33 results on '"Mayte Suaréz-Fariñas"'
Search Results
2. Comprehensive Immunoprofiling of Pediatric Zika Reveals Key Role for Monocytes in the Acute Phase and No Effect of Prior Dengue Virus Infection
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Daniela Michlmayr, Eun-Young Kim, Adeeb H. Rahman, Rohit Raghunathan, Seunghee Kim-Schulze, Yan Che, Selim Kalayci, Zeynep H. Gümüş, Guillermina Kuan, Angel Balmaseda, Andrew Kasarskis, Steven M. Wolinsky, Mayte Suaréz-Fariñas, and Eva Harris
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Biology (General) ,QH301-705.5 - Abstract
Summary: Zika virus (ZIKV) is an emerging, mosquito-borne flavivirus responsible for recent epidemics across the Americas, and it is closely related to dengue virus (DENV). Here, we study samples from 46 DENV-naive and 43 DENV-immune patients with RT-PCR-confirmed ZIKV infection at early-acute, late-acute, and convalescent time points from our pediatric cohort study in Nicaragua. We analyze the samples via RNA sequencing (RNA-seq), CyTOF, and multiplex cytokine/chemokine Luminex to generate a comprehensive, innate immune profile during ZIKV infection. Immunophenotyping and analysis of cytokines/chemokines reveal that CD14+ monocytes play a key role during ZIKV infection. Further, we identify CD169 (Siglec-1) on CD14+ monocytes as a potential biomarker of acute ZIKV infection. Strikingly distinct transcriptomic and immunophenotypic signatures are observed at all three time points. Interestingly, pre-existing dengue immunity has minimal impact on the innate immune response to Zika. Finally, this comprehensive immune profiling and network analysis of ZIKV infection in children serves as a valuable resource. : At three time points after Zika virus infection, Michlmayr et al. perform comprehensive immunoprofiling of pediatric cohort samples via RNA-seq, CyTOF, and Luminex cytokine/chemokine array, resulting in distinct temporal patterns of gene expression, cell profiles, and cytokines/chemokines. They show CD14+ monocytes play a central role, identify CD169 as a potential biomarker of acute ZIKV infection along with upregulation of CXCL10, and find no impact of prior dengue virus infection on the innate immune response to Zika. Keywords: Zika virus, monocytes, dengue virus, innate immunity, immune profiling, RNA-seq, CyTOF, network model, biomarker, Luminex
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- 2020
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3. Infarct‐related structural disconnection and delirium in surgical aortic valve replacement patients
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Jeffrey N. Browndyke, Lewis E. Tomalin, Guray Erus, Jessica R. Overbey, Amy Kuceyeski, Alan J. Moskowitz, Emilia Bagiella, Alexander Iribarne, Michael Acker, Michael Mack, Joseph Mathew, Patrick O'Gara, Annetine C. Gelijns, Mayte Suarez‐Farinas, Steven R. Messé, and for the Cardiothoracic Surgical Trials Network (CTSN) Investigators
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Although acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically “silent” infarcts and in‐hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR. Methods A secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non‐White, 74 ± 7 years). Delirium during in‐hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas‐based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed‐effect, zero‐inflated gaussian modeling analyses, accounting for brain region‐specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy. Results 23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct‐related structural disconnection (DWI‐ISD) was observed in frontal and temporal lobe regions (p‐FDR
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- 2024
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4. To explore the causal association between the serum lipid profile and inflammatory bowel disease using bidirectional Mendelian randomisation analysis
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Mayte Suarez-Farinas, Xiaoli Pang, Huizhong Yang, Mingyu Li, and Suyan Tian
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background Despite studies confirming that patients with inflammatory bowel disease (IBD) present with dyslipidaemia, the associations between IBD and the serum lipid profile have not been determined. The present study aimed to investigate the causal relationship between the serum lipid profile and IBD risk and elucidate the nature of the interactions between them.Methods Two-sample Mendelian randomisation (MR) analysis was performed to investigate the causal links between total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo A), apolipoprotein B (Apo B) and lipoprotein (a) (Lp(a)) and IBD. The study was carried out using the R TwoSampleMR and Mendelian randomisation packages.Results All MR methods, including the weighted median, weighted mode, inverse-variance weighted model, MR-PRESSO, contamination mixture and MR Egger, supported a null causal relationship between TG, TC, HDL-C, LDL-C, Apo A, Apo B and Lp(a) and between IBD, Crohn’s disease and ulcerative colitis. Null causal effects of lipid indices on IBD were validated through independent genome-wide association studies (GWAS), indicating that the findings are robust.Conclusion Our findings suggest that none of the seven lipid indices may be a potential risk factor for the onset of IBD. However, additional research is needed since our MR analyses cannot assess the potential non-linear causal relationship between serum lipids and IBD.
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- 2024
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5. Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection
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Ishan Paranjpe, Pushkala Jayaraman, Chen-Yang Su, Sirui Zhou, Steven Chen, Ryan Thompson, Diane Marie Del Valle, Ephraim Kenigsberg, Shan Zhao, Suraj Jaladanki, Kumardeep Chaudhary, Steven Ascolillo, Akhil Vaid, Edgar Gonzalez-Kozlova, Justin Kauffman, Arvind Kumar, Manish Paranjpe, Ross O. Hagan, Samir Kamat, Faris F. Gulamali, Hui Xie, Joceyln Harris, Manishkumar Patel, Kimberly Argueta, Craig Batchelor, Kai Nie, Sergio Dellepiane, Leisha Scott, Matthew A. Levin, John Cijiang He, Mayte Suarez-Farinas, Steven G. Coca, Lili Chan, Evren U. Azeloglu, Eric Schadt, Noam Beckmann, Sacha Gnjatic, Miram Merad, Seunghee Kim-Schulze, Brent Richards, Benjamin S. Glicksberg, Alexander W. Charney, and Girish N. Nadkarni
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Medicine - Abstract
Abstract Background Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Methods Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p
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- 2023
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6. Achieving Better Understanding of Obstructive Sleep Apnea Treatment Effects on Cardiovascular Disease Outcomes through Machine Learning Approaches: A Narrative Review
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Oren Cohen, Vaishnavi Kundel, Philip Robson, Zainab Al-Taie, Mayte Suárez-Fariñas, and Neomi A. Shah
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obstructive sleep apnea ,cardiovascular disease ,machine learning ,artificial intelligence ,heterogeneity of treatment effects ,ethics in machine learning and artificial intelligence ,Medicine - Abstract
Obstructive sleep apnea (OSA) affects almost a billion people worldwide and is associated with a myriad of adverse health outcomes. Among the most prevalent and morbid are cardiovascular diseases (CVDs). Nonetheless, randomized controlled trials (RCTs) of OSA treatment have failed to show improvements in CVD outcomes. A major limitation in our field is the lack of precision in defining OSA and specifically subgroups with the potential to benefit from therapy. Further, this has called into question the validity of using the time-honored apnea–hypopnea index as the ultimate defining criteria for OSA. Recent applications of advanced statistical methods and machine learning have brought to light a variety of OSA endotypes and phenotypes. These methods also provide an opportunity to understand the interaction between OSA and comorbid diseases for better CVD risk stratification. Lastly, machine learning and specifically heterogeneous treatment effects modeling can help uncover subgroups with differential outcomes after treatment initiation. In an era of data sharing and big data, these techniques will be at the forefront of OSA research. Advanced data science methods, such as machine-learning analyses and artificial intelligence, will improve our ability to determine the unique influence of OSA on CVD outcomes and ultimately allow us to better determine precision medicine approaches in OSA patients for CVD risk reduction. In this narrative review, we will highlight how team science via machine learning and artificial intelligence applied to existing clinical data, polysomnography, proteomics, and imaging can do just that.
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- 2024
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7. The Immune Signatures data resource, a compendium of systems vaccinology datasets
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Joann Diray-Arce, Helen E. R. Miller, Evan Henrich, Bram Gerritsen, Matthew P. Mulè, Slim Fourati, Jeremy Gygi, Thomas Hagan, Lewis Tomalin, Dmitry Rychkov, Dmitri Kazmin, Daniel G. Chawla, Hailong Meng, Patrick Dunn, John Campbell, The Human Immunology Project Consortium (HIPC), Minnie Sarwal, John S. Tsang, Ofer Levy, Bali Pulendran, Rafick Sekaly, Aris Floratos, Raphael Gottardo, Steven H. Kleinstein, and Mayte Suárez-Fariñas
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Science - Abstract
Measurement(s) Transcriptomics • Hemagglutination Inhibition Assay • IgG IgM IgA Total Measurement • Virus-neutralizing Antibody • ELISA Technology Type(s) Microarray • RNA sequencing • Hemagglutination Inhibition Assay • ELISA • Microneutralization Assay • serum neutralization of viral infectivity assay Sample Characteristic - Organism Homo sapiens
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- 2022
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8. cosinoRmixedeffects: an R package for mixed-effects cosinor models
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Ruixue Hou, Lewis E. Tomalin, and Mayte Suárez-Fariñas
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Circadian data ,Cosinor ,Mixed-effects ,Wearable data ,R package ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Wearable devices enable monitoring and measurement of physiological parameters over a 24-h period, and some of which exhibit circadian rhythm characteristics. However, the currently available R package cosinor could only analyze daily cross-sectional data and compare the parameters between groups with two levels. To evaluate longitudinal changes in the circadian patterns, we need to extend the model to a mixed-effect model framework, allowing for random effects and interaction between COSINOR parameters and time-varying covariates. Results We developed the cosinoRmixedeffects R package for modelling longitudinal periodic data using mixed-effects cosinor models. The model allows for covariates and interactions with the non-linear parameters MESOR, amplitude, and acrophase. To facilitate ease of use, the package utilizes the syntax and functions of the widely used emmeans package to obtain estimated marginal means and contrasts. Estimation and hypothesis testing involving the non-linear circadian parameters are carried out using bootstrapping. We illustrate the package functionality by modelling daily measurements of heart rate variability (HRV) collected among health care workers over several months. Differences in circadian patterns of HRV between genders, BMI, and during infection with SARS-CoV2 are evaluated to illustrate how to perform hypothesis testing. Conclusion cosinoRmixedeffects package provides the model fitting, estimation and hypothesis testing for the mixed-effects COSINOR model, for the linear and non-linear circadian parameters MESOR, amplitude and acrophase. The model accommodates factors with any number of categories, as well as complex interactions with circadian parameters and categorical factors.
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- 2021
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9. The innate immune response following multivalent dengue vaccination and implications for protection against dengue challenge
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Ruixue Hou, Lewis E. Tomalin, Jessica Pintado Silva, Seunghee Kim-Schulze, Stephen S. Whitehead, Ana Fernandez-Sesma, Anna P. Durbin, and Mayte Suárez-Fariñas
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Immunology ,Infectious disease ,Medicine - Abstract
Understanding the immune response to dengue virus (DENV) is essential for developing a dengue vaccine that is protective against all 4 DENV serotypes. We evaluated the immune response after vaccination (live attenuated tetravalent dengue vaccine TV005 or trivalent admixture) and after challenge with DEN2Δ30 (Tonga/74) to better understand the importance of homotypic immunity in vaccine protection. Significant increases in IP-10 expression were observed following receipt of either the trivalent or tetravalent vaccine. After challenge, a large increase in IP-10 expression was observed in the placebo and trivalent admixture groups but not in the tetravalent vaccine group. MCP-1, IL-1RA, and MIP-1β exhibited a similar pattern as IP-10. These results demonstrate protective effects of trivalent and tetravalent vaccines against DENV and suggest that the tetravalent vaccine has a better protective effect compared with the trivalent admixture. We also explored the postvaccination and postchallenge immune response differences between Black and White participants. White participants responded to vaccine differently than Black participants; Black participants receiving trivalent and tetravalent vaccines responded strongly and White participants responded only transiently in trivalent group. In response to challenge, White participants elicited a stronger response than Black participants. These results may explain why White participants may have a more vigorous DENV immune response than Black participants, as reported in literature.
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- 2022
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10. Deep Analysis of the Peripheral Immune System in IBD Reveals New Insight in Disease Subtyping and Response to Monotherapy or Combination TherapySummary
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Roman Kosoy, Seunghee Kim-Schulze, Adeeb Rahman, Joshua R. Friedman, Ruiqi Huang, Lauren A. Peters, El-ad Amir, Jacqueline Perrigoue, Aleksandar Stojmirovic, Won-min Song, Hao Ke, Ryan Ungaro, Saurabh Mehandru, Judy Cho, Marla Dubinsky, Mark Curran, Carrie Brodmerkel, Eric E. Schadt, Bruce E. Sands, Jean-Frederic Colombel, Andrew Kasarskis, Carmen A. Argmann, and Mayte Suárez-Fariñas
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Immunophenotype ,FACS ,CyTOF ,Anti-TNF ,Thiopurine ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background: Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations. Methods: We performed fluorescence-activated cell sorting or CyTOF analysis on blood from 728 Crohn’s disease, 464 ulcerative colitis, and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use. Results: We observed few immune cell types commonly affected in IBD (lowered natural killer cells, B cells, and CD45RA– CD8 T cells). Generally, the immunophenome was distinct between ulcerative colitis and Crohn’s disease. Within disease subtype, there were further distinctions, with specific immune cell types associating with disease duration, behavior, and location. Thiopurine monotherapy altered abundance of many cell types, often in the same direction as disease association, while anti-tumor necrosis factor (anti-TNF) monotherapy demonstrated an opposing pattern. Concomitant use of an anti-TNF and thiopurine was not synergistic, but rather was additive. For example, thiopurine monotherapy use alone or in combination with anti-TNF was associated with a dramatic reduction in major subclasses of B cells. Conclusions: We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs.
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- 2021
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11. HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy
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Kanika Kanchan, Stepan Grinek, Henry T. Bahnson, Ingo Ruczinski, Gautam Shankar, David Larson, George Du Toit, Kathleen C. Barnes, Hugh A. Sampson, Mayte Suarez-Farinas, Gideon Lack, Gerald T. Nepom, Karen Cerosaletti, and Rasika A. Mathias
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Genetics ,Immunology ,Medicine - Abstract
We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection.
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- 2022
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12. Factors Associated With Longitudinal Psychological and Physiological Stress in Health Care Workers During the COVID-19 Pandemic: Observational Study Using Apple Watch Data
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Robert P Hirten, Matteo Danieletto, Lewis Tomalin, Katie Hyewon Choi, Micol Zweig, Eddye Golden, Sparshdeep Kaur, Drew Helmus, Anthony Biello, Renata Pyzik, Claudia Calcagno, Robert Freeman, Bruce E Sands, Dennis Charney, Erwin P Bottinger, James W Murrough, Laurie Keefer, Mayte Suarez-Farinas, Girish N Nadkarni, and Zahi A Fayad
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Public aspects of medicine ,RA1-1270 - Abstract
BackgroundThe COVID-19 pandemic has resulted in a high degree of psychological distress among health care workers (HCWs). There is a need to characterize which HCWs are at an increased risk of developing psychological effects from the pandemic. Given the differences in the response of individuals to stress, an analysis of both the perceived and physiological consequences of stressors can provide a comprehensive evaluation of its impact. ObjectiveThis study aimed to determine characteristics associated with longitudinal perceived stress in HCWs and to assess whether changes in heart rate variability (HRV), a marker of autonomic nervous system function, are associated with features protective against longitudinal stress. MethodsHCWs across 7 hospitals in New York City, NY, were prospectively followed in an ongoing observational digital study using the custom Warrior Watch Study app. Participants wore an Apple Watch for the duration of the study to measure HRV throughout the follow-up period. Surveys measuring perceived stress, resilience, emotional support, quality of life, and optimism were collected at baseline and longitudinally. ResultsA total of 361 participants (mean age 36.8, SD 10.1 years; female: n=246, 69.3%) were enrolled. Multivariate analysis found New York City’s COVID-19 case count to be associated with increased longitudinal stress (P=.008). Baseline emotional support, quality of life, and resilience were associated with decreased longitudinal stress (P
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- 2021
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13. Dietary restriction in the long-chain acyl-CoA dehydrogenase knockout mouse
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Eugène F. Diekman, Michel van Weeghel, Mayte Suárez-Fariñas, Carmen Argmann, Pablo Ranea-Robles, Ronald J.A. Wanders, Gepke Visser, Ingeborg van der Made, Esther E. Creemers, and Sander M. Houten
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Mouse model ,Dietary restriction ,Caloric restriction ,Fatty acid oxidation ,Cardiac function ,Inborn error of metabolism ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Patients with a disorder of mitochondrial long-chain fatty acid β-oxidation (FAO) have reduced fasting tolerance and may present with hypoketotic hypoglycemia, hepatomegaly, (cardio)myopathy and rhabdomyolysis. Patients should avoid a catabolic state because it increases reliance on FAO as energy source. It is currently unclear whether weight loss through a reduction of caloric intake is safe in patients with a FAO disorder. We used the long-chain acyl-CoA dehydrogenase knockout (LCAD KO) mouse model to study the impact of dietary restriction (DR) on the plasma metabolite profile and cardiac function. For this, LCAD KO and wild type (WT) mice were subjected to DR (70% of ad libitum chow intake) for 4 weeks and compared to ad libitum chow fed mice. We found that DR had a relatively small impact on the plasma metabolite profile of WT and LCAD KO mice. Echocardiography revealed a small decrease in left ventricular systolic function of LCAD KO mice, which was most noticeable after DR, but there was no evidence of DR-induced cardiac remodeling. Our results suggest that weight loss through DR does not have acute and detrimental consequences in a mouse model for FAO disorders.
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- 2021
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14. The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins
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Patrick M. Brunner, Mayte Suárez-Fariñas, Helen He, Kunal Malik, Huei-Chi Wen, Juana Gonzalez, Tom Chih-Chieh Chan, Yeriel Estrada, Xiuzhong Zheng, Saakshi Khattri, Annunziata Dattola, James G. Krueger, and Emma Guttman-Yassky
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Medicine ,Science - Abstract
Abstract Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-β) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.
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- 2017
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15. Gut microbiota density influences host physiology and is shaped by host and microbial factors
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Eduardo J Contijoch, Graham J Britton, Chao Yang, Ilaria Mogno, Zhihua Li, Ruby Ng, Sean R Llewellyn, Sheela Hira, Crystal Johnson, Keren M Rabinowitz, Revital Barkan, Iris Dotan, Robert P Hirten, Shih-Chen Fu, Yuying Luo, Nancy Yang, Tramy Luong, Philippe R Labrias, Sergio Lira, Inga Peter, Ari Grinspan, Jose C Clemente, Roman Kosoy, Seunghee Kim-Schulze, Xiaochen Qin, Anabella Castillo, Amanda Hurley, Ashish Atreja, Jason Rogers, Farah Fasihuddin, Merjona Saliaj, Amy Nolan, Pamela Reyes-Mercedes, Carina Rodriguez, Sarah Aly, Kenneth Santa-Cruz, Lauren Peters, Mayte Suárez-Fariñas, Ruiqi Huang, Ke Hao, Jun Zhu, Bin Zhang, Bojan Losic, Haritz Irizar, Won-Min Song, Antonio Di Narzo, Wenhui Wang, Benjamin L Cohen, Christopher DiMaio, David Greenwald, Steven Itzkowitz, Aimee Lucas, James Marion, Elana Maser, Ryan Ungaro, Steven Naymagon, Joshua Novak, Brijen Shah, Thomas Ullman, Peter Rubin, James George, Peter Legnani, Shannon E Telesco, Joshua R Friedman, Carrie Brodmerkel, Scott Plevy, Judy H Cho, Jean-Frederic Colombel, Eric E Schadt, Carmen Argmann, Marla Dubinsky, Andrew Kasarskis, Bruce Sands, and Jeremiah J Faith
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gut microbiome ,microbiota density ,inflammatory bowel disease ,fecal microbiota transplantation ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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- 2019
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16. Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
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Lauren K Hoffman, Lewis E Tomalin, Gregory Schultz, Michael D Howell, Niroshana Anandasabapathy, Afsaneh Alavi, Mayte Suárez-Fariñas, and Michelle A Lowes
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Medicine ,Science - Abstract
Hidradenitis suppurativa (HS) is a chronic skin disease of the pilo-sebaceous apocrine unit characterized by significant inflammation and an impaired quality of life. The pathogenesis of HS remains unclear. To determine the HS skin and blood transcriptomes and HS blood proteome, patient data from previously published studies were analysed and integrated from a cohort of patients with moderate to severe HS (n = 17) compared to healthy volunteers (n = 10). The analysis utilized empirical Bayes methods to determine differentially expressed genes (DEGs) (fold change (FCH) >2.0 and false discovery rate (FDR) 1.5, FDR
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- 2018
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17. Molecular and Cellular Profiling of Scalp Psoriasis Reveals Differences and Similarities Compared to Skin Psoriasis.
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Juan Ruano, Mayte Suárez-Fariñas, Avner Shemer, Margeaux Oliva, Emma Guttman-Yassky, and James G Krueger
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Medicine ,Science - Abstract
Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis in other skin areas. We sought to determine the cellular and molecular phenotype of scalp psoriasis by performing a comparative analysis of scalp and skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement and 10 control subjects without psoriasis. Our results suggest that even in the scalp, psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprint were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with that of skin psoriasis, which was mainly associated with activation of TNFα/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes.
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- 2016
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18. Based on Molecular Profiling of Gene Expression, Palmoplantar Pustulosis and Palmoplantar Pustular Psoriasis Are Highly Related Diseases that Appear to Be Distinct from Psoriasis Vulgaris.
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Robert Bissonnette, Mayte Suárez-Fariñas, Xuan Li, Kathleen M Bonifacio, Carrie Brodmerkel, Judilyn Fuentes-Duculan, and James G Krueger
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Medicine ,Science - Abstract
INTRODUCTION:There is a controversy surrounding the existence of palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) as separate clinical entities or as variants of the same clinical entity. We used gene expression microarray to compare gene expression in PPP and PPPP. METHODOLOGY/PRINCIPAL FINDINGS:Skin biopsies from subjects with PPP (3), PPPP (6), psoriasis vulgaris (10) and acral skin from normal subjects (7) were analyzed using gene expression microarray. Principal component analysis showed that PPP and PPPP were different from psoriasis vulgaris and normal acral skin. However gene expression of PPP and PPPP clustered together and could not be used to differentiate PPP from PPPP. Gene-wise comparison between PPP and PPPP found no gene to be differentially expressed at a false discovery rate lower than 0.05. Surprisingly we found a higher expression of several genes involved in neural pathways (e.g. GPRIN and ADAM23) in PPP/PPPP as compared to psoriasis vulgaris and normal acral skin. Immunohistochemistry confirmed those findings and showed a keratinocyte localization for those proteins. CONCLUSION SIGNIFICANCE:PPP and PPPP could not be differentiated using gene expression microarray suggesting that they are not distinct clinical entities. Increased expression of GPRIN1, and ADAM23 in keratinocytes suggests that these proteins could be new therapeutic targets for PPP/PPPP.
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- 2016
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19. Correction: Based on Molecular Profiling of Gene Expression, Palmoplantar Pustulosis and Palmoplantar Pustular Psoriasis Are Highly Related Diseases that Appear to Be Distinct from Psoriasis Vulgaris.
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Robert Bissonnette, Mayte Suárez-Fariñas, Xuan Li, Kathleen M Bonifacio, Carrie Brodmerkel, Judilyn Fuentes-Duculan, and James G Krueger
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0155215.].
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- 2016
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20. Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models
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Liliana Menalled, Bassem F. El-Khodor, Monica Patry, Mayte Suárez-Fariñas, Samantha J. Orenstein, Benjamin Zahasky, Christina Leahy, Vanessa Wheeler, X. William Yang, Marcy MacDonald, A. Jennifer Morton, Gill Bates, Janet Leeds, Larry Park, David Howland, Ethan Signer, Allan Tobin, and Daniela Brunner
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies. With a battery of tests of sensory-motor function, such as the open field and prepulse inhibition tests, we replicate previous results showing a strong and progressive behavioral deficit in the R6/2 line with an average of 129 CAG repeats in a mixed CBA/J and C57BL/6J background. We present the first behavioral characterization of a new model, an R6/2 line with an average of 248 CAG repeats in a pure C57BL/6J background, which also showed a progressive and robust phenotype. The BACHD in a FVB/N background showed robust and progressive behavioral phenotype, while the YAC128 full-length model on either an FVB/N or a C57BL/6J background generally showed milder deficits. Finally, the HdhQ111 knock-in mouse on a CD1 background showed very mild deficits. This first extensive standardized cross-characterization of several HD animal models under standardized conditions highlights several behavioral outcomes, such as hypoactivity, amenable to standardized preclinical therapeutic drug screening.
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- 2009
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21. Psoriasis is characterized by deficient negative immune regulation compared to transient delayed-type hypersensitivity reactions [v1; ref status: indexed, http://f1000r.es/5ga]
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Nicholas Gulati, Mayte Suárez-Fariñas, Joel Correa da Rosa, and James G. Krueger
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Control of Gene Expression ,Dermatologic Pharmacology ,Genomics ,Medicine ,Science - Abstract
Diphencyprone (DPCP) is a hapten that causes delayed-type hypersensitivity (DTH) reactions in human skin, and is used as a topical therapeutic for alopecia areata, warts, and cutaneous melanoma metastases. We examined peak DTH reactions induced by DPCP (3 days post-challenge) by comprehensive gene expression and histological analysis. To better understand how these DTH reactions naturally resolve, we compared our DPCP biopsies to those from patients with psoriasis vulgaris, a chronic inflammatory disease that does not resolve. By both microarray and qRT-PCR, we found that psoriasis lesional skin has significantly lower expression of many negative immune regulators compared to peak DPCP reactions. These regulators include: interleukin-10, cytotoxic T lymphocyte-associated 4 (CTLA4), programmed cell death 1 (PD1), programmed cell death 1 ligand 1 (PDL1), programmed cell death 1 ligand 2 (PDL2), and indoleamine 2,3-dioxygenase (IDO1). Their decreased expression was confirmed at the protein level by immunohistochemistry. To more completely determine the balance of positive vs. negative immune regulators in both DPCP reactions and psoriasis, we developed one comprehensive gene list for positive regulatory (inflammatory) genes, and another for negative regulatory (immunosuppressive) genes, through Gene Ontology terms and literature review. With this approach, we found that DPCP reactions have a higher ratio of negative to positive regulatory genes (both in terms of quantity and expression levels) than psoriasis lesional skin. These data suggest that the disease chronicity that distinguishes psoriasis from transient DTH reactions may be related to absence of negative immune regulatory pathways, and induction of these is therefore of therapeutic interest. Further study of these negative regulatory mechanisms that are present in DPCP reactions, but not in psoriasis, could reveal novel players in the pathogenesis of chronic inflammation. The DPCP system used here thus provides a tractable model for primary discovery of pathways potentially involved in immune regulation in peripheral tissues.
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- 2015
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22. A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.
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James G Krueger, Mayte Suárez-Fariñas, Inna Cueto, Artemis Khacherian, Robert Matheson, Lawrence C Parish, Craig Leonardi, Denise Shortino, Akanksha Gupta, Jonathan Haddad, George P Vlasuk, and Eric W Jacobson
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Medicine ,Science - Abstract
Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p
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- 2015
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23. Histological Stratification of Thick and Thin Plaque Psoriasis Explores Molecular Phenotypes with Clinical Implications.
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Jaehwan Kim, Pranay Nadella, Dong Joo Kim, Carrie Brodmerkel, Joel Correa da Rosa, James G Krueger, and Mayte Suárez-Fariñas
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Medicine ,Science - Abstract
Psoriasis, which presents as red, scaly patches on the body, is a common, autoimmune skin disease that affects 2 to 3 percent of the world population. To leverage recent molecular findings into the personalized treatment of psoriasis, we need a strategy that integrates clinical stratification with molecular phenotyping. In this study, we sought to stratify psoriasis patients by histological measurements of epidermal thickness, and to compare their molecular characterizations by gene expression, serum cytokines, and response to biologics. We obtained histological measures of epidermal thickness in a cohort of 609 psoriasis patients, and identified a mixture of two subpopulations-thick and thin plaque psoriasis-from which they were derived. This stratification was verified in a subcohort of 65 patients from a previously published study with significant differences in inflammatory cell infiltrates in the psoriatic skin. Thick and thin plaque psoriasis shared 84.8% of the meta-analysis-derived psoriasis transcriptome, but a stronger dysregulation of the meta-analysis-derived psoriasis transcriptome was seen in thick plaque psoriasis on microarray. RT-PCR revealed that gene expression in thick and thin plaque psoriasis was different not only within psoriatic lesional skin but also in peripheral non-lesional skin. Additionally, differences in circulating cytokines and their changes in response to biologic treatments were found between the two subgroups. All together, we were able to integrate histological stratification with molecular phenotyping as a way of exploring clinical phenotypes with different expression levels of the psoriasis transcriptome and circulating cytokines.
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- 2015
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24. CARD14 expression in dermal endothelial cells in psoriasis.
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Jamie L Harden, Steven M Lewis, Katherine C Pierson, Mayte Suárez-Fariñas, Tim Lentini, Francesca S Ortenzio, Lisa C Zaba, Raphaela Goldbach-Mansky, Anne M Bowcock, and Michelle A Lowes
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Medicine ,Science - Abstract
Mutations in the caspase recruitment domain, family member 14 (CARD14) gene have recently been described in psoriasis patients, and explain the psoriasis susceptibility locus 2 (PSORS2). CARD14 is a scaffolding protein that regulates NF-κB activation, and psoriasis-associated CARD14 mutations lead to enhanced NF-κB signaling. CARD14 is expressed mainly in epidermal keratinocytes, but also in unidentified dermal cells. In this manuscript, the identity of the dermal cell types expressing CARD14, as well the potential functional consequence of overactive CARD14 in these dermal cell types, was determined. Using two-color immunofluorescence, dermal CARD14 did not co-localize with T-cells, dendritic cells, or macrophages. However, dermal CARD14 did highly co-localize with CD31(+) endothelial cells (ECs). CARD14 was also expressed non-dermal endothelial cells, such as aortic endothelial cells, which may indicate a role of CARD14(+)ECs in the systemic inflammation and cardiovascular comorbidities associated with psoriasis. Additionally, phosphorylated NF-κB was found in psoriatic CARD14(+) CD31(+) ECs, demonstrating this pathway is active in dermal ECs in psoriasis. Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. These results provide preliminary evidence that CARD14 expression in ECs may contribute to psoriasis through increased expression of chemokines and facilitating recruitment of immune cells into skin.
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- 2014
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25. IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model.
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Andrea Chiricozzi, Kristine E Nograles, Leanne M Johnson-Huang, Judilyn Fuentes-Duculan, Irma Cardinale, Kathleen M Bonifacio, Nicholas Gulati, Hiroshi Mitsui, Emma Guttman-Yassky, Mayte Suárez-Fariñas, and James G Krueger
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Medicine ,Science - Abstract
IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the "RHE" genes in psoriasis patients treated in vivo with this IL-17 antagonist.
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- 2014
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26. Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma.
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Shali Zhang, Hideki Fujita, Hiroshi Mitsui, Valerie R Yanofsky, Judilyn Fuentes-Duculan, Julia S Pettersen, Mayte Suárez-Fariñas, Juana Gonzalez, Claire Q F Wang, James G Krueger, Diane Felsen, and John A Carucci
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Medicine ,Science - Abstract
Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-γ producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.
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- 2013
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27. Multi-TGDR: a regularization method for multi-class classification in microarray experiments.
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Suyan Tian and Mayte Suárez-Fariñas
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Medicine ,Science - Abstract
As microarray technology has become mature and popular, the selection and use of a small number of relevant genes for accurate classification of samples has arisen as a hot topic in the circles of biostatistics and bioinformatics. However, most of the developed algorithms lack the ability to handle multiple classes, arguably a common application. Here, we propose an extension to an existing regularization algorithm, called Threshold Gradient Descent Regularization (TGDR), to specifically tackle multi-class classification of microarray data. When there are several microarray experiments addressing the same/similar objectives, one option is to use a meta-analysis version of TGDR (Meta-TGDR), which considers the classification task as a combination of classifiers with the same structure/model while allowing the parameters to vary across studies. However, the original Meta-TGDR extension did not offer a solution to the prediction on independent samples. Here, we propose an explicit method to estimate the overall coefficients of the biomarkers selected by Meta-TGDR. This extension permits broader applicability and allows a comparison between the predictive performance of Meta-TGDR and TGDR using an independent testing set.Using real-world applications, we demonstrated the proposed multi-TGDR framework works well and the number of selected genes is less than the sum of all individualized binary TGDRs. Additionally, Meta-TGDR and TGDR on the batch-effect adjusted pooled data approximately provided same results. By adding Bagging procedure in each application, the stability and good predictive performance are warranted.Compared with Meta-TGDR, TGDR is less computing time intensive, and requires no samples of all classes in each study. On the adjusted data, it has approximate same predictive performance with Meta-TGDR. Thus, it is highly recommended.
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- 2013
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28. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation.
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Mayte Suárez-Fariñas, Robert Arbeit, Weiwen Jiang, Francesca S Ortenzio, Tim Sullivan, and James G Krueger
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Medicine ,Science - Abstract
Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR < 0.05) including IL-17 pathways that are up-regulated in psoriasis vulgaris. Targeting TLRs 7, 8 and 9 with IMO-8400 resulted in modulation of more than 2300 mRNAs while targeting TLRs 7 and 9 with IMO-3100 resulted in modulation of more than 1900 mRNAs. Both agents strongly decreased IL-17A expression (>12-fold reduction), normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia). These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology.
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- 2013
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29. Post-therapeutic relapse of psoriasis after CD11a blockade is associated with T cells and inflammatory myeloid DCs.
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Leanne M Johnson-Huang, Cara A Pensabene, Kejal R Shah, Katherine C Pierson, Toyoko Kikuchi, Tim Lentini, Patricia Gilleaudeau, Mary Sullivan-Whalen, Inna Cueto, Artemis Khatcherian, Luke A Hyder, Mayte Suárez-Fariñas, James G Krueger, and Michelle A Lowes
- Subjects
Medicine ,Science - Abstract
UnlabelledTo understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3(+) T cells, neutrophils, CD11c(+) and CD83(+) myeloid dendritic cells (DCs), but no increase in CD1c(+) resident myeloid DCs. In relapsed lesions, there were many CD11c(+)CD1c(-), inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c(+) cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis.Trial registrationClinicaltrials.gov NCT00115076.
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- 2012
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30. Meta-analysis derived (MAD) transcriptome of psoriasis defines the 'core' pathogenesis of disease.
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Suyan Tian, James G Krueger, Katherine Li, Ali Jabbari, Carrie Brodmerkel, Michelle A Lowes, and Mayte Suárez-Fariñas
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Medicine ,Science - Abstract
The cause of psoriasis, a common chronic inflammatory skin disease, is not fully understood. Microarray experiments have been widely used in recent years to identify genes associated with psoriasis pathology, by comparing expression levels of lesional (LS) with adjacent non-lesional (NL) skin. It is commonly observed that the differentially expressed genes (DEGs) differ greatly across experiments, due to variations introduced in the microarray experiment pipeline. Therefore, a statistically based meta-analytic approach, which combines the results of individual studies, is warranted. In this study, a meta-analysis was conducted on 5 microarray data sets, including 193 LS and NL pairs. We termed this the Meta-Analysis Derived (MAD) transcriptome. In "MAD-5" transcriptome, 677 genes were up-regulated and 443 were down-regulated in LS skin compared to NL skin. This represents a much larger set than the intersection of DEGs of these 5 studies, which consisted of 100 DEGs. We also analyzed 3 of the studies conducted on the Affymetrix hgu133plus2 chips and found a greater number of DEGs (1084 up- and 748 down-regulated). Top canonical pathways over-represented in the MAD transcriptome include Atherosclerosis Signaling and Fatty Acid Metabolism, while several "new" genes identified are involved in Cardiovascular Development and Lipid Metabolism. These findings highlight the relationship between psoriasis and systemic manifestations such as the metabolic syndrome and cardiovascular disease. Then, the Meta Threshold Gradient Descent Regularization (MTGDR) algorithm was used to select potential markers distinguishing LS and NL skin. The resulting set (20 genes) contained many genes that were part of the residual disease genomic profile (RDGP) or "molecular scar" after successful treatment, and also genes subject to differential methylation in LS tissues. To conclude, this MAD transcriptome yielded a reference list of reliable psoriasis DEGs, and represents a robust pool of candidates for further discovery of pathogenesis and treatment evaluation.
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- 2012
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31. Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β.
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Pamela Aubert, Mayte Suárez-Fariñas, Hiroshi Mitsui, Leanne M Johnson-Huang, Jamie Lynn Harden, Katherine C Pierson, Joseph G Dolan, Inna Novitskaya, Israel Coats, Jacob Estes, Edward W Cowen, Nicole Plass, Chyi-Chia Richard Lee, Hong-Wei Sun, Michelle A Lowes, and Raphaela Goldbach-Mansky
- Subjects
Medicine ,Science - Abstract
The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+) dermal dendritic cells and CD163(+) macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+) T cells and HLA-DR(+) cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.
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- 2012
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32. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.
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Mayu O Frank, Julia Kaufman, Suyan Tian, Mayte Suárez-Fariñas, Salina Parveen, Nathalie E Blachère, Michael J Morris, Susan Slovin, Howard I Scher, Matthew L Albert, and Robert B Darnell
- Subjects
Medicine ,Science - Abstract
Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.
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- 2010
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33. Evaluation of the psoriasis transcriptome across different studies by gene set enrichment analysis (GSEA).
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Mayte Suárez-Fariñas, Michelle A Lowes, Lisa C Zaba, and James G Krueger
- Subjects
Medicine ,Science - Abstract
BackgroundOur objective was to develop a consistent molecular definition of psoriasis. There have been several published microarray studies of psoriasis, and we compared disease-related genes identified across these different studies of psoriasis with our own in order to establish a consensus.Methodology/principal findingsWe present a psoriasis transcriptome from a group of 15 patients enrolled in a clinical study, and assessed its biological validity using a set of important pathways known to be involved in psoriasis. We also identified a key set of cytokines that are now strongly implicated in driving disease-related pathology, but which are not detected well on gene array platforms and require more sensitive methods to measure mRNA levels in skin tissues. Comparison of our transcriptome with three other published lists of psoriasis genes showed apparent inconsistencies based on the number of overlapping genes. We extended the well-established approach of Gene Set Enrichment Analysis (GSEA) to compare a new study with these other published list of differentially expressed genes (DEG) in a more comprehensive manner. We applied our method to these three published psoriasis transcriptomes and found them to be in good agreement with our study.Conclusions/significanceDue to wide variability in clinical protocols, platform and sample handling, and subtle disease-related signals, intersection of published DEG lists was unable to establish consensus between studies. In order to leverage the power of multiple transcriptomes reported by several laboratories using different patients and protocols, more sophisticated methods like the extension of GSEA presented here, should be used in order to overcome the shortcomings of overlapping individual DEG approach.
- Published
- 2010
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