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2. SARS-CoV-2 Testing in the Community: Testing Positive Samples with the TaqMan SARS-CoV-2 Mutation Panel To Find Variants in Real Time

Author

Ashford, Fiona, Best, Angus, Dunn, Steven J, Ahmed, Zahra, Siddiqui, Henna, Melville, Jordan, Wilkinson, Samuel, Mirza, Jeremy, Cumley, Nicola, Stockton, Joanne, Ferguson, Jack, Wheatley, Lucy, Ratcliffe, Elizabeth, Casey, Anna, Plant, Tim, Aggarwal, Dinesh, Blane, Beth, Brooks, Ellena, Carabelli, Alessandro M, Churcher, Carol M, Galai, Katerina, Girgis, Sophia T, Gupta, Ravi K, Hadjirin, Nazreen F, Leek, Danielle, Ludden, Catherine, McManus, Georgina M, Palmer, Sophie, Peacock, Sharon J, Smith, Kim S, Allara, Elias, Bibby, David, Bishop, Chloe, Bosworth, Andrew, Bradshaw, Daniel, Chalker, Vicki, Chand, Meera, Dabrera, Gavin, Ellaby, Nicholas, Gallagher, Eileen, Groves, Natalie, Harrison, Ian, Hartman, Hassan, Hopes, Richard, Hubb, Jonathan, Hutchings, Stephanie, Lackenby, Angie, Ledesma, Juan, Lee, David, Manesis, Nikos, Manso, Carmen, Mbisa, Tamyo, Miah, Shahjahan, Muir, Peter, Myers, Richard, Osman, Husam, Patel, Vineet, Pearson, Clare, Platt, Steven, Pymont, Hannah M, Ramsay, Mary, Robinson, Esther, Schaefer, Ulf, Thornton, Alicia, Twohig, Katherine A, Vipond, Ian B, Williams, David, Hamilton, William L, Warne, Ben, Aigrain, Louise, Alderton, Alex, Amato, Roberto, Ariani, Cristina V, Barrett, Jeff, Bassett, Andrew R, Beale, Mathew A, Beaver, Charlotte, Bellis, Katherine L, Betteridge, Emma, Bonfield, James, Bronner, Iraad F, Chapman, Michael HS, Danesh, John, Davies, Robert, Dorman, Matthew J, Drury, Eleanor, Durham, Jillian, Farr, Ben W, Foulser, Luke, Goncalves, Sonia, Goodwin, Scott, Gourtovaia, Marina, Harrison, Ewan M, Jackson, David K, James, Keith, Jamrozy, Dorota, Johnston, Ian, Kane, Leanne, Kay, Sally, and Keatley, Jon-Paul

Subjects
Human Genome, Prevention, Biodefense, Genetics, Lung, Vaccine Related, Emerging Infectious Diseases, Good Health and Well Being, COVID-19, COVID-19 Testing, Humans, Mutation, SARS-CoV-2, COVID-19 Genomics UK (COG-UK) Consortium, PCR, SNPs, genome sequencing, genotyping, real time, variants of concern, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Microbiology
Abstract

Genome sequencing is a powerful tool for identifying SARS-CoV-2 variant lineages; however, there can be limitations due to sequence dropout when used to identify specific key mutations. Recently, ThermoFisher Scientific has developed genotyping assays to help bridge the gap between testing capacity and sequencing capability to generate real-time genotyping results based on specific variants. Over a 6-week period during the months of April and May 2021, we set out to assess the ThermoFisher TaqMan mutation panel genotyping assay, initially for three mutations of concern and then for an additional two mutations of concern, against SARS-CoV-2-positive clinical samples and the corresponding COVID-19 Genomics UK Consortium (COG-UK) sequencing data. We demonstrate that genotyping is a powerful in-depth technique for identifying specific mutations, is an excellent complement to genome sequencing, and has real clinical health value potential, allowing laboratories to report and take action on variants of concern much more quickly.

Published
2022

3. A giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory support

Author

Fallon, Julianne M, Parker, Alex M, Dunn, Steven P, and Kennedy, Jamie LW

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Bioengineering, Heart Disease, Cardiovascular, Biopsy, Female, Giant Cells, Heart Failure, Heart-Assist Devices, Humans, Immunosuppression Therapy, Immunosuppressive Agents, Magnetic Resonance Imaging, Cine, Middle Aged, Myocarditis, Myocardium, Recurrence, Giant cell myocarditis, mechanical circulatory support, immunosuppression, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Giant cell myocarditis is a rare but often devastating diagnosis. Advances in cardiac imaging and mechanical circulatory support have led to earlier and more frequent diagnoses and successful management. This disease state has wide variation in acuity of presentation, and consequently, optimal treatment ranging from intensity and type of immunosuppression to mechanical circulatory support is not well defined. The following case describes the management of a patient with an unusual presentation of giant cell myocarditis over a 10 year course of advanced heart failure therapies and immunomodulatory support. This case highlights emerging concepts in the management of giant cell myocarditis including sub-acute presentations, challenges in diagnosis, and treatment modalities in the modern era.

Published
2020

6. Corneal Graft Rejection 10 Years After Penetrating Keratoplasty in the Cornea Donor Study

Author

Dunn, Steven P, Gal, Robin L, Kollman, Craig, Raghinaru, Dan, Dontchev, Mariya, Blanton, Christopher L, Holland, Edward J, Lass, Jonathan H, Kenyon, Kenneth R, Mannis, Mark J, Mian, Shahzad I, Rapuano, Christopher J, Stark, Walter J, and Beck, Roy W

Subjects
Organ Transplantation, Eye Disease and Disorders of Vision, Neurodegenerative, Clinical Research, Transplantation, Rare Diseases, 6.4 Surgery, Evaluation of treatments and therapeutic interventions, Eye, Aged, Allografts, Corneal Edema, Follow-Up Studies, Fuchs' Endothelial Dystrophy, Graft Rejection, Graft Survival, Humans, Incidence, Keratoplasty, Penetrating, Middle Aged, Postoperative Complications, Risk Factors, Tissue Donors, Transplant Recipients, corneal graft rejection, penetrating keratoplasty, corneal graft failure, Writing Committee for the Cornea Donor Study Research Group, Clinical Sciences, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

PurposeThe aim of this study was to assess the effect of donor and recipient factors on corneal allograft rejection and evaluate whether a rejection event was associated with graft failure.MethodsOne thousand ninety subjects undergoing penetrating keratoplasty for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 12 years. Associations of baseline recipient and donor factors with the occurrence of a rejection event were assessed in univariate and multivariate proportional hazards models.ResultsAmong 651 eyes with a surviving graft at 5 years, the 10-year graft failure (±99% confidence interval) rates were 12% ± 4% among eyes with no rejection events in the first 5 years, 17% ± 12% in eyes with at least 1 probable, but no definite rejection event, and 22% ± 20% in eyes with at least 1 definite rejection event. The only baseline factor significantly associated with a higher risk of definite graft rejection was a preoperative history of glaucoma, particularly when previous glaucoma surgery had been performed and glaucoma medications were being used at the time of transplant (10-year incidence 35% ± 23% compared with 14% ± 4% in eyes with no history of glaucoma/intraocular pressure treatment, P = 0.008).ConclusionsPatients who experienced a definite rejection event frequently developed graft failure raising important questions as to how we might change acute and long-term corneal graft management. Multivariate analysis indicated that previous use of glaucoma medications and glaucoma filtering surgery was a significant risk factor related to a definite rejection event.

Published
2014

7. The Effect of Donor Age on Penetrating Keratoplasty for Endothelial Disease Graft Survival after 10 Years in the Cornea Donor Study

Author

Group, Writing Committee for the Cornea Donor Study Research, Mannis, Mark J, Holland, Edward J, Gal, Robin L, Dontchev, Mariya, Kollman, Craig, Raghinaru, Dan, Dunn, Steven P, Schultze, Robert L, Verdier, David D, Lass, Jonathan H, Raber, Irving M, Sugar, Joel, Gorovoy, Mark S, Sugar, Alan, Stulting, R Doyle, Montoya, Monty M, Penta, Jeffrey G, Benetz, Beth Ann, and Beck, Roy W

Subjects
Eye Disease and Disorders of Vision, Clinical Trials and Supportive Activities, Transplantation, Clinical Research, Eye, Adolescent, Adult, Age Factors, Aged, Aging, Child, Corneal Edema, Double-Blind Method, Eye Banks, Female, Follow-Up Studies, Fuchs' Endothelial Dystrophy, Graft Survival, Humans, Keratoplasty, Penetrating, Male, Middle Aged, Prospective Studies, Registries, Tissue Donors, Young Adult, Writing Committee for the Cornea Donor Study Research Group, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry
Abstract

ObjectiveTo determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age.DesignMulticenter, prospective, double-masked clinical trial.ParticipantsA total of 1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs' dystrophy (62%), pseudophakic/aphakic corneal edema (34%), or another corneal endothelial disorder (4%) and followed for up to 12 years.MethodsForty-three eye banks provided corneas from donors aged 12 to 75 years, using a randomized approach to assign donor corneas to study participants without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines.Main outcome measuresGraft failure defined as a regraft or, in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months.ResultsIn the primary analysis, the 10-year success rate was 77% for 707 corneas from donors aged 12 to 65 years compared with 71% for 383 donors aged 66 to 75 years (difference, +6%; 95% confidence interval, -1 to +12; P = 0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success beyond the first 5 years (P

Published
2013

15. High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

Author

Moysey, Ruth K., Li, Yi, Paston, Samantha J., Baston, Emma E., Sami, Malkit S., Cameron, Brian J., Gavarret, Jessie, Todorov, Penio, Vuidepot, Annelise, Dunn, Steven M., Pumphrey, Nicholas J., Adams, Katherine J., Yuan, Fang, Dennis, Rebecca E., Sutton, Deborah H., Johnson, Andy D., Brewer, Joanna E., Ashfield, Rebecca, Lissin, Nikolai M., and Jakobsen, Bent K.

Published
2010
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18. C‐GRApH : A Validated Scoring System for Early Stratification of Neurologic Outcome After Out‐of‐Hospital Cardiac Arrest Treated With Targeted Temperature Management

Author

Kiehl, Erich L., primary, Parker, Alex M., additional, Matar, Ralph M., additional, Gottbrecht, Matthew F., additional, Johansen, Michelle C., additional, Adams, Mark P., additional, Griffiths, Lori A., additional, Dunn, Steven P., additional, Bidwell, Katherine L., additional, Menon, Venu, additional, Enfield, Kyle B., additional, and Gimple, Lawrence W., additional

Published
2017
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19. The effect of donor age on penetrating keratoplasty for endothelial disease: graft survival after 10 years in the Cornea Donor Study

Author

Writing Committee for the Cornea Donor Study Research Group, Mannis, Mark J, Holland, Edward J, Gal, Robin L, Dontchev, Mariya, Kollman, Craig, Raghinaru, Dan, Dunn, Steven P, Schultze, Robert L, Verdier, David D, Lass, Jonathan H, Raber, Irving M, Sugar, Joel, Gorovoy, Mark S, Sugar, Alan, Stulting, R Doyle, Montoya, Monty M, Penta, Jeffrey G, Benetz, Beth Ann, and Beck, Roy W

Subjects
Adult, Male, Aging, Adolescent, Clinical Trials and Supportive Activities, Clinical Sciences, Eye Banks, Eye, Ophthalmology & Optometry, Writing Committee for the Cornea Donor Study Research Group, Young Adult, Penetrating, Double-Blind Method, Clinical Research, Opthalmology and Optometry, Humans, Registries, Prospective Studies, Child, Eye Disease and Disorders of Vision, Aged, Transplantation, Fuchs' Endothelial Dystrophy, Corneal Edema, Graft Survival, Age Factors, Middle Aged, Tissue Donors, Keratoplasty, Public Health and Health Services, Female, Follow-Up Studies
Abstract

ObjectiveTo determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age.DesignMulticenter, prospective, double-masked clinical trial.ParticipantsA total of 1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs' dystrophy (62%), pseudophakic/aphakic corneal edema (34%), or another corneal endothelial disorder (4%) and followed for up to 12 years.MethodsForty-three eye banks provided corneas from donors aged 12 to 75 years, using a randomized approach to assign donor corneas to study participants without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines.Main outcome measuresGraft failure defined as a regraft or, in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months.ResultsIn the primary analysis, the 10-year success rate was 77% for 707 corneas from donors aged 12 to 65 years compared with 71% for 383 donors aged 66 to 75 years (difference, +6%; 95% confidence interval, -1 to +12; P = 0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success beyond the first 5 years (P

Published
2013

21. Geothermometry of the western half of the Central Metasedimentary Belt, Grenville Province, Ontario, and its implications

Author

Dunn, Steven R., Markley, Michelle J., Kotikian, Maneh, Achenbach, Kay, Montanye, Bo, and Peck, William H.

Abstract

Calcite-graphite carbon isotope thermometry results are presented for 150 new marble samples across the western Central Metasedimentary Belt (CMB) of the Ontario segment of the Grenville Province. The results show a gradual increase in peak metamorphic temperature from under 500 °C in the Tudor Township area in the east to over 700 °C along the western margin of the CMB. Modestly elevated d13C values above 3‰ across all terranes in the study area suggest a common temporal, and perhaps depositional origin, for the ~1.3 Ma limestone protoliths. The preserved thermal gradient is consistent with variations in marble mineralogy and character. Based on published geochronology, we argue that these temperatures correspond to peak metamorphism during the 1090–1020 Ma Ottawan orogeny, with the exception of preserved contact aureoles most notably associated with the Tudor gabbro and the Cheddar granite. The lack of significant thermal discontinuities at terrane boundaries and other shear zones, including the Bancroft shear zone and the CMB boundary zone, indicate that the entire region including the adjacent Central Gneiss Belt remained largely intact during and after the Ottawan peak metamorphic event. Variations in deformation style of pre-existing igneous complexes appear to correspond to the Ottawan thermal conditions, which include crystalline thrust sheets at high temperature, and mildly foliated domes to undeformed plutons at decreasing temperatures. In light of the peak temperatures and smooth thermal gradient we show to be superimposed on the established Grenvillian architecture, much of the western CMB should be considered part of the allochthonous medium pressure belt, and separate from the Ottawan orogenic lid that defines the eastern CMB.

Published
2019
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22. Impact of genetic polymorphisms on clinical response to antithrombotics

Author

Lanham,Kena, Oestreich,Julie H, Dunn,Steven P, Steinhubl,Steven R, Lanham,Kena, Oestreich,Julie H, Dunn,Steven P, and Steinhubl,Steven R

Abstract

Kena J Lanham1,2, Julie H Oestreich3, Steven P Dunn1,2, Steven R Steinhubl41Pharmacy Services, UK HealthCare, University of Kentucky, Lexington, Kentucky, USA; 2Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA; 3Department of Pharmacy Practice, College of Pharmacy, University of Nebraska, Omaha, Nebraska, USA; 4The Medicines Company, Zurich, Switzerland and The Geisinger Clinic, Danville, Pennsylvania, USAAbstract: Antithrombotic therapy, including anticoagulants as well as antiplatelet drugs, is an important component in the treatment of cardiovascular disease. Variability in response to such medications, of which pharmacogenetic response is a major source, can decrease or enhance the benefits expected. This review is a comprehensive assessment of the literature published to date on the effects of genetic polymorphisms on the actions of a variety of antithrombotic medications, including warfarin, clopidogrel, prasugrel, and aspirin. Literature evaluating surrogate markers in addition to the impact of pharmacogenetics on clinical outcomes has been reviewed. The results of the studies are conflicting as to what degree pharmacogenetics will affect medication management in cardiovascular disease. Additional research is necessary to discover, characterize, and prospectively evaluate genetic and non-genetic factors that impact antithrombotic treatment in order to maximize the effectiveness and limit the harmful effects of these valuable agents.Keywords: aspirin, warfarin, clopidogrel, prasugrel, pharmacogenetic, antithrombotic, antiplatelet

Published
2010

23. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Cheng, Ching-Yu, primary, Schache, Maria, additional, Ikram, M. Kamran, additional, Young, Terri L., additional, Guggenheim, Jeremy A., additional, Vitart, Veronique, additional, MacGregor, Stuart, additional, Verhoeven, Virginie J.M., additional, Barathi, Veluchamy A., additional, Liao, Jiemin, additional, Hysi, Pirro G., additional, Bailey-Wilson, Joan E., additional, St. Pourcain, Beate, additional, Kemp, John P., additional, McMahon, George, additional, Timpson, Nicholas J., additional, Evans, David M., additional, Montgomery, Grant W., additional, Mishra, Aniket, additional, Wang, Ya Xing, additional, Wang, Jie Jin, additional, Rochtchina, Elena, additional, Polasek, Ozren, additional, Wright, Alan F., additional, Amin, Najaf, additional, van Leeuwen, Elisabeth M., additional, Wilson, James F., additional, Pennell, Craig E., additional, van Duijn, Cornelia M., additional, de Jong, Paulus T.V.M., additional, Vingerling, Johannes R., additional, Zhou, Xin, additional, Chen, Peng, additional, Li, Ruoying, additional, Tay, Wan-Ting, additional, Zheng, Yingfeng, additional, Chew, Merwyn, additional, Burdon, Kathryn P., additional, Craig, Jamie E., additional, Iyengar, Sudha K., additional, Igo, Robert P., additional, Lass, Jonathan H., additional, Chew, Emily Y., additional, Haller, Toomas, additional, Mihailov, Evelin, additional, Metspalu, Andres, additional, Wedenoja, Juho, additional, Simpson, Claire L., additional, Wojciechowski, Robert, additional, Höhn, René, additional, Mirshahi, Alireza, additional, Zeller, Tanja, additional, Pfeiffer, Norbert, additional, Lackner, Karl J., additional, Bettecken, Thomas, additional, Meitinger, Thomas, additional, Oexle, Konrad, additional, Pirastu, Mario, additional, Portas, Laura, additional, Nag, Abhishek, additional, Williams, Katie M., additional, Yonova-Doing, Ekaterina, additional, Klein, Ronald, additional, Klein, Barbara E., additional, Hosseini, S. Mohsen, additional, Paterson, Andrew D., additional, Makela, Kari-Matti, additional, Lehtimaki, Terho, additional, Kahonen, Mika, additional, Raitakari, Olli, additional, Yoshimura, Nagahisa, additional, Matsuda, Fumihiko, additional, Chen, Li Jia, additional, Pang, Chi Pui, additional, Yip, Shea Ping, additional, Yap, Maurice K.H., additional, Meguro, Akira, additional, Mizuki, Nobuhisa, additional, Inoko, Hidetoshi, additional, Foster, Paul J., additional, Zhao, Jing Hua, additional, Vithana, Eranga, additional, Tai, E-Shyong, additional, Fan, Qiao, additional, Xu, Liang, additional, Campbell, Harry, additional, Fleck, Brian, additional, Rudan, Igor, additional, Aung, Tin, additional, Hofman, Albert, additional, Uitterlinden, André G., additional, Bencic, Goran, additional, Khor, Chiea-Chuen, additional, Forward, Hannah, additional, Pärssinen, Olavi, additional, Mitchell, Paul, additional, Rivadeneira, Fernando, additional, Hewitt, Alex W., additional, Williams, Cathy, additional, Oostra, Ben A., additional, Teo, Yik-Ying, additional, Hammond, Christopher J., additional, Stambolian, Dwight, additional, Mackey, David A., additional, Klaver, Caroline C.W., additional, Wong, Tien-Yin, additional, Saw, Seang-Mei, additional, Baird, Paul N., additional, Reinhart, William, additional, Belin, Michael W., additional, Schultze, Robert L., additional, Morason, Todd, additional, Sugar, Alan, additional, Mian, Shahzad, additional, Soong, Hunson Kaz, additional, Colby, Kathryn, additional, Jurkunas, Ula, additional, Yee, Richard, additional, Vital, Mark, additional, Alfonso, Eduardo, additional, Karp, Carol, additional, Lee, Yunhee, additional, Yoo, Sonia, additional, Hammersmith, Kristin, additional, Cohen, Elisabeth, additional, Laibson, Peter, additional, Rapuano, Christopher, additional, Ayres, Brandon, additional, Croasdale, Christopher, additional, Caudill, James, additional, Patel, Sanjay, additional, Baratz, Keith, additional, Bourne, William, additional, Maguire, Leo, additional, Sugar, Joel, additional, Tu, Elmer, additional, Djalilian, Ali, additional, Mootha, Vinod, additional, McCulley, James, additional, Bowman, Wayne, additional, Cavanaugh, H. Dwight, additional, Verity, Steven, additional, Verdier, David, additional, Renucci, Ann, additional, Oliva, Matt, additional, Rotkis, Walter, additional, Hardten, David R., additional, Fahmy, Ahmad, additional, Brown, Marlene, additional, Reeves, Sherman, additional, Davis, Elizabeth A., additional, Lindstrom, Richard, additional, Hauswirth, Scott, additional, Hamilton, Stephen, additional, Lee, W. Barry, additional, Price, Francis, additional, Price, Marianne, additional, Kelly, Kathleen, additional, Peters, Faye, additional, Shaughnessy, Michael, additional, Steinemann, Thomas, additional, Dupps, B.J., additional, Meisler, David M., additional, Mifflin, Mark, additional, Olson, Randal, additional, Aldave, Anthony, additional, Holland, Gary, additional, Mondino, Bartly J., additional, Rosenwasser, George, additional, Gorovoy, Mark, additional, Dunn, Steven P., additional, Heidemann, David G., additional, Terry, Mark, additional, Shamie, Neda, additional, Rosenfeld, Steven I., additional, Suedekum, Brandon, additional, Hwang, David, additional, Stone, Donald, additional, Chodosh, James, additional, Galentine, Paul G., additional, Bardenstein, David, additional, Goddard, Katrina, additional, Chin, Hemin, additional, Mannis, Mark, additional, Varma, Rohit, additional, and Borecki, Ingrid, additional

Published
2013
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28. High affinity soluble ILT2 receptor: a potent inhibitor of CD8+T cell activation

Author

Moysey, Ruth, Li, Yi, Paston, Samantha, Baston, Emma, Sami, Malkit, Cameron, Brian, Gavarret, Jessie, Todorov, Penio, Vuidepot, Annelise, Dunn, Steven, Pumphrey, Nicholas, Adams, Katherine, Yuan, Fang, Dennis, Rebecca, Sutton, Deborah, Johnson, Andy, Brewer, Joanna, Ashfield, Rebecca, Lissin, Nikolai, and Jakobsen, Bent

Abstract

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t1/2) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitrowithout affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8+cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8+CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.

Published
2010
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29. Flat-top narrow-band spectral response obtained from cascaded resonant grating reflection filters

Author

Jacob, Donald K., Dunn, Steven C., and Moharam, M. G.

Abstract

Cascaded identical resonant grating reflection filters are shown to exhibit flattened spectral responses when the individual filter elements are cascaded π out of phase. Off resonance, the net response of a cascaded arrangement is given approximately by the sum of the individual filter responses. Cascading filters π out of phase thus result in a reduction in the off-resonance reflection levels and correspondingly an increase in the spectral bandpass ratio. The spectral bandpass ratio is a figure of merit used to gauge the flatness of a response and is defined as the ratio of the linewidth at an efficiency of 90% to the linewidth at an efficiency of 10%. Cascading two and three filters in this manner results in respective increases in the spectral bandpass ratio of three times and more than five times that of a single filter.

Published
2002

30. Soluble trivalent engagers redirect cytolytic T cell activity toward tumor endothelial marker 1

Author

Fierle, Julie K., Brioschi, Matteo, de Tiani, Mariastella, Wetterwald, Laureline, Atsaves, Vasileios, Abram-Saliba, Johan, Petrova, Tatiana V., Coukos, George, and Dunn, Steven M.

Abstract

Tumor endothelial marker 1 (TEM1) is an emerging cancer target with a unique dual expression profile. First, TEM1 is expressed in the stroma and neo-vasculature of many human carcinomas but is largely absent from healthy adult tissues. Second, TEM1 is expressed by tumor cells of mesenchymal origin, notably sarcoma. Here, we present two fully human anti-TEM1 single-chain variable fragment (scFv) reagents, namely, 1C1m and 7G22, that recognize distinct regions of the extracellular domain and possess substantially different affinities. In contrast to other, well-described anti-TEM1 binders, these fragments confer cytolytic activity when expressed as 2ndgeneration chimeric antigen receptors (CARs). Moreover, both molecules selectively redirect human T cell effector functions toward TEM1+tumor cells when incorporated into experimental soluble bispecific trivalent engagers that we term TriloBiTEs (tBs). Furthermore, systemic delivery of 1C1m-tB prevents the establishment of Ewing sarcoma tumors in a xenograft model. Our observations confirm TEM1 as a promising target for cancer immunotherapy and illustrate the prospective translational potential of certain scFv-based reagents.

Published
2021
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31. Randomized Comparison of Ganciclovir Plus Intravenous Immune Globulin (IVIG) with IVIG Alone for Prevention of Primary Cytomegalovirus Disease in Children Receiving Liver Transplants

Author

King, Susan M., Superina, Riccardo, Andrews, Walter, Winston, Drew J., Dunn, Steven, Busuttil, Ronald W., Colombani, Paul, and Paradis, Khazal

Abstract

A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kgrd]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.

Published
1997
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