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1. Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling.

Author

Alexandros P Grammatikos, Debjani Ghosh, Amy Devlin, Vasileios C Kyttaris, and George C Tsokos

Subjects
Medicine, Science
Abstract

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.

Published
2013
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2. Contributors

Author

Nancy Agmon-Levin, Graciela S. Alarcón, Olga Amengual, Stacy P. Ardoin, Swati Arora, Yemil Atisha-Fregoso, John P. Atkinson, Tatsuya Atsumi, Isabelle Ayoub, Maria-Louise Barilla-LaBarca, Bonnie L. Bermas, Sasha Bernatsky, George Bertsias, Tanmayee Bichile, Patrick Blanco, Miyuki Bohgaki, Gisela Bonsmann, Maria Orietta Borghi, Dimitrios T. Boumpas, Rebecka Bourn, Jill P. Buyon, Roberto Caricchio, Edward K.L. Chan, Christopher Chang, Manon Charrier, Cecilia Beatrice Chighizola, Ann E. Clarke, José C. Crispín, Bettina Cuneo, Thomas Dörner, Erika M. Damato, Alastair K.O. Denniston, Amy Devlin, Betty Diamond, T. Ernandez, Titilola Falasinnu, Ruth Fernandez-Ruiz, Brianna Fitzpatrick, Lindsy Forbess, Eleni A. Frangou, Marvin J. Fritzler, Shu Man Fu, Richard Furie, Felicia Gaskin, Dafna Gladman, Caroline Gordon, Amrie C. Grammer, Eric L. Greidinger, Teri M. Greiling, Shuhong Han, James E. Hansen, Sarfaraz A. Hasni, Fadi Hassan, Christian M. Hedrich, Keiju Hiromura, Diane Horowitz, Xin Huang, David Hunt, Peter M. Izmirly, Judith A. James, Wael N. Jarjour, Caroline A. Jefferies, Caroline Jefferies, Xiaoyue Jiang, Mariana J. Kaplan, Takayuki Katsuyama, Munther Khamashta, Kathryn M. Kingsmore, Takao Koike, Dwight H. Kono, Martin A. Kriegel, Annegret Kuhn, Vasileios C Kyttaris, Antonio La Cava, Alexandra Ladouceur, Robert G. Lahita, Aysche Landmann, Estibaliz Lazaro, Mara L. Lennard Richard, Andreia C. Lino, Peter E. Lipsky, M. Kathryn Liszewski, Mindy S. Lo, Qianjin Lu, Mary Mahieu, Susan Malkiel, Susan Manzi, Galina Marder, T.N. Mayadas, Pier Luigi Meroni, Joan T. Merrill, Chandra Mohan, Chi Chiu Mok, Vaishali R. Moulton, Philip I. Murray, Mohammad E. Naffaa, Masaomi Nangaku, Timothy Niewold, K. Okubo, Nancy J. Olsen, Trina Pal, Ziv Paz, Andras Perl, Guillermo J. Pons-Estel, Bo Qu, Anisur Rahman, Ziaur S.M. Raman, Rosalind Ramsey-Goldman, Westley H. Reeves, Christophe Richez, Florencia Rosetti, Brad H. Rovin, Robert L. Rubin, Stephanie Saeli, G. Saggu, Lisa R. Sammaritano, Minoru Satoh, Amr H. Sawalha, Amit Saxena, Savino Sciascia, Syahrul Sazliyana Shaharir, Amir Sharabi, Nan Shen, Robert H. Shmerling, Julia F. Simard, Vanja Sisirak, Samantha Slight-Webb, Isaac Ely Stillman, Sun-Sang J. Sung, Payal Thakkar, Argyrios N. Theofilopoulos, Donald E. Thomas, Jr, Hiromi Tissera, Zahi Touma, Betty P. Tsao, Manuel F. Ugarte-Gil, Murray B. Urowitz, Silvio Manfredo Vieira, Benjamin Wainwright, Daniel J. Wallace, Hongyang Wang, Haijing Wu, Soad Haj Yahia, C. Yung Yu, Zhenhuan Zhao, and Haoyang Zhuang

Published
2021
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3. A population-level investigation of cancer clinical trials participation in a UK region

Author

Anna Gavin, Jingwen J. Chen, Richard H. Wilson, Amy Devlin, Victoria Cairnduff, Conan Donnelly, Amy C. Wotherspoon, Eileen Morgan, and Melanie Morris

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Multivariate analysis, Adolescent, Epidemiology, Population, Northern Ireland, Disease, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Humans, Registries, 030212 general & internal medicine, Child, education, Aged, Clinical Trials as Topic, education.field_of_study, business.industry, Public Health, Environmental and Occupational Health, Cancer, Middle Aged, medicine.disease, United Kingdom, Cancer registry, Clinical trial, Oncology, Child, Preschool, Population Surveillance, 030220 oncology & carcinogenesis, Cohort, Physical therapy, Marital status, Female, Patient Participation, business, Demography
Abstract

The aim of this study was to document cancer trial participation since establishment of the Northern Ireland Cancer Trials Network and investigate population and disease factors associated with trial participation. An independent cohort of over 51 000 cancer patients from the Northern Ireland Cancer Registry covering the same population (2007-2012) was linked to a database of 1316 interventional cancer trial participants in a UK region. The primary outcome measure was participation in an intervention clinical trial. Patients were followed up until 31 March 2013. Kaplan-Meier tests and Cox proportional hazard models using person days at risk to allow for death were used to investigate factors associated with trial participation. Multivariate analysis assessed the impact of age, cancer type and stage, distance from the cancer centre (radiotherapy), marital status, deprivation quintile and rurality. Participation was analysed separately for children (

Published
2017
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4. Variation in initial kidney replacement therapy for end-stage renal disease due to lupus nephritis in the United States

Author

Wolfgang C. Winkelmayer, Daniel H. Solomon, Graciela S. Alarcón, Amy Devlin, Bing Lu, Sushrut S. Waikar, Tamara Shaykevich, and Karen H. Costenbader

Subjects
Adult, Employment, Male, medicine.medical_specialty, Time Factors, Adolescent, medicine.medical_treatment, Lupus nephritis, Comorbidity, Disease, Peritoneal dialysis, End stage renal disease, Young Adult, chemistry.chemical_compound, Sex Factors, Rheumatology, Renal Dialysis, Internal medicine, Odds Ratio, Humans, Medicine, Registries, Healthcare Disparities, Practice Patterns, Physicians', Intensive care medicine, Minority Groups, Dialysis, Kidney transplantation, Aged, Creatinine, Chi-Square Distribution, Insurance, Health, business.industry, Patient Selection, Age Factors, Middle Aged, medicine.disease, Kidney Transplantation, Lupus Nephritis, United States, Renal Replacement Therapy, Logistic Models, Socioeconomic Factors, chemistry, Kidney Failure, Chronic, Female, Hemodialysis, business, Peritoneal Dialysis
Abstract

Objective Little is known about the patterns of use of initial kidney replacement therapies among patients with lupus nephritis (LN) end-stage renal disease (ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients. Methods Patients with incident LN ESRD (1995–2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors, and comorbidities were considered as potential predictors of ESRD treatment choice, i.e., peritoneal dialysis (PD), hemodialysis (HD), or preemptive kidney transplantation in age-adjusted and multivariable-adjusted logistic regression analyses. Results Of the 11,317 individuals with incident LN ESRD, 82.0% initiated HD, 12.2% initiated PD, and 2.8% underwent preemptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin levels, and lower serum creatinine levels. African Americans (versus whites), Medicaid beneficiaries and those with no health insurance (versus private insurance), and those unemployed (versus employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease, and the inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with preemptive kidney transplant (versus dialysis) as well. Conclusion Few patients with LN ESRD receive initial PD or preemptive kidney transplantation. Race, ethnicity, employment, and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.

Published
2011
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6. Systemic Lupus Erythematosus and Infections

Author

Amy Devlin and Robert H. Shmerling

Subjects
High rate, medicine.medical_specialty, medicine.medical_treatment, Immunosuppression, Biology, Immune dysregulation, Immune Dysfunction, medicine.disease_cause, immune system diseases, Epidemiology, Immunology, medicine, skin and connective tissue diseases, Autoantibody production, Anti-SSA/Ro autoantibodies
Abstract

Although the life expectancy of patients with systemic lupus erythematosus (SLE) has improved, increased vulnerability to infection continues to be a major cause of morbidity and mortality. In addition to intrinsic immune dysregulation, drug-induced immunosuppression contributes to the susceptibility of SLE patients to both common and rare infections. Abnormal autoantibody production and clearance, humoral defects, and cellular immune dysfunction predispose patients with SLE to infection. This chapter reviews the spectrum of infections encountered by patients with SLE, epidemiological features of these infections, and intrinsic and treatment-associated immune dysregulation. A practical approach to diagnosis and strategies to prevent infection are also considered with a focus on ways to diminish the high rates of infection and related morbidity among patients with SLE.

Published
2016
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7. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis

Author

Amy Devlin, Shahzad Shaefi, Atul Malhotra, Daniel Talmor, Stephen H. Loring, Sydney B. Montesi, and Jeremy R. Beitler

Subjects
Adult, medicine.medical_specialty, Pediatrics, ARDS, Supine position, Patient positioning, Clinical Trials and Supportive Activities, Clinical Sciences, Critical Care and Intensive Care Medicine, Patient Positioning, Article, law.invention, Prone position, Rare Diseases, Randomized controlled trial, law, Clinical Research, Anesthesiology, Multicenter trial, medicine, Prone Position, Tidal Volume, Odds Ratio, Supine Position, Acute lung injury, Humans, Intensive care medicine, Lung, Tidal volume, Randomized Controlled Trials as Topic, Respiratory Distress Syndrome, Acute respiratory distress syndrome, business.industry, Respiration, medicine.disease, Respiration, Artificial, Emergency & Critical Care Medicine, Meta-analysis, Artificial, Public Health and Health Services, business
Abstract

Purpose: Prone positioning for ARDS has been performed for decades without definitive evidence of clinical benefit. A recent multicenter trial demonstrated for the first time significantly reduced mortality with prone positioning. This meta-analysis was performed to integrate these findings with existing literature and test whether differences in tidal volume explain conflicting results among randomized trials. Methods: Studies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review. Included were randomized trials evaluating the effect on mortality of prone versus supine positioning during conventional ventilation for ARDS. The primary outcome was risk ratio of death at 60 days meta-analyzed using random effects models. Analysis stratified by high (>8 ml/kg predicted body weight) or low (≤8 ml/kg PBW) mean baseline tidal volume was planned a priori. Results: Seven trials were identified including 2,119 patients, of whom 1,088 received prone positioning. Overall, prone positioning was not significantly associated with the risk ratio of death (RR 0.83; 95 % CI 0.68-1.02; p = 0.073; I ;bsup& 2 ;esup& = 64 %). When stratified by high or low tidal volume, prone positioning was associated with a significant decrease in RR of death only among studies with low baseline tidal volume (RR 0.66; 95 % CI 0.50-0.86; p = 0.002; I ;bsup& 2 ;esup& = 25 %). Stratification by tidal volume explained over half the between-study heterogeneity observed in the unstratified analysis. Conclusions: Prone positioning is associated with significantly reduced mortality from ARDS in the low tidal volume era. Substantial heterogeneity across studies can be explained by differences in tidal volume. © 2013 Springer-Verlag Berlin Heidelberg and ESICM.

Published
2014
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8. A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus

Author

Lisa M. Fitzgerald, Katalin Kis-Toth, George C. Tsokos, Amy Devlin, Michele D. Finnell, Vasileios C. Kyttaris, and Alexandros P. Grammatikos

Subjects
Adult, Male, T cell, Immunology, Disease, Article, Pathogenesis, Transcriptome, Arthritis, Rheumatoid, immune system diseases, T-Lymphocyte Subsets, medicine, 2',5'-Oligoadenylate Synthetase, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, skin and connective tissue diseases, CD70, Aged, Regulation of gene expression, business.industry, Case-control study, Middle Aged, Interleukin-10, Interleukin 10, medicine.anatomical_structure, Cross-Sectional Studies, Gene Expression Regulation, Case-Control Studies, Leukocytes, Mononuclear, Female, business, Biomarkers, CD27 Ligand
Abstract

Systemic Lupus Erythematosus (SLE) remains a challenging disease to diagnose and follow, as no reliable biomarkers are known to date. We designed a gene expression panel with 40 genes known to play a role in SLE pathogenesis. We found that the combined expression of these genes in SLE T cells can accurately differentiate SLE from healthy individuals and patients with other autoimmune diseases. The accuracy of the test increased further (83%) when only three out of the initial genes (OAS2, CD70 and IL10) were used. A T cell score, calculated from the combined expression levels of these genes, correlated positively with various SLE activity markers in a cross-sectional cohort and in a few patients that were followed prospectively. These data showcase the usefulness of measuring mRNA levels of key molecules in diagnosing and following patients with SLE.

Published
2013

9. List of Contributors

Author

Mary E. Abusief, Dolores Acevedo-Garcia, Christine Albert, D. Lee Alekel, Laia Alemany, Kelli D. Allen, Lauren M. Anderson, Benjamin J. Apelberg, Hani K. Atrash, Donna Day Baird, Noel Bairey C. Merz, Carol M. Baldwin, Robert L. Barbieri, Shirley R. Baron, Shari S. Bassuk, Lisa M. Bates, Jeannette M. Beasley, Iris R. Bell, C.S. Bergeman, Lisa F. Berkman, Jonine L. Bernstein, Leslie Bernstein, Elizabeth R. Bertone-Johnson, Mieke Beth Thomeer, Toni L. Bisconti, Janet Blair, Robin P. Bonifas, Xavier F. Bosch, Judith Bradford, Freddie Bray, Jennifer D. Brooks, Joyce Bromberger, Joelle M. Brown, Laia Bruni, Cynthia M. Bulik, Ronald T. Burkman, Marcy Burstein, Cheryl Bushnell, Mary K. Buss, Jane A. Cauley, Connie L. Celum, Xinhua Chen, Myriam Chevarie-Davis, Stephanie Chiuve, Patricia O. Chocano-Bedoya, Harjinder Chowdhary, David C. Christiani, Nadia T. Chung, Carolyn M. Clancy, Cari Jo Clark, David Conen, K.H. Costenbader, Amy Devlin, Mireia Diaz, Jeroen Douwes, Mark Drangsholt, Ira Driscoll, Catherine E. DuBeau, Emmeline Edwards, Vera Ehrenstein, Agustín Escalante, Mark A. Espeland, Kathryn C. Fitzgerald, Betsy Foxman, Eduardo Franco, William D. Fraser, Karen I. Fredriksen-Goldsen, Ellen E. Freeman, Melissa C. Friesen, Anne M. Gadermann, Mia M. Gaudet, Emmy Gavrilidis, Charlotte A Gaydos, Kimberly Geronimo, Arline T. Geronimus, Robin Mary Gillespie, Edward Giovannucci, Karen Glanz, Robert J. Glynn, Ellen Gold, Shari Goldfarb, Marlene B. Goldman, Emily W. Gower, David A. Grainger, Adèle C. Green, Catherine L. Haggerty, Rebecca Hardy, Bernard L. Harlow, Siobán D. Harlow, Patricia Hartge, Christine Haskin, Robin Herbert, Victoria L. Holt, Robert N. Hoover, Maria K. Houtchens, Corinne G. Husten, Loris Y. Hwang, Noreen A. Hynes, Peter James, Elizabeth Jewell, Susan K. Johnson, Pamela Joshi, Corinne E. Joshu, Mary L. Kamb, Carrie Karvonen-Gutierrez, Ronald C. Kessler, Maheruh Khandker, Samia J. Khoury, Autumn M. Klein, Natasha A. Koloski, Diana Kuh, Jayashri Kulkarni, Lewis H. Kuller, James V. Lacey, Andrea Z. LaCroix, Francine Laden, Timothy L. Lash, Shannon K. Laughlin-Tommaso, Cathy C. Lee, Ji Youn Lee, Stephanie L. Lee, Linda LeResche, Suzanne G. Leveille, Jannet F. Lewis, Frank R. Lin, Stacy Tessler Lindau, Marja-Liisa Lindbohm, Simin Liu, Donald M. Lloyd-Jones, Joannie Lortet-Tieulent, Andrea Lucas, Rachel H. Mackey, Jeanne Mager Stellman, Ann Marie Malarcher, JoAnn E. Manson, Lynette J. Margesson, M. Maria Glymour, Jeanne M. Marrazzo, Karen Matthews, Suzanne E. Mazzeo, Ellen P. McCarthy, Valerie McCormack, Thomas F. McElrath, Romy-Leigh McMaster, Kathleen M. McTigue, Kathleen Ries Merikangas, C. Noel Bairey Merz, Karen Messing, Anthony B. Miller, Daniel R. Mishell, Stacey A. Missmer, Connie Mobley, Anna-Barbara Moscicki, Tyler Muffly, Christina A. Muzny, Amanda E. Nelson, Toben F. Nelson, Katharine K. O’Dell, Catherine M. Olsen, Sara H. Olson, Theresa L. Osypuk, Julie R. Palmer, Pangaja Paramsothy, Ann L. Parke, Heather Patrick, Jessica K. Paulus, Lynn Paxton, Neil Pearce, Tara Perti, Lindsay Pitzer, Elizabeth A. Platz, Nancy Potischman, Laura Punnett, Rosalind Ramsey-Goldman, Usha Ranji, Radhai M. Rastogi, Jane F. Reckelhoff, Barbara Resnick, Kathryn M. Rexrode, Ellen S. Rigterink, Eileen Rillamas-Sun, Cara A. Robinson, Jennifer G. Robinson, Mark E. Robson, Anne M. Rompalo, Audrey F. Saftlas, Alina Salganicoff, Markku Sallmén, Silvia de Sanjosé, Gloria E. Sarto, Samantha Sass, Sharon A. Savage, Joellen Schildkraut, Karen Schmaling, Anja Schmitz, Theresa O. Scholl, Jane R. Schwebke, Stacey B. Scott, Soraya Seedat, Mary V. Seeman, Adeline Seow, Rashmee U. Shah, Beth A. Collins Sharp, Hai-Rim Shin, Donna Shoupe, Debra T. Silverman, Rachel C. Snow, Eglacy C. Sophia, MaryFran R. Sowers, Heike Spaderna, Mandy Stahre, Elizabeth G. Stewart, Cynthia A. Stuenkel, Barbara Stussman, Sharain Suliman, Nicholas J. Talley, Helena Taskinen, Laura L. Tatpati, Linda J. Titus, Bruce L. Tjaden, Britton Trabert, Sara E. Trace, William Traverse, Rebecca Troisi, Philip J. Troped, Debra Umberson, Kristen Upson, Aimee Van Wagenen, Anna Wald, James K.C. Wang, Mary H. Ward, Shu-Qin Wei, Gerdi Weidner, Nicolas Wentzensen, James L. Whiteside, Kristi Williams, Gayle C. Windham, Ann E. Wiringa, Lauren A. Wise, Marion Wofford, Anna H. Wu, Kristine Yaffe, Frances M. Yang, Muhammad B. Yunus, Shelia Hoar Zahm, Chloe A. Zera, and Monica L. Zilberman

Published
2013
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