Recognition Of Antigen-Specific B-Cell Receptors From Chronic Lymphocytic Leukemia Patients By Synthetic Antigen Surrogates,
2014
Zucker School of Medicine at Hofstra/Northwell
Recognition Of Antigen-Specific B-Cell Receptors From Chronic Lymphocytic Leukemia Patients By Synthetic Antigen Surrogates, M. Sarkar, Y. Liu, J. Morimoto, H. Peng, C. Aquino, C. Rader, N. Chiorazzi, T. Kodadek
Journal Articles
In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with …
The Role Of Skin Trauma In The Distribution Of Morphea Lesions: A Cross-Sectional Survey Of The Morphea In Adults And Children Cohort Iv,
2014
Northwell Health
The Role Of Skin Trauma In The Distribution Of Morphea Lesions: A Cross-Sectional Survey Of The Morphea In Adults And Children Cohort Iv, D. Grabell, C. Hsieh, R. Andrew, K. Martires, A. Kim, R. Vasquez, H. Jacobe
Journal Articles
Background: Skin trauma may play a role in the development of morphea lesions. The association between trauma and the distribution of cutaneous lesions has never been examined to our knowledge. Objective: We sought to determine whether patients enrolled in the Morphea in Adults and Children (MAC) cohort exhibit skin lesions distributed in areas of prior (isotopic) or ongoing (isomorphic) trauma. Methods: This was a cross-sectional analysis of the MAC cohort. Results: Of 329 patients in the MAC cohort, 52 (16%) had trauma-associated lesions at the onset of disease. Patients with lesions in an isotopic distribution had greater clinical severity as …
Splenic B-1a Cells Expressing Cd138 Spontaneously Secrete Large Amounts Of Immunoglobulin In Naive Mice,
2014
Northwell Health
Splenic B-1a Cells Expressing Cd138 Spontaneously Secrete Large Amounts Of Immunoglobulin In Naive Mice, N. E. Holodick, T. Vizconde, T. L. Rothstein
Journal Articles
B-1a cells constitutively secrete natural antibody that provides immediate protection against microbial pathogens and functions homeostatically to speed removal of apoptotic cell debris. Although B-1a cells are especially prominent in the peritoneal and pleural cavities, some B-1a cells reside in the spleen. A small subset of splenic B-1a cells in naive, unimmunized mice express CD138, a recognized plasma cell antigen, whereas the bulk of splenic B-1a cells are CD138 negative. Splenic B-1a cells in toto have been shown to generate much more antibody per cell than peritoneal B-1a cells; however, specific functional information regarding CD138(+) splenic B-1a cells has been …
Structure And Function Of Renal Macrophages And Dendritic Cells From Lupus-Prone Mice,
2014
Northwell Health
Structure And Function Of Renal Macrophages And Dendritic Cells From Lupus-Prone Mice, R. Sahu, R. Bethunaickan, S. Singh, A. Davidson
Journal Articles
Objective. To characterize renal macrophages and dendritic cells (DCs) in 2 murine models of lupus nephritis. Methods. We used a bead-based enrichment step followed by cell sorting to isolate populations of interest from young mice and nephritic mice. Cell morphology was examined by microscopy. Arginase and nitrite production was examined using biochemical assays. The antigen-presenting functions of the cells were determined using mixed lymphocyte reactions. Selected cytokine, chemokine, and Toll-like receptor (TLR) profiles were examined using real-time quantitative polymerase chain reaction. Results. We identified 2 populations of macrophages and 3 populations of DCs in both of our murine models of …
User Centered Clinical Decision Support Tools: Adoption Across Clinician Training Level,
2014
Northwell Health
User Centered Clinical Decision Support Tools: Adoption Across Clinician Training Level, L. J. Mccullagh, A. Sofianou, J. Kannry, D. M. Mann, T. G. Mcginn
Journal Articles
BACKGROUND: Dissemination and adoption of clinical decision support (CDS) tools is a major initiative of the Affordable Care Act's Meaningful Use program. Adoption of CDS tools is multipronged with personal, organizational, and clinical settings factoring into the successful utilization rates. Specifically, the diffusion of innovation theory implies that 'early adopters' are more inclined to use CDS tools and younger physicians tend to be ranked in this category. OBJECTIVE: This study examined the differences in adoption of CDS tools across providers' training level. PARTICIPANTS: From November 2010 to 2011, 168 residents and attendings from an academic medical institution were enrolled into …
A 129-Kb Deletion On Chromosome 12 Confers Substantial Protection Against Rheumatoid Arthritis, Implicating The Gene Slc2a3,
2014
Zucker School of Medicine at Hofstra/Northwell
A 129-Kb Deletion On Chromosome 12 Confers Substantial Protection Against Rheumatoid Arthritis, Implicating The Gene Slc2a3, C. D. Veal, K. E. Reekie, J. C. Lorentzen, P. K. Gregersen, L. Padyukov, A. J. Brookes
Journal Articles
We describe a copy-number variant (CNV) for which deletion alleles confer a protective affect against rheumatoid arthritis (RA). This CNV reflects net unit deletions and expansions to a normal two-unit tandem duplication located on human chr12p13.31, a region with conserved synteny to the rat RA susceptibility quantitative trait loci Oia2. Genotyping, using the paralogue ratio test and SNP intensity data, in Swedish samples (2,403 cases, 1,269 controls) showed that the frequency of deletion variants is significantly lower in cases (P=0.0012, OR=0.442 [95%CI 0.258-0.755]). Reduced frequencies of deletion variants were also seen in replication materials comprising 9,201 UK samples (1,846 cases, …
Drivers Of Hospitalization For Patients With Atrial Fibrillation: Results From The Outcomes Registry For Better Informed Treatment Of Atrial Fibrillation (Orbit-Af),
2014
Zucker School of Medicine at Hofstra/Northwell
Drivers Of Hospitalization For Patients With Atrial Fibrillation: Results From The Outcomes Registry For Better Informed Treatment Of Atrial Fibrillation (Orbit-Af), B. A. Steinberg, S. Kim, G. C. Fonarow, L. Thomas, J. Ansell, P. R. Kowey, K. W. Mahaffey, B. J. Gersh, E. Hylek, Informed Outcomes Registry Better, +6 Additional Authors
Journal Articles
Background Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF. Methods The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization. Results Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = …
D-Dimer As A Predictor Of Venous Thromboembolism In Acutely Ill, Hospitalized Patients: A Subanalysis Of The Randomized Controlled Magellan Trial,
2014
Zucker School of Medicine at Hofstra/Northwell
D-Dimer As A Predictor Of Venous Thromboembolism In Acutely Ill, Hospitalized Patients: A Subanalysis Of The Randomized Controlled Magellan Trial, A. T. Cohen, T. E. Spiro, A. C. Spyropoulos, Y. H. Desanctis, M. Homering, H. R. Buller, L. Haskell, D. Hu, R. Hull, P. Burton, +4 Additional Authors
Journal Articles
Background D-dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients. Objectives To analyze the relationships between D-dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649). Patients/methods This was a multicenter, randomized, controlled trial. Patients aged >= 40years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40mg once daily for 10 +/- 4days then placebo up to day 35, or oral rivaroxaban 10mg once daily for 35 +/- 4days. Patients (n=7581) were grouped by baseline D-dimer2xthe upper limit of normal. VTE and …
Factors Associated With Damage Accrual In Patients With Systemic Lupus Erythematosus: Results From The Systemic Lupus International Collaborating Clinics (Slicc) Inception Cohort,
2014
Zucker School of Medicine at Hofstra/Northwell
Factors Associated With Damage Accrual In Patients With Systemic Lupus Erythematosus: Results From The Systemic Lupus International Collaborating Clinics (Slicc) Inception Cohort, I. N. Bruce, A. G. O'Keeffe, V. Farewell, J. G. Hanly, S. Manzi, L. Su, D. D. Gladman, S. C. Bae, C. Aranow, M. B. Urowitz, +30 Additional Authors
Journal Articles
BACKGROUND AND AIMS: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. RESULTS: …
Immunochip Analysis Identifies Multiple Susceptibility Loci For Systemic Sclerosis,
2014
Zucker School of Medicine at Hofstra/Northwell
Immunochip Analysis Identifies Multiple Susceptibility Loci For Systemic Sclerosis, M. D. Mayes, L. Bossini-Castillo, O. Gorlova, J. E. Martin, X. D. Zhou, W. V. Chen, S. Assassi, P. K. Gregersen, A. T. Lee, J. Martin, +66 Additional Authors
Journal Articles
In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three …
Immunochip Identifies Novel, And Replicates Known, Genetic Risk Loci For Rheumatoid Arthritis In Black South Africans,
2014
Zucker School of Medicine at Hofstra/Northwell
Immunochip Identifies Novel, And Replicates Known, Genetic Risk Loci For Rheumatoid Arthritis In Black South Africans, N. Govind, A. Choudhury, B. Hodkinson, C. Ickinger, J. Frost, A. Lee, P. K. Gregersen, R. J. Reynolds, S. L. Bridges, M. Tikly, +2 Additional Authors
Journal Articles
The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single …
Lack Of Concordance Between Empirical Scores And Physician Assessments Of Stroke And Bleeding Risk In Atrial Fibrillation Results From The Outcomes Registry For Better Informed Treatment Of Atrial Fibrillation (Orbit-Af) Registry,
2014
Zucker School of Medicine at Hofstra/Northwell
Lack Of Concordance Between Empirical Scores And Physician Assessments Of Stroke And Bleeding Risk In Atrial Fibrillation Results From The Outcomes Registry For Better Informed Treatment Of Atrial Fibrillation (Orbit-Af) Registry, B. A. Steinberg, S. Kim, L. Thomas, G. C. Fonarow, E. Hylek, J. Ansell, A. S. Go, P. Chang, P. Kowey, E. D. Peterson, +4 Additional Authors
Journal Articles
Background-Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear. Methods and Results-We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS(2)) and Anticoagulation and …
A Role For Noncoding Variation In Schizophrenia,
2014
Zucker School of Medicine at Hofstra/Northwell
A Role For Noncoding Variation In Schizophrenia, P. Roussos, A. C. Mitchell, G. Voloudakis, J. F. Fullard, V. M. Pothula, J. Tsang, E. A. Stahl, A. Georgakopoulos, P. K. Gregersen, P. Sklar, +15 Additional Authors
Journal Articles
A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal …
Fine Mapping Major Histocompatibility Complex Associations In Psoriasis And Its Clinical Subtypes,
2014
Zucker School of Medicine at Hofstra/Northwell
Fine Mapping Major Histocompatibility Complex Associations In Psoriasis And Its Clinical Subtypes, Y. Okada, B. Han, L. C. Tsoi, P. E. Stuart, E. Ellinghaus, T. Tejasvi, V. Chandran, F. Pellett, P. K. Gregersen, S. Raychaudhuri, +12 Additional Authors
Journal Articles
Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C*06:02 demonstrated the lowest p value …
Fine Mapping Seronegative And Seropositive Rheumatoid Arthritis To Shared And Distinct Hla Alleles By Adjusting For The Effects Of Heterogeneity,
2014
Zucker School of Medicine at Hofstra/Northwell
Fine Mapping Seronegative And Seropositive Rheumatoid Arthritis To Shared And Distinct Hla Alleles By Adjusting For The Effects Of Heterogeneity, B. Han, D. Diogo, S. Eyre, H. Kallberg, A. Zhernakova, J. Bowes, L. Padyukov, Y. Okada, P. K. Gregersen, S. Raychaudhuri, +8 Additional Authors
Journal Articles
Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRbeta1 (p = 1.4 x 10(-13), odds ratio [OR] = 1.30) and for aspartate at …
Genetics Of Rheumatoid Arthritis Contributes To Biology And Drug Discovery,
2014
Zucker School of Medicine at Hofstra/Northwell
Genetics Of Rheumatoid Arthritis Contributes To Biology And Drug Discovery, Y. Okada, D. Wu, G. Trynka, T. Raj, C. Terao, K. Ikari, Y. Kochi, K. Ohmura, P. K. Gregersen, R. M. Plenge, +85 Additional Authors
Journal Articles
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating approximately 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico …
Genome-Wide Methylation Analyses In Glioblastoma Multiforme,
2014
Zucker School of Medicine at Hofstra/Northwell
Genome-Wide Methylation Analyses In Glioblastoma Multiforme, R. K. Lai, Y. W. Chen, X. W. Guan, D. Nousome, C. Sharma, P. Canoll, J. Bruce, A. Lee, P. Gregersen, J. Barnholtz-Sloan, +8 Additional Authors
Journal Articles
Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery …
Integration Of Sequence Data From A Consanguineous Family With Genetic Data From An Outbred Population Identifies Plb1 As A Candidate Rheumatoid Arthritis Risk Gene,
2014
Zucker School of Medicine at Hofstra/Northwell
Integration Of Sequence Data From A Consanguineous Family With Genetic Data From An Outbred Population Identifies Plb1 As A Candidate Rheumatoid Arthritis Risk Gene, Y. Okada, D. Diogo, J. D. Greenberg, F. Mouassess, W. A. L. Achkar, R. S. Fulton, J. C. Denny, N. Gupta, P. K. Gregersen, R. M. Plenge, +38 Additional Authors
Journal Articles
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G. C (p.G755R) mutation at the PLB1 gene on …
Interferon Alpha On Nzm2328.Lc1r27: Enhancing Autoimmunity And Immune Complex-Mediated Glomerulonephritis Without End Stage Renal Failure,
2014
Zucker School of Medicine at Hofstra/Northwell
Interferon Alpha On Nzm2328.Lc1r27: Enhancing Autoimmunity And Immune Complex-Mediated Glomerulonephritis Without End Stage Renal Failure, C. Dai, H. Y. Wang, S. S. J. Sung, R. Sharma, C. Kannapell, W. Han, Q. Wang, A. Davidson, F. Gaskin, S. M. Fu
Journal Articles
Interferon alpha (IFN alpha) may play a significant role in systemic lupus erythematosus (SLE) pathogenesis. Recent literature suggests that IFN alpha does not correlate with disease activities and blockade of IFN alpha is not effective in treating SLE. This study aims to delineate further the role of IFN alpha in SLE. 12-week old NZM2328 and its congenic NZM2328.Lc1R27 (R27) female mice were challenged with adenovirus-IFN alpha (adeno-IFN alpha) or adenovirus-LacZ (adeno-LacZ). Only adeno-IFN alpha treated NZM2328 developed severe proteinuria and died of chronic glomerulonephritis (GN) and end stage renal disease. Adeno-IFN alpha treated R27 did develop immune complex-mediated GN but …
Pathogenetic Role Of Glomerular Cxcl13 Expression In Lupus Nephritis,
2014
Zucker School of Medicine at Hofstra/Northwell
Pathogenetic Role Of Glomerular Cxcl13 Expression In Lupus Nephritis, K. Worthmann, F. Gueler, S. Von Vietinghoff, A. Davalos-Militz, F. Wiehler, A. Davidson, T. Witte, H. Haller, M. Schiffer, L. Schiffer, +1 Additional Author
Journal Articles
Podocytes maintain the structure and function of the glomerular filtration barrier. However, podocytes have recently been implicated in the innate immune response, and their function as non-haematopoietic antigen-presenting cells was highlighted. We have shown previously that excessive expression of the chemokine CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, we found that CXCL13 is elevated significantly in the serum of patients with SLE-nephritis. In this study, we were able to show for the first time that (i) CXCL13 is expressed locally in glomeruli in a model for SLE-nephritis in mice …
