black, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Taylor, Forbes Manson, Panagiotis Sergouniotis, Andrew Webster, Alison Hardcastle, Vincent Plagnol, Nikolas Pontikos, Michael Cheetham, Gavin Arno, Alessia Fiorentino, Chris Inglehearn, Carmel Toomes, Manir Ali, Claire Smith, Kamron Khan, Susan Downes, Jing Yu, Stephanie Halford, Suzanne Broadgate, and Veronica van Heyningen
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Male ,Muscle Proteins ,Retinal Drusen ,Drusen ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Exome sequencing ,Aged ,Retrospective Studies ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,biology ,business.industry ,Intracellular Signaling Peptides and Proteins ,Genetic Variation ,LIM Domain Proteins ,Middle Aged ,Macular degeneration ,medicine.disease ,eye diseases ,3. Good health ,Complement system ,Ophthalmology ,Complement Factor H ,Factor H ,030221 ophthalmology & optometry ,biology.protein ,Female ,sense organs ,Haploinsufficiency ,business ,Complement control protein - Abstract
Purpose To characterize the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe subtype of age-related macular degeneration (AMD), in a subgroup of patients. Design Multicenter case series, in vitro experimentation, and retrospective analysis of previously reported variants. Participants Seven families with apparently autosomal dominant EOMD. Methods Patients underwent a comprehensive ophthalmic assessment. Affected individuals from families A, B, and E underwent whole exome sequencing. The probands from families C, D, F, and G underwent Sanger sequencing analysis of the complement factor H (CFH) gene. Mutant recombinant factor H like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed. Main Outcome Measures Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD. Results All affected participants demonstrated bilateral drusen. The earliest reported age of onset was 16 years (median, 46 years). Ultra-rare (minor allele frequency [MAF], ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G→T het; c.619+1G→A het, c.380G→A, p.(Arg127His) het; c.694C→T p.(Arg232Ter) het (identified in 2 unrelated families in this cohort); and c.1291T→A, p.(Cys431Ser). All mutations affect complement control protein domains 2 through 7, and thus are predicted to impact both FHL-1, the predominant isoform in Bruch’s membrane (BrM) of the macula, and factor H (FH). In vitro analysis of recombinant proteins FHL-1R127H, FHL-1A415f/s, and FHL-1C431S demonstrated that they are not secreted, and thus are loss-of-function proteins. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) impact FHL-1 and FH. In total, 86.2% (25/29) of EOMD-associated variants cause haploinsufficiency of FH or FHL-1. Conclusions Early-onset macular drusen is an underrecognized, phenotypically severe subtype of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathologic similarities.
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- 2019
24. Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Stanley R. Riddell, Venu G. Pillarisetty, Qianchuan He, Cassian Yee, Robin L. Jones, Robert H. Pierce, R. Graeme Black, Lee D. Cranmer, Shihong Zhang, Brian A. Van Tine, Sydney Spadinger, Lu Yao, and Karan Kohli
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Biopsy ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Major histocompatibility complex ,Article ,Immunophenotyping ,Interferon-gamma ,Sarcoma, Synovial ,Young Adult ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,MHC class I ,medicine ,Humans ,Aged ,Tumor microenvironment ,biology ,business.industry ,Histocompatibility Antigens Class I ,Immunotherapy ,Middle Aged ,Liposarcoma, Myxoid ,Tumor antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Cytokines ,Female ,business ,Biomarkers - Abstract
Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.
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- 2019
25. 139 Establishment of canine CAR T cells treatment model for solid tumor immunotherapy development
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Karan Kohli, R. Graeme Black, Kraig Abrams, Peter F Moore, Beverly Torok-Storb, Brett Schroeder, Mari Maeda-Whitaker, Stephen Gottschalk, Brian Hayes, Seth M. Pollack, Cassandra Miller, Bernard Séguin, and Shihong Zhang
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Cetuximab ,medicine.diagnostic_test ,biology ,Canine Sarcoma ,business.industry ,medicine.medical_treatment ,T cell ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Chimeric antigen receptor ,Flow cytometry ,medicine.anatomical_structure ,medicine ,Cancer research ,biology.protein ,Immunohistochemistry ,Antibody ,business ,medicine.drug - Abstract
Background Chimeric antigen receptor (CAR) T cell therapy has transformed therapy for hematological malignancies but has not yet been established as standard of care for any solid tumors. One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant, immunocompetent animal models. In this study, we sought to establish CAR T cells for naturally occurring canine sarcomas in client owned animals as a model for human CAR T cell therapy. Methods Archived FFPE, freshly isolated canine solid tumor samples as well as tumor lines were tested for B7H3 expression by immunohistochemistry (IHC) and flow cytometry analysis. We designed CARs using the scFv from the human B7H3-specific antibody MGA271 and confirmed the cross-reactivity to canine B7H3 (construct information see figure 1A). A truncated EGFR (tEGFR) was included in the construct to allow for IHC and flow cytometry testing for the presence of CAR T cells. Killing efficiency was evaluated using 3D tumor spheroid killing assays to monitor dynamics. Safety of the CAR products following lymphodepletion was confirmed in two healthy dogs (figure 1B). Results Canine solid tumors were confirmed to be B7H3 positive in almost all cases. Using the GALV-pseudotyped retrovirus system, transduction was efficient with up to 70% CAR+ cells. Post-transduction expansion was over 100 folds. B7H3 CAR transduced canine T cells were able to eliminate B7H3+ canine tumor spheroids effectively (figure 2). Safety of the CAR T cells (dose: 1 × 109/m2) were confirmed in both healthy animals following cyclophosphamide lymphodepletion. After week 6, cetuximab was given to the subjects to deplete EGFR+ cells. Subject 2 experienced fever after CAR T cell administration. Both dogs showed elevated serum ALP and ALT levels and returned to normal (figure 3). No other treatment-related adverse events were observed. Information of the CAR T cell products can be found in table 1. Conclusions We demonstrated that, similar to human cancers, B7H3 is a target in canine solid tumors. We successfully generated canine B7H3 specific CAR T cell products that are highly efficient at killing canine 3D tumor spheroids using a production protocol that closely models human CAR T cell production procedure and confirmed the safety in vivo. We plan to test and optimize various approaches to enhance CAR T cell efficacy for solid tumor treatment both in vitro and in canine sarcoma patients. Ethics Approval The study was approved by Fred Hutchinson Cancer Research Center‘s Institutional Animal Care and Use Committee (IACUC), approval number PROTO201900860
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- 2020
26. Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial
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Lee D. Cranmer, Mary W. Redman, Roxanne Moore, Elizabeth T. Loggers, Michael J. Wagner, Brett Schroeder, Rylee Johnson, Seth M. Pollack, Graeme Black, Sabrina McDonnell, Jeffrey Gregory, Shihong Zhang, Kelsey Baker, Vanessa C. Copeland, Robin L. Jones, and Kathryn Trieselmann
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Anthracycline ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Undifferentiated Pleomorphic Sarcoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,Anthracyclines ,030212 general & internal medicine ,Aged ,Aged, 80 and over ,Performance status ,business.industry ,Brief Report ,Sarcoma ,Middle Aged ,medicine.disease ,Clinical trial ,Doxorubicin ,030220 oncology & carcinogenesis ,Female ,Embryonal rhabdomyosarcoma ,business - Abstract
Importance Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes. Objective To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas. Design, Setting, and Participants This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma. Interventions Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab. Main Outcomes and Measures Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines. Results A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rankP = .03). No dose-limiting toxic effects were observed. Conclusions and Relevance In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Trial Registration ClinicalTrials.gov Identifier:NCT02888665
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- 2020
27. Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy
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Jianhong Cao, Jose G. Mantilla, Brett Schroeder, Shihong Zhang, Karan Kohli, Robin L. Jones, Sydney Spadinger, Ernest U. Conrad, Ralph Graeme Black, Cassian Yee, Seth M. Pollack, and Stanley R. Riddell
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Myocarditis ,sarcoma ,Cyclophosphamide ,medicine.medical_treatment ,Immunology ,Case Report ,Major histocompatibility complex ,Antiviral Agents ,Immunotherapy, Adoptive ,Lymphocyte Depletion ,03 medical and health sciences ,Interferon-gamma ,Sarcoma, Synovial ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Humans ,Interferon gamma ,Antineoplastic Agents, Alkylating ,Histiocyte ,RC254-282 ,Pharmacology ,biology ,Clinical Trials, Phase I as Topic ,business.industry ,Interleukin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Histiocytes ,Immunotherapy ,medicine.disease ,Prognosis ,Regimen ,030104 developmental biology ,030220 oncology & carcinogenesis ,oncology ,biology.protein ,Molecular Medicine ,CD8-positive T-lymphocytes ,Drug Therapy, Combination ,business ,medicine.drug - Abstract
BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.
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- 2020
28. 139 Establishment of canine CAR T cells treatment model for solid tumor immunotherapy development
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Zhang, Shihong, primary, Kohli, Karan, additional, Graeme Black, R, additional, Hayes, Brian, additional, Miller, Cassandra, additional, Maeda-Whitaker, Mari, additional, Schroeder, Brett, additional, Abrams, Kraig, additional, Seguin, Bernard, additional, Gottschalk, Stephen, additional, Moore, Peter, additional, Torok-Storb, Beverly, additional, and Pollack, Seth, additional
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- 2020
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29. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy
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Theodore S. Nowicki, Antoni Ribas, Venu G. Pillarisetty, Cassian Yee, Brett Schroeder, Lee D. Cranmer, Jianhong Cao, Michael J. Wagner, Karan Kohli, Ralph Graeme Black, Lu Yao, Erik A. Farrar, Douglas S. Hawkins, Dawn Stief, Jean S. Campbell, Stanley R. Riddell, Edward Y. Kim, Heather L. Sloan, Seth M. Pollack, Shihong Zhang, Robert H. Pierce, and Robin L. Jones
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Cytotoxicity, Immunologic ,Cancer Research ,Adoptive cell transfer ,Transplantation Conditioning ,Time Factors ,Cytotoxicity ,medicine.medical_treatment ,Adoptive ,Pilot Projects ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Immunologic ,antigens ,Tumor Microenvironment ,Immunology and Allergy ,Medicine ,Neoplasm ,RC254-282 ,Cancer ,Interleukin-15 ,Tumor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Sarcoma ,Liposarcoma ,Middle Aged ,Liposarcoma, Myxoid ,Treatment Outcome ,Oncology ,Interleukin 15 ,Molecular Medicine ,immunotherapy ,Development of treatments and therapeutic interventions ,Biotechnology ,medicine.drug ,Adult ,Cyclophosphamide ,Clinical Trials and Supportive Activities ,Immunology ,cell engineering ,adoptive ,Peripheral blood mononuclear cell ,Cell Line ,Vaccine Related ,Sarcoma, Synovial ,Memory T Cells ,Rare Diseases ,Antigen ,Antigens, Neoplasm ,Clinical Research ,Cell Line, Tumor ,Genetics ,Humans ,Cell Proliferation ,Pharmacology ,Immune Cell Therapies and Immune Cell Engineering ,Synovial ,5.2 Cellular and gene therapies ,business.industry ,Membrane Proteins ,Immunotherapy ,Myeloablative Agonists ,medicine.disease ,immunity ,Coculture Techniques ,cytokines ,Orphan Drug ,Cancer research ,Myxoid ,business ,Immunologic Memory ,cellular ,neoplasm ,Ex vivo - Abstract
Author(s): Kohli, Karan; Yao, Lu; Nowicki, Theodore Scott; Zhang, Shihong; Black, Ralph Graeme; Schroeder, Brett A; Farrar, Erik A; Cao, Jianhong; Sloan, Heather; Stief, Dawn; Cranmer, Lee D; Wagner, Michael J; Hawkins, Douglas S; Pillarisetty, Venu G; Ribas, Antoni; Campbell, Jean; Pierce, Robert H; Kim, Edward Y; Jones, Robin L; Riddell, Stanley R; Yee, Cassian; Pollack, Seth M | Abstract: BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
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- 2021
30. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration
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Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
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Male ,0301 basic medicine ,Retinal degeneration ,Biallelic Mutation ,RHOA ,PROTEIN ,Eye ,Medical and Health Sciences ,ACTIVATION ,chemistry.chemical_compound ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Missense mutation ,Exome ,Aetiology ,Genetics (clinical) ,Genetics & Heredity ,Genetics ,biology ,Retinal Degeneration ,Cell Polarity ,MOSAIC EYES ,Biological Sciences ,Middle Aged ,Phenotype ,inherited retinal dystrophy ,Pedigree ,UK Inherited Retinal Disease Consortium ,Female ,apicobasal polarity ,Retinal Dystrophies ,Adult ,NIHR Bioresource - Rare Diseases Consortium ,ARHGEF18 ,Genotype ,Mutation, Missense ,Nerve Tissue Proteins ,Retina ,03 medical and health sciences ,Rare Diseases ,retinitis pigmentosa ,Report ,CRB1 ,Retinitis pigmentosa ,medicine ,Humans ,Amino Acid Sequence ,Eye Proteins ,Eye Disease and Disorders of Vision ,Alleles ,Human Genome ,Neurosciences ,Genetic Variation ,Membrane Proteins ,Epithelial Cells ,Retinal ,CELL FEATURES ,medicine.disease ,NUCLEOTIDE EXCHANGE FACTOR ,p114RhoGEF ,030104 developmental biology ,INTEGRATIVE GENOMICS VIEWER ,OKO-MEDUZY ,chemistry ,Mutation ,MORPHOGENESIS ,030221 ophthalmology & optometry ,biology.protein ,Missense ,rhoA GTP-Binding Protein ,Rho Guanine Nucleotide Exchange Factors ,Genome-Wide Association Study - Abstract
Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
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- 2017
31. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis
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Axel Petzold, Laura J Balcer, Peter A Calabresi, Fiona Costello, Teresa C Frohman, Elliot M Frohman, Elena H Martinez-Lapiscina, Ari J Green, Randy Kardon, Olivier Outteryck, Friedemann Paul, Sven Schippling, Patrik Vermersch, Pablo Villoslada, Lisanne J Balk, Orhan Aktas, Philipp Albrecht, Jane Ashworth, Nasrin Asgari, Laura Balcer, Lisanne Balk, Graeme Black, Daniel Boehringer, Raed Behbehani, Leslie Benson, Robert Bermel, Jacqueline Bernard, Alexander Brandt, Jodie Burton, Peter Calabresi, Jonathan Calkwood, Christian Cordano, Ardith Courtney, Andrés Cruz-Herranz, Ricarda Diem, Avril Daly, Helene Dollfus, Christina Fasser, Carsten Finke, Jette Frederiksen, Elliot Frohman, Teresa Frohman, Elenaw Garcia-Martin, Inés González Suárez, Gorm Pihl-Jensen, Jennifer Graves, Ari Green, Joachim Havla, Bernhard Hemmer, Su-Chun Huang, Jaime Imitola, Hong Jiang, David Keegan, Eric Kildebeck, Alexander Klistorner, Benjamin Knier, Scott Kolbe, Thomas Korn, Bart LeRoy, Letizia Leocani, Dorothee Leroux, Netta Levin, Petra Liskova, Birgit Lorenz, Jana Lizrova Preiningerova, Elena Hernández Martínez-Lapiscina, Janine Mikolajczak, Xavier Montalban, Mark Morrow, Rachel Nolan, Timm Oberwahrenbrock, Frederike Cosima Oertel, Celia Oreja-Guevara, Benjamin Osborne, Athina Papadopoulou, Marius Ringelstein, Shiv Saidha, Bernardo Sanchez-Dalmau, Jaume Sastre-Garriga, Robert Shin, Neil Shuey, Kerstin Soelberg, Ahmed Toosy, Rubén Torres, Angela Vidal-Jordana, Amy Waldman, Owen White, Ann Yeh, Sui Wong, Hanna Zimmermann, Ophthalmology, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Mental Health, APH - Methodology, Neurology, Petzold, A, Balcer, Lj, Calabresi, Pa, Costello, F, Frohman, Tc, Frohman, Em, Martinez-Lapiscina, Eh, Green, Aj, Kardon, R, Outteryck, O, Paul, F, Schippling, S, Vermersch, P, Villoslada, P, Balk, Lj, on behalf of ERN-EYE, Imsvisual, and Leocani, L
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Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Optic Neuritis ,genetic structures ,Nerve fiber layer ,Retina ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Atrophy ,Optical coherence tomography ,Ophthalmology ,Multiple Sclerosi ,medicine ,Humans ,Optic neuritis ,Aged ,Neuromyelitis optica ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Optic Neuriti ,Retinal ,Middle Aged ,medicine.disease ,eye diseases ,medicine.anatomical_structure ,chemistry ,030221 ophthalmology & optometry ,Optometry ,Female ,Neurology (clinical) ,sense organs ,business ,030217 neurology & neurosurgery ,Tomography, Optical Coherence ,Human - Abstract
Background Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. Methods In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Findings Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference â20·10 μm, 95% CI â22·76 to â17·44; p
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- 2017
32. Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular Involvement
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Mohammed E. El-Asrag, Panagiotis I. Sergouniotis, Martin McKibbin, Vincent Plagnol, Eamonn Sheridan, Naushin Waseem, Zakia Abdelhamed, Declan McKeefry, Kristof Van Schil, James A. Poulter, Colin A. Johnson, Ian M. Carr, Bart P. Leroy, Elfride De Baere, Chris F. Inglehearn, Andrew R. Webster, Carmel Toomes, Manir Ali, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Simon Ramsden, Forbes Manson, Alison Hardcastle, Michel Michaelides, Michael Cheetham, Gavin Arno, Niclas Thomas, Shomi Bhattacharya, Tony Moore, Andrea Nemeth, Susan Downes, Stefano Lise, and Emma Lord
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Adult ,Molecular Sequence Data ,Biology ,Compound heterozygosity ,Frameshift mutation ,Macular Degeneration ,chemistry.chemical_compound ,symbols.namesake ,Report ,Retinal Dystrophies ,Genetics ,Humans ,Exome ,Pakistan ,Genetics (clinical) ,Exome sequencing ,Sanger sequencing ,Base Sequence ,Homozygote ,Membrane Proteins ,Retinal ,Sequence Analysis, DNA ,Disease gene identification ,Immunohistochemistry ,United Kingdom ,Pedigree ,chemistry ,Mutation ,symbols - Abstract
Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs∗3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165∗] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.
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- 2015
33. Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy
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Andrew Mumford, Carmel Toomes, David Bennett, Mark Toshner, Alessia Fiorentino, Michael Cheetham, Anton Vonk noordegraaf, David Allsup, Nikolas Pontikos, Matthew A Brown, Mohammed Elasrag, Michel Michaelides, Roger James, Claire Booth, Dorothy Thompson, Keren Carss, James Poulter, Daniel Gale, Sinisa Savic, Graeme Black, WASEEM QASIM, Johan Heemskerk, Allan Lawrie, and Saghar Bagheri, MD, PhD
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Adult ,Male ,genetic structures ,Retinal dystrophy ,education ,DNA Mutational Analysis ,Presynaptic Terminals ,Biology ,Photoreceptor synapse ,Immunohistology ,03 medical and health sciences ,0302 clinical medicine ,Dna genetics ,Retinitis pigmentosa ,Retinal Dystrophies ,Electroretinography ,medicine ,Humans ,Exome ,DNA sequencing ,Microscopy, Confocal ,Blindness ,Macular degeneration ,Homozygote ,A protein ,High-Throughput Nucleotide Sequencing ,Membrane Transport Proteins ,Anatomy ,DNA ,Middle Aged ,medicine.disease ,eye diseases ,Pedigree ,Multicenter study ,Research centre ,Mutation ,030221 ophthalmology & optometry ,Optometry ,Female ,sense organs ,030217 neurology & neurosurgery ,Photoreceptor Cells, Vertebrate - Abstract
PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.
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- 2017
34. Incidence and patterns of detection and management of childhood-onset hereditary retinal disorders in the UK
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Jugnoo Rahi, Kevin Gregory-Evans, Esther Hamblion, Graeme Black, and Marcela Votruba
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Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Cross-sectional study ,Visual impairment ,Population ,Vision Disorders ,Comorbidity ,Risk Assessment ,Cellular and Molecular Neuroscience ,Age Distribution ,Surveys and Questionnaires ,Retinal Dystrophies ,Epidemiology ,medicine ,Humans ,Cumulative incidence ,Prospective Studies ,Sex Distribution ,Child ,education ,Prospective cohort study ,education.field_of_study ,business.industry ,Incidence ,Incidence (epidemiology) ,Infant ,Eye Diseases, Hereditary ,medicine.disease ,United Kingdom ,Sensory Systems ,Ophthalmology ,Cross-Sectional Studies ,Child, Preschool ,Female ,medicine.symptom ,business - Abstract
Background: A prospective, national population-based cross-sectional study to enable understanding of the burden and management in the UK of hereditary retinal disorders presenting in childhood. Methods: Children aged
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- 2011
35. A synonymous codon variant in two patients with autosomal recessive bestrophinopathy alters in vitro splicing of BEST1
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Davidson, Alice E., Sergouniotis, Panagiotis I., Rosemary Burgess-Mullan, Nichola Hart-Holden, Sancy Low, Foster, Paul J., Forbes Manson, Graeme Black, and Webster, Andrew R.
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Adult ,Male ,Fundus Oculi ,RNA Splicing ,Computational Biology ,Genes, Recessive ,Middle Aged ,Fluorescence ,Fibronectins ,Protein Structure, Tertiary ,Young Adult ,HEK293 Cells ,alpha-Globins ,Chloride Channels ,Mutation ,Retinal Dystrophies ,Humans ,Female ,Bestrophins ,Child ,Codon ,Eye Proteins ,Research Article - Abstract
Purpose Autosomal recessive bestrophinopathy (ARB) is a newly defined retinal dystrophy caused by biallelic mutations in bestrophin-1 (BEST1) and is hypothesized to represent the null bestrophin-1 phenotype in humans. The aim was to determine whether a synonymous BEST1 variant, c.102C>T, identified in two unrelated ARB patients, alters pre-mRNA splicing of the gene. Additionally a detailed phenotypic characterization of this distinctive condition is presented for both patients. Methods BEST1 was analyzed by direct sequencing. Patients underwent standard ophthalmic assessment. In silico and in vitro analysis using a minigene system was performed to assess whether a synonymous variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing of BEST1. Results Both ARB patients harbored either proven (patient 1; c.102C>T p.Gly34Gly and c.572T>C p.Leu191Pro) or presumed (patient 2; c.102C>T p.Gly34Gly and c.1470_1471delCA, p.His490GlnfsX24) biallelic mutations in BEST1 and were found to have phenotypes consistent with ARB. In vitro analysis of the synonymous variant, c.102C>T p.Gly34Gly, demonstrated it to introduce a cryptic splice donor site 52 nucleotides upstream of the actual splice donor site. Conclusions The novel BEST1 variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing in vitro and is potentially pathogenic. In vivo this splicing variant is predicted to lead to the production of an mRNA transcript with a premature termination codon (p.Glu35TrpfsX11) that is predicted to be degraded by NMD.
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- 2010
36. Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin
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Zeinab Ravesh, Mohammed Elasrag, Nicole Weisschuh, Martin McKibbin, Peggy Reuter, Watson, Christopher M., Britta Baumann, Poulter, James A., Sundus Sajid, Panagiotou, Evangelia S., Sullivan, James O., Zakia Abdelhamed, Michael Bonin, Mehdi Soltanifar, Graeme Black, Muhammad Amin-ud Din, Carmel Toomes, Muhammad Ansar, Inglehearn, Chris F., Bernd Wissinger, and Manir Ali
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Adult ,Male ,Adolescent ,RNA Splicing ,DNA Mutational Analysis ,Homozygote ,Proteins ,Genes, Recessive ,Exons ,Middle Aged ,Consanguinity ,Mutation ,Humans ,Female ,Pakistan ,Child ,Retinitis Pigmentosa ,Research Article - Abstract
Purpose: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. Methods: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects. Results: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244–2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. Conclusions: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa.
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- 2015
37. IGF-II Deficiency in the Primordial Growth Disorder 3-M Syndrome
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Philip Murray, Daniel Hanson, Andrew Whatmore, Graeme Black, and Peter Clayton
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- 2011
38. Author’s reply
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Alan A.E Ridgway, Graeme Black, and Helen Stewart
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Ophthalmology - Published
- 2000
39. Bilateral subfoveal choroidal neovascularization in Turner's syndrome: coincidence or consequence?
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Beatty, S., Graeme Black, Rhatigan, M., and Bishop, P.
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Diagnosis, Differential ,Adolescent ,Choroid ,Fundus Oculi ,Prednisolone ,Humans ,Turner Syndrome ,Female ,Fluorescein Angiography ,Glucocorticoids ,Choroidal Neovascularization
40. Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis)
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Fisher, S. E., Graeme Black, Lloyd, S. E., Hatchwell, E., Wrong, O., Thakker, R. V., and Craig, I. W.
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Dent's disease, an X-linked renal tubular disorder, is a form of Fanconi syndrome which is characterized by proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. Previous studies localised the gene responsible to Xp11.22, within a microdeletion involving the hypervariable locus DXS255. Further analysis using new probes which flank this locus indicate that the deletion is less than 515 kb. A 185 kb YAC containing DXS255 was used to screen a cDNA library from adult kidney in order to isolate coding sequences falling within the deleted region which may be implicated in the disease aetiology. We identified two clones which are evolutionarily conserved, and detect a 9.5 kb transcript which is expressed predominantly in the kidney. Sequence analysis of 780 bp of ORF from the clones suggests that the identified gene, termed hCIC-K2, encodes a new member of the CIC family of voltage-gated chloride channels. Genomic fragments detected by the cDNA clones are completely absent in patients who have an associated microdeletion. On the basis of the expression pattern, proposed function and deletion mapping, hCIC-K2 is a strong candidate for Dent's disease.
41. BIGH3 mutation spectrum in corneal dystrophies
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Fl, Munier, Be, Frueh, Othenin-Girard P, Uffer S, Cousin P, Mx, Wang, Héon E, Graeme Black, Ma, Blasi, Balestrazzi E, Lorenz B, Escoto R, Barraquer R, Hoeltzenbein M, Gloor B, Fossarello M, Ad, Singh, Arsenijevic Y, Zografos L, and Df, Schorderet
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BIGH3-related corneal dystrophies ,Settore MED/30 - MALATTIE APPARATO VISIVO
42. Discovery of U2AF1 neoantigens in myeloid neoplasms
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Marie Bleakley, Ralph Graeme Black, David Wu, Melinda Ann Biernacki, Jessica Lok, Kimberly A Foster, Carrie Cummings, Kyle B Woodward, Tim Monahan, Vivian G Oehler, Derek L Stirewalt, Anthony Rongvaux, and Hans Joachim Deeg
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Myelodysplastic syndromes (MDS) arise from somatic mutations acquired in hematopoietic stem and progenitor cells, causing cytopenias and predisposing to transformation into secondary acute myeloid leukemia (sAML). Recurrent mutations in spliceosome genes, including U2AF1, are attractive therapeutic targets as they are prevalent in MDS and sAML, arise early in neoplastic cells, and are generally absent from normal cells, including normal hematopoietic cells. MDS and sAML are susceptible to T cell-mediated killing, and thus engineered T-cell immunotherapies hold promise for their treatment. We hypothesized that targeting spliceosome mutation-derived neoantigens with transgenic T-cell receptor (TCR) T cells would selectively eradicate malignant cells in MDS and sAML.Methods We identified candidate neoantigen epitopes from recurrent protein-coding mutations in the spliceosome genes SRSF2 and U2AF1 using a multistep in silico process. Candidate epitopes predicted to bind human leukocyte antigen (HLA) class I, be processed and presented from the parent protein, and not to be subject to tolerance then underwent in vitro immunogenicity screening. CD8+ T cells recognizing immunogenic neoantigen epitopes were evaluated in in vitro assays to assess functional avidity, confirm the predicted HLA restriction, the potential for recognition of similar peptides, and the ability to kill neoplastic cells in an antigen-specific manner. Neoantigen-specific TCR were sequenced, cloned into lentiviral vectors, and transduced into third-party T cells after knock-out of endogenous TCR, then tested in vitro for specificity and ability to kill neoplastic myeloid cells presenting the neoantigen. The efficacy of neoantigen-specific T cells was evaluated in vivo in a murine cell line-derived xenograft model.Results We identified two neoantigens created from a recurrent mutation in U2AF1, isolated CD8+ T cells specific for the neoantigens, and demonstrated that transferring their TCR to third-party CD8+ T cells is feasible and confers specificity for the U2AF1 neoantigens. Finally, we showed that these neoantigen-specific TCR-T cells do not recognize normal hematopoietic cells but efficiently kill malignant myeloid cells bearing the specific U2AF1 mutation, including primary cells, in vitro and in vivo.Conclusions These data serve as proof-of-concept for developing precision medicine approaches that use neoantigen-directed T-cell receptor-transduced T cells to treat MDS and sAML.
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- 2023
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43. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy
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Robin L Jones, Erik A Farrar, Jianhong Cao, Venu G Pillarisetty, Stanley R Riddell, Jean Campbell, Brett A Schroeder, Ralph Graeme Black, Shihong Zhang, Karan Kohli, Robert H Pierce, Lu Yao, Theodore Scott Nowicki, Heather Sloan, Dawn Stief, Lee D Cranmer, Douglas S Hawkins, and Edward Y Kim
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.Conclusions ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
- Published
- 2021
- Full Text
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44. 139 Establishment of canine CAR T cells treatment model for solid tumor immunotherapy development
- Author
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Peter Moore, Stephen Gottschalk, Shihong Zhang, Karan Kohli, R Graeme Black, Brian Hayes, Cassandra Miller, Mari Maeda-Whitaker, Brett Schroeder, Kraig Abrams, Bernard Seguin, Beverly Torok-Storb, and Seth Pollack
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
- Full Text
- View/download PDF
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