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Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy
Xavier M. Teitsma1,
Johannes W. G. Jacobs1,
Michal Mokry2,3,
Michelle E. A. Borm4,
Attila Pethö-Schramm5,
Jacob M. van Laar1,
Johannes W. J. Bijlsma1 &
Floris P. J. Lafeber1
Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy.
Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (≥3 months in drug-free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4+) and CD14+ cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses.
Network analyses within CD4+ cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p ≤ 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14+ cells.
Within networks of co-expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR.
Clinicaltrials.gov, NCT01034137. Registered on 16 December 2009.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial tissue inflammation of the peripheral joints, often followed by destruction of those affected joints [1, 2]. Although the cause of RA is not fully understood, it is recognized to be a multifactorial disease involving both environmental and genetic factors that influence the susceptibility and severity of the disease [3,4,5]. Approximately 50% of the risk for developing RA is attributable to genetic predisposing factors. Previous studies have shown that, for example, the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) and peptidyl arginine deiminase, type 14 (PADI4) genes and various human leucocyte antigen (HLA) class II alleles are associated with an increased risk [4, 6,7,8]. Furthermore, the heterogeneity of RA is demonstrated by the variability in the presence of autoantibodies, the diverse clinical disease manifestations and different grades of responses to disease-modifying anti-rheumatic drugs (DMARDs). Adequately targeting the disease from the start is essential to preserve physical function and ensure long-term beneficial outcome, especially in early RA [9]. A better understanding of gene expression profiles could help to distinguish between patients with different pathogenic mechanisms and could lead to improved clinical outcomes when more individualised therapy is initiated from the start. An anchor drug in the treatment of RA is methotrexate, one effect of which is inhibition of dihydrofolate reductase that is not only important for cell proliferation and cell growth but also for inducing protein synthesis [10]. The various mechanisms of methotrexate involved in the treatment of RA still have not yet been fully elucidated, but it is believed that an anti-inflammatory effect also plays a large role as in vitro and in vivo studies have demonstrated previously [11]. Although methotrexate is recommended as an initial treatment strategy [12], a large number of patients needs additional treatment with a biological DMARD or withdraw from this therapy because of inefficacy or adverse effects [13,14,15]. Tocilizumab is a humanized monoclonal antibody inhibiting interleukin (IL)-6 signalling by blocking the binding of IL-6 to its receptor, and has been proven in randomized controlled trials to be effective across different RA populations in reducing disease activity and inhibiting the progression of joint damage [16,17,18,19,20,21,22,23,24,25,26,27,28]. IL-6 is a pro-inflammatory cytokine that is secreted by multiple cell types (e.g. T cells, B cells, monocytes, and osteoblasts) and stimulates the immune response and osteoclast formation [29, 30]. In the present study, we aimed to identify biological networks and signature protein coding genes that are associated with achieving sustained drug-free remission (sDFR) after initiating treatment with tocilizumab, methotrexate, or the combination of both, by performing whole transcriptome ribonucleic acid sequencing (RNA-seq) of positive cluster of differentiation 4 (CD4+) and CD14+ cells obtained from DMARD-naive early RA patients. Additionally, we were interested whether pathways related to achieving sDFR were treatment dependent by investigating gene expression profiles between the tocilizumab and methotrexate arms, or whether sDFR was dependent on general predisposing factors present within all strategy arms. As genotypes differ between RA patients, identification of biological pathways associated with achieving sDFR could enable application of more personalized treatment strategies which, in those who are newly diagnosed, would result in better disease activity control and prevention of disease progression.
Data was used from the 2-year, multicentre, double-blind, placebo-controlled, randomized U-Act-Early trial (ClinicalTrials.gov identifier: NCT01034137) in which DMARD-naive patients with early RA were treated-to-target with tocilizumab plus methotrexate, or tocilizumab, or methotrexate therapy. The study design and details have been described previously [21]. Briefly, 317 patients with active RA (disease activity score assessing 28 joints (DAS28) >2.6) were randomized (1:1:1) to initiate tocilizumab (8 mg/kg), step-up methotrexate (starting dose 10 mg/week), or tocilizumab plus methotrexate therapy and were treated until the treatment target (sustained remission; defined as a DAS28 < 2.6 and a maximum swollen joint count of ≤4 for ≥24 weeks) was achieved. If remission was not reached, hydroxychloroquine (200 mg twice per day) was added to the regimen (initial treatment strategy) and was discontinued 12 weeks thereafter if the target still was not achieved. Patients who did not achieve remission following the initial treatment strategy switched to a subsequent treatment regimen; patients who started with tocilizumab or methotrexate therapy then switched to combination therapy with tocilizumab plus methotrexate, and those who had initiated this treatment strategy switched to the standard of care (i.e. methotrexate combined with a tumour necrosis factor inhibitor). When the primary outcome, sustained remission, was achieved, medication was tapered and discontinued if remission was maintained. Methotrexate was first tapered at 5-mg/4-week steps until 10 mg and then discontinued; thereafter tocilizumab was tapered to 4 mg/kg and finally stopped after 3 months. For the present study, we used data from those achieving sDFR (defined as being drug-free for ≥3 months and maintaining this state until the end of the 2-year study period where one visit of low-disease activity (DAS28 < 3.2) was allowed) in the three treatment strategies. As controls, we selected patients within each treatment who never achieved a drug-free status at any time point during the whole study period, although they could have achieved sustained remission and subsequently were tapering medication.
Before patients received their first dose of medication, whole blood samples were collected and CD4+ plus CD14+ cells were extracted using fluorescence-activated cell sorting (FACS). Thereafter, total RNA was isolated from these cells using the RNeasy® Mini Kit (Qiagen, Netherlands) following the manufacturer's recommendations. The quantity of the isolated RNA was assessed with ND1000/ND2000 NanoDrop® and the quality was assessed with the Agilent 2100 Bioanalyzer® (Agilent Technologies, Germany). The mean (standard deviation (SD)) RNA Integrity Number (RIN) of the samples was 9.3 (0.3) with a mean (SD) RNA concentration of 220 (76) ng/µl. Thereafter, the RNA tubes were stored at −80 °C. For the RNA-seq, libraries were constructed using the NEXTflex™ Rapid RNA-Seq kit (Bio Scientific) and mRNA was selected using NEXTflex™ poly-A tail following the manufacturer's recommendations. Thereafter, the library was ready and sent to the Utrecht Sequencing Facility to be sequenced on the Illumina Nextseq500 platform using a single-end 75-base pair high-output run. After the library was sequenced, a standard pipeline was used that includes a quality control, processing of the reads, alignment to a reference genome, transcript annotation, and finally an estimation of the read counts of the transcripts. A flowchart of the study is presented in Fig. 1.
A Flowchart of the study. Whole blood samples were collected from 60 patients and thereafter CD4+ and CD14+ cells were extracted using fluorescence-activated cell sorting (FACS). Then RNA was isolated from these cells and, via reverse transcription, the library was prepared and sequenced (RNA-seq). Thereafter, a (standard) pipeline was applied for quality control and processing of the reads; read counts were used for detecting differentially expressed genes (DEGs) and these were then used for detecting networks of co-expressed genes. Pathway analyses in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were performed in the most important networks
Principal component analysis (PCA) of the raw read counts was performed to identify possible confounders for the level of expression. Thereafter, the DESeq2 package was used to test for differential gene expression by use of negative binomial generalized linear models [31]. The model was corrected for gender and C-reactive protein (CRP) levels as they had been identified as confounders in the PCA (data not shown). The weighted gene co-expression network analysis (WGCNA) package was then used to construct networks of co-expressed genes (i.e. modules) of the 1000 most differentially expressed genes (DEGs) among the three treatment arms [32]. A continuous (range −1,1) adjacency matrix was constructed for all pairs of genes using Pearson's correlation coefficient (PCC). Subsequently, the correlation matrix was transformed into connection strengths using a soft threshold to obtain a scale-free network whereas the threshold power, based on the explained variance, was determined separately for each treatment arm. The connection strengths were then used to calculate the topological overlap matrix, which measures the interconnectivity of pairs of genes. Modules of correlated genes were identified using hierarchical average clustering, which groups genes with similar expression patterns, and modules that were highly correlated (PCC ≥0.80) were merged. Each module is labelled by a colour and the minimum number of genes per module was set at 20, except for the tocilizumab plus methotrexate arm (CD14+ cells) and tocilizumab arm (CD4+ cells) where the threshold was set at 10 to create sufficient numbers of modules. Genes not assigned to any of the modules were housed in the grey module and disregarded. After the modules had been identified and merged, the module eigengene (E) was calculated (range 0–1; with "1" indicating highest E), which can be considered as the first principal component of the expression matrix and thus representing the average gene expression profile within the module. The module that correlated best with achieving sDFR (no = 0, yes = 1) was considered the most relevant and was used for further pathway analysis. Additionally, the correlation between clinical traits and the expression profile was also analysed to determine if other factors besides achieving sDFR were important in the module of interest. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the GOseq package, which accounts for gene length bias using a probability weighting function [33]. P values were corrected for multiple testing when performing pathway analysis (Benjamini-Hochberg correction) [34]. VisANT 5.0 software was used to visualize the connectivity between genes in the module of interest and to identify signature genes that are considered to play an important role in the biological processes as they are characterized by a high connectivity with other genes [35, 36]. Statistical significance was determined at P < 0.05 (two tailed) and network analyses were performed using the statistical program R version 3.3.1.
In total, 60 individual patient samples (tocilizumab plus methotrexate, 19 (n = 14 achieved sDFR, n = 5 controls); tocilizumab, 24 (n = 13 achieved sDFR, n = 11 controls); methotrexate, 17 (n = 10 achieved sDFR, n = 7 controls)) were included in the present analysis. The mean (SD) age of all patients was 53 (14) years with a median (interquartile range (IQR)) symptom duration of 23 (18–40) days; 60% were rheumatoid factor positive and 60% anti-cyclic citrullinated peptide positive. The majority were female (68%) and patients had at baseline a mean (SD) DAS28 of 4.9 (1.1); median (IQR) CRP level was 9 (3–19) mg/L and erythrocyte sedimentation rate 20 (12–32) mm/h. No significant differences in clinical characteristics were found between those achieving sDFR and the controls within the strategy arms (p ≥ 0.07, Additional file 1: Table S1). For each sample, the expression of approximately 20,000 protein coding genes was measured in both CD4+ and CD14+ cells and normalized read counts were determined for each gene. Hierarchical cluster analyses of the relevant DEGs are shown in Fig. 2. In the sequenced CD4+ cell population, weighted network analyses identified two, four, and four modules after merging that were significantly correlated with achieving sDFR in the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy arms, respectively (Table 1). In the tocilizumab plus methotrexate arm, the salmon module was found to be most significantly related to sDFR (PCC 0.58, p = 0.009); in the tocilizumab arm it was the purple module (PCC 0.52, p = 0.009), and in the methotrexate arm the black module (PCC 0.60, p = 0.010). The number of genes included in the modules is 40, 26, and 49, respectively (Additional file 2: Table S2). When performing network analyses within the CD14+ cells, no modules were found that were significantly correlated with achieving sDFR in the tocilizumab plus methotrexate and methotrexate arms (Additional file 3: Table S3). In the tocilizumab arm, only one module (pink) was significantly correlated (PCC 0.41, p = 0.049). However, within this module, symptom duration was an important contributing trait as it was highly correlated (PCC 0.93, p < 0.001) with the average expression profile (E). Because the correlation between the pink module and achieving sDFR was low (<0.50) and symptom duration was a more contributing factor to the gene expression in this module, it was disregarded for further analyses. Pathway analyses were therefore only performed for the modules found relevant within the CD4+ cells of the three treatment arms.
Hierarchical cluster dendrograms of the differently expressed genes included in the network analysis within the (a) tocilizumab plus methotrexate, (b) tocilizumab, and (c) methotrexate strategy arms. Each line represents an individual gene and the branches correspond to modules of co-expressed genes, which are labelled by colours
Table 1 Correlations and corresponding P values between modules and achieving sustained drug-free remission within sequenced CD4+ cells
GO and KEGG pathway analysis
In the salmon module (tocilizumab plus methotrexate arm), 325 significantly expressed GO terms were identified; in the purple module (tocilizumab arm) 304 GO terms were identified; and in the black module (methotrexate arm) 560 GO terms were identifies. The top five most significantly overrepresented GO terms (excluding terms with only one DEG) within the treatment arms are shown in Fig. 3. The most significant GO term in the tocilizumab plus methotrexate, tocilizumab, and methotrexate arms were "nuclear-transcribed mRNA catabolic process" (p < 1.00E–04), "granulocyte migration" (p = 2.70E–04), and "response to bacterium" (p = 1.92E–07), respectively. In addition, pathway analyses were performed using the KEGG database; "ribosome" was the only significant (p < 1.00E–04) pathway in the tocilizumab plus methotrexate arm; in the tocilizumab arm, no significant pathways were identified, and in the methotrexate arm "p53 signalling" (p = 8.44E–06) and "JAK-STAT signalling" (p = 2.22E–04) were significant pathways.
The top five most significantly overrepresented gene ontology (GO) terms within the (a) tocilizumab plus methotrexate, (b) tocilizumab, and (c) methotrexate strategy arms. GO terms with >1 DEGs were included in this overview
Signature genes
The interaction between genes in the modules selected for pathway analyses (tocilizumab plus methotrexate arm, salmon module; tocilizumab arm, purple module; methotrexate arm, black module) is shown in Fig. 4. Signature genes are visualized in the rounded rectangular nodes and genes with a lower connectivity are presented as round nodes. Across the three treatment arms, the large majority of the genes included in the modules were upregulated (green nodes) in those achieving sDFR. In the tocilizumab plus methotrexate arm, genes within the salmon module correlated best and, to select the most important genes, we applied a stricter cut-off. However, even when using a stricter cut-off, the average correlation between genes was the lowest (PCC 0.52) in this treatment arm when compared to the tocilizumab (PCC 0.67) and methotrexate (PCC 0.74) arms. Genes showing ≥10 connections within the modules were labelled as signature genes, except for the tocilizumab plus methotrexate arm, where genes were considered as important when showing ≥20 connections. In total, 9 (8 upregulated, 1 downregulated), 7 (6 upregulated, 1 downregulated), and 14 (11 upregulated, 3 downregulated) signature genes were identified in the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy arms, respectively.
Network visualization of the interaction of gene co-expression within the tocilizumab plus methotrexate (a, salmon module), tocilizumab (b, purple module), and methotrexate (c, black module). Upregulated genes are expressed in green nodes and downregulated genes in red nodes. The rounded rectangular nodes display the highest co-expressed genes within the module (signature genes)
In the present study, using analysis of networks of differentially co-expressed genes, several biological pathways were identified that were associated with achieving sDFR in DMARD-naive patients with early RA after initiating tocilizumab plus methotrexate-, tocilizumab-, or methotrexate-based treatment strategies. Across the three treatment arms, we found different networks, implying that there are several predisposing genes for achieving sDFR and, depending on the treatment strategy selected, patients have a higher chance of achieving sDFR if these are up- or downregulated. Some genes in particular that are included in the networks may play an important role as they are characterized by a high connectivity with other (signature) genes and therefore have the strongest influence on the pathways found relevant.
In the tocilizumab plus methotrexate strategy arm, the most important GO term was "nuclear-transcribed mRNA catabolic process, nonsense-mediated decay", which is a pathway important in altering gene expression by degrading mRNA when converting amino acid-specific codons into premature stop codons (i.e. early termination of translation into proteins) [37]. After the genetic information from DNA is copied into RNA molecules during transcription, mRNA is decoded by ribosomes in the cytoplasm and is translated, using transfer RNA, into a specific sequence of amino acids (i.e. proteins). Translation starts with a start codon, which is the first codon of a mRNA transcript translated by a ribosome, and ends with a stop codon. Mutations, also known as single-nucleotide polymorphisms (SNPs), can occur in the sequence of nucleotide bases in DNA resulting in a different protein product. SNPs may not only increase the susceptibility to certain diseases but are also responsible for the differences in treatment response because of genetic variations. Other significant GO terms within this treatment arm are also related to processes involved in translation (GO:0006412) of mRNA by ribosomes (GO:0005840, GO:0003735) and is in accordance with the only identified significant KEGG pathway ("Ribosome"). Thus, it seems that pathways important for achieving sDFR in patients treated with tocilizumab plus methotrexate are in general related to processes involved with protein synthesis, especially during translation from mRNA into a sequence of amino acids. In the tocilizumab strategy arm, the most important GO terms in the purple module were related with migration of white blood cells (granulocytes and myeloid leukocytes) as a response to inflammation or to an external stimulus (i.e. leukocyte chemotaxis). Furthermore, G-protein-coupled receptor (GPCR) activity and signalling pathway (GO:0008227, GO:0007187) were significant GO terms within this module. GPCRs constitute a superfamily of receptor proteins that are involved in a many (patho)physiological processes and an important role of these receptors is to regulate the immune system and inflammation by activating internal signal transduction across the cell membrane, which eventually leads to cellular responses [38]. It is estimated that approximately two-third of all available drugs targets the GPCRs; the most commonly used in RA is methotrexate that works via a specific subtype of adenosine receptors, which is part of the large GPCR family [38]. The exact mechanism and the downstream effect ultimately leading to cellular responses of many GPCRs are still not fully elucidated, but they have been shown to be effective in several auto-immune diseases in reducing disease symptoms when specific receptors are targeted. Although it is known that tocilizumab inhibits the binding of IL-6 to its receptor, which belongs to the family of the type I cytokine receptors and thus does not seem to directly affect GPCRs, it might have an indirect effect on certain GPCRs. Further research is, however, required to determine and understand the potential effect of tocilizumab on these receptors. In the methotrexate arm, all selected GO terms were related to a response to some kind of bacterium or biotic (i.e. biological material) stimulus resulting in a change of state or activity of a cell. When analysing the GO ancestor chart, all terms were direct subtypes of "response to stimulus" (GO:0050896) indicating that the genes included in the black module may play a direct role in the response to therapy. However, the exact mechanisms of methotrexate in RA remain partially unclear, but multiple processes seem to play a role in suppressing disease activity. Although it is known, for example, that methotrexate inhibits cell proliferation and apoptosis, it was also found to inhibit cytokine production by inducing T-cell and B-cell activation [39]. Although many ex vivo and in vitro studies have been performed, the exact mechanism of action of cytokine level reduction by methotrexate remains largely not understood [39]. An important function of methotrexate may be the inhibiting effect on "Janus Kinase Signal Transducer and Activator of Transcription (JAK-STAT)" signalling, which was also a significantly expressed KEGG pathway in the black module (methotrexate arm). JAKs are enzymes transducing signals of cytokine receptors and, by inhibiting one or more enzymes, they prevent activation of cytokines important for the immune response [40]. A previous study has shown that methotrexate suppresses the JAK-STAT pathway; this could be an important mechanism for reducing RA disease activity [41]. Another significant KEGG pathway in the methotrexate arm was associated with signalling of the tumour protein p53 ("p53 signalling pathway"), which functions as a tumour suppressor and is thus not directly related to the pathogenesis of RA. This protein was, however, previously found to be involved with methotrexate-resistance in osteosarcoma and, therefore, it seems that genes important in the p53 pathway may be related to the response to methotrexate therapy in general [42].
In the present study, we analysed two different clusters of cells, CD4+ T-helper cells and CD14+ monocytes, for transcriptional profiling as both are important in modulating the immune response but have different functions and could thus have different pathways involved. T-helper cells are essential in the adaptive immunity by producing cytokines when pathogens are presented by monocytes and are therefore regulators of the immune response. Besides recruiting lymphocytes (antigen presentation), monocytes also perform phagocytosis after becoming macrophages, and are thus also important for the removal of pathogens. Although both clusters of cells are important within RA, when performing gene co-expression network analyses, no relevant modules were found in the CD14+ cells and only transcripts sequenced from CD4+ cells seems to play a role in achieving sDFR in DMARD-naive patients after initiating a tocilizumab- or methotrexate-based strategy. Other cells, such as B lymphocytes, also play an important role in auto-immune diseases and thus may contribute to the understanding of genetic variations within RA patients. However, these cells were not analysed in this study as they were not isolated because of the limited quantity of blood that had been collected at baseline and cost-related considerations.
In conclusion, by performing network analyses of co-expressed genes we have identified several pathways related to achieving sDFR within DMARD-naive early RA patients after initiation of tocilizumab plus methotrexate-, tocilizumab-, or methotrexate-based treatment strategies. Within each of these three strategy arms, we found different biological pathways implicating that are different networks of predisposing genes related to achieving sDFR which are dependent on the type of treatment strategy selected. In addition, we identified several important genes within the networks that could potentially act as prognostic biomarkers for RA.
Cluster of differentiation
Disease activity score assessing 28 joints
Differentially expressed gene
FACS:
Fluorescence-activated cell sorting
GPCR:
G-protein-coupled receptor
HLA:
Human leucocyte antigen
JAK-STAT:
Janus kinase signal transducer and activator of transcription
KEGG:
Kyoto Encyclopedia of Genes and Genomes
mRNA:
PAD14:
Peptidyl arginine deiminase, type 14
PCA:
PCC:
Pearson's correlation coefficient
PTPN22:
Protein tyrosine phosphatase, non-receptor type 22
RIN:
RNA integrity number
RNA-seq:
sDFR:
Sustained drug-free remission
SNPs:
Single-nucleotide polymorphisms
WGCNA:
Weighted gene co-expression network analysis
Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med. 2007;120(11):936–9.
Bijlsma JWJ, Hachulla E. Eular textbook on rheumatic diseases, 2nd ed. BMJ; 2015.
Liao KP, Alfredsson L, Karlson EW. Environmental influences on risk for rheumatoid arthritis. Curr Opin Rheumatol. 2009;21(3):279–83.
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094–108.
Suzuki A, Yamamoto K. From genetics to functional insights into rheumatoid arthritis. Clin Exp Rheumatol. 2015;33(4 Suppl 92):S40–3.
Zanelli E, Breedveld FC, de Vries RR. HLA class II association with rheumatoid arthritis: facts and interpretations. Hum Immunol. 2000;61(12):1254–61.
Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. Autoimmun Rev. 2010;9(5):A288–92.
Ali AM, Vino S. Genetic markers as therapeutic target in rheumatoid arthritis: a game changer in clinical therapy? Rheumatol Int. 2016;36(11):1601–7.
Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum. 2007;56(10):3226–35.
Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. Clin Ther. 2014;36(3):427–35.
Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 2006;58(4):473–92.
Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.
Romao VC, Lima A, Bernardes M, Canhao H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res. 2014;60(2–3):289–310.
Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68(7):1100–4.
Bologna C, Viu P, Picot MC, Jorgensen C, Sany J. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study. Br J Rheumatol. 1997;36(5):535–40.
Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54(9):2817–29.
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987–97.
Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968–80.
Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23.
Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081–91.
Bijlsma JW, Welsing PM, Woodworth TG, Middelink LM, Petho-Schramm A, Bernasconi C, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343–55.
Weinblatt ME, Kremer J, Cush J, Rigby W, Teng LL, Devenport J, et al. Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: twenty-four-week results of an open-label, clinical practice study. Arthritis Care Res. 2013;65(3):362–71.
Dougados M, Kissel K, Sheeran T, Tak PP, Conaghan PG, Mola EM, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50.
Yazici Y, Curtis JR, Ince A, Baraf H, Malamet RL, Teng LL, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012;71(2):198–205.
Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63(3):609–21.
Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96.
Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19(1):12–9.
Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–7.
Plushner SL. Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2008;42(11):1660–8.
Patel AM, Moreland LW. Interleukin-6 inhibition for treatment of rheumatoid arthritis: a review of tocilizumab therapy. Drug Des Devel Ther. 2010;4:263–78.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinf. 2008;9:559.
Young MD, Wakefield MJ, Smyth GK, Oshlack A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 2010;11(2):R14.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.
Hu Z, Mellor J, Wu J, DeLisi C. VisANT: an online visualization and analysis tool for biological interaction data. BMC Bioinf. 2004;5:17.
Hu Z, Snitkin ES, DeLisi C. VisANT: an integrative framework for networks in systems biology. Brief Bioinform. 2008;9(4):317–25.
Baker KE, Parker R. Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol. 2004;16(3):293–9.
Neumann E, Khawaja K, Muller-Ladner U. G protein-coupled receptors in rheumatology. Nat Rev Rheumatol. 2014;10(7):429–36.
Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008;47(3):249–55.
Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol. 2005;32(9):1650–3.
Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate is a JAK/STAT pathway inhibitor. PLoS One. 2015;10(7):e0130078.
Yang XR, Xiong Y, Duan H, Gong RR. Identification of genes associated with methotrexate resistance in methotrexate-resistant osteosarcoma cell lines. J Orthop Surg Res. 2015;10:136.
The authors especially thank Arno Concepcion for isolating the RNA. Also, we thank the Utrecht Sequencing Facility for their support in the sequencing, which is partially subsidized by Hubrecht Laboratory, Utrecht University, and University Medical Center Utrecht, and Noortje van den Dungen and Nico Lansu for creating the RNA libraries. Furthermore, the authors thank all participating institutions and personnel who were involved in the study, particularly (research) nurses, physicians' assistants, and rheumatologists. Lastly, the authors thank all the patients enrolled in the study for their kind willingness to participate.
The U-Act-Early trial was funded by Roche Nederland BV.
The dataset generated during the present study is available from the corresponding author on reasonable request.
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, Netherlands
Xavier M. Teitsma
, Johannes W. G. Jacobs
, Jacob M. van Laar
, Johannes W. J. Bijlsma
& Floris P. J. Lafeber
Epigenomics Facility, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, Netherlands
Michal Mokry
Division of Paediatrics, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, Netherlands
Roche Nederland BV, Beneluxlaan 2a, 3446, GR, Woerden, Netherlands
Michelle E. A. Borm
F Hoffmann-La Roche, Grenzacherstrasse 124, 4070, CH, Basel, Switzerland
Attila Pethö-Schramm
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XMT: study design, data collection, data interpretation, and writing. JWGJ: study design, data interpretation, and writing. MM: data collection and writing. MEAB: data interpretation and writing. AP-S: data interpretation and writing. JMvL: data interpretation and writing. JWJB: study design, data interpretation, and writing. FPJL: study design, data interpretation, and writing. All authors read and approved the manuscript.
Correspondence to Xavier M. Teitsma.
The medical ethics research committee of the University Medical Center Utrecht approved the study for all participating hospitals. All patients signed informed consent before entering the study.
JWGJ and JWJB received reimbursements from Roche Nederland BV for including patients to participate in the U-Act-Early trial. JWJB reports grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and UCB. JMvL received financial contributions from MSD, Pfizer, Eli Lilly, and BMS. FPJL reports grants from Roche. AP-S is an employee of F Hoffmann-La Roche and MEAB is an employee of Roche Nederland BV. XMT and MM declare that they have no competing interests.
Baseline characteristics of the patients included in the analyses. (DOCX 17 kb)
Description of the differentially co-expressed genes in the salmon module (tocilizumab plus methotrexate arm), the purple module (tocilizumab arm), and the black module (methotrexate arm). (DOCX 22 kb)
Correlations and corresponding P values between the modules and achieving sustained drug-free remission within sequenced CD14+ cells. (DOCX 25 kb)
Teitsma, X.M., Jacobs, J.W.G., Mokry, M. et al. Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy. Arthritis Res Ther 19, 170 (2017) doi:10.1186/s13075-017-1378-x
Drug-free remission


Sculpture Milwaukee 2019 announced another batch of sculptures for the outdoor exhibit on Wisconsin Avenue June 7 to Oct. 27.
Sculpture Milwaukee has announced a second group of artists for its 2019 outdoor exhibit along Wisconsin Avenue, including surrealist Max Ernst.
Sculpture Milwaukee previously announced that it will show works by John Baldessari and Roxy Paine along Wisconsin Avenue from June 7 to Oct. 27.
In addition to Ernst's "Seraphine-cherubin" (1967), new additions include Angela Bulloch's "Heavy Metal Stack of Six: Trichrome Blue" (2016); Sam Durant's "Empathy for Everyone" and "We Are the Ones We've Been Waiting For" (both 2018); Barry Flanagan's "Large Boxing Hare on Anvil" (1984); William J. O'Brien's "Sun & Moon Protector" (2016); Tony Matelli's "Hera (half)" (2018); and Actual Size Artworks' "Magical Thinking" (2019).
Actual Size Artworks is the Madison team of Gail Simpson and Aris Georigiadis; Sculpture Milwaukee describes "Magical Thinking" as an "upturned magician's hat."
Presenting sponsor Northwestern Mutual will host Baldessari's "Penguin" and Paine's "Cleft" in the Northwestern Mutual Gardens at the eastern end of Wisconsin Avenue.
Other confirmed sculptures include Radcliffe Bailey's "Pensive," which suggests W.E.B. Du Bois in the mode of Rodin's "The Thinker"; Elmgreen & Dragset's "A Greater Perspective"; Beverly Pepper's "Curvae in Curvae"; and Richard Woods' "Untitled (Milwaukee)."
The exhibition, approaching its third year, plans to place 22 sculptures on or near Wisconsin Avenue downtown. Installation will begin in May.
All sculptures will be available for purchase, with a percentage of proceeds to be used for future Sculpture Milwaukee installations.
Sculpture Milwaukee is curated by Marilu Knode, former director of the Laumeier Sculpture Park, and Russell Bowman, a Chicago-based art adviser and the former director of the Milwaukee Art Museum.
This story was updated on April 23. Contact Jim Higgins at jim.higgins@jrn.com. Follow him on Twitter at @jhiggy.


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Android Kunjappan Version 5.25 Hind Full Movie Leaked Online Download By Tamilrockers
Teodora Torrendo
Android Kunjappan Version 5.25 Hind Full Movie
Android Kunjappan Version 5.25 Hind Full Movie Leaked Online Download By Tamilrockers. Android Kunjappan Version 5.25 is the best comedy film and written by Ratheesh Balakrishnan Poduval and starrer with Soubin Shahir. We can download and watch this movie on Tamilrockers, filmywap in all HD formats.
Director & Writer: Ratheesh Balakrishnan Poduval
Producer: Santhosh T Kuruvilla
Music: Bijibal
Cast: Soubin Shahir, Suraj Venjaramoodu, Saiju Kuruppu, Kendy Zirdo
The popular Tamil movie director Parubha's upcoming movie Android kunjappan has made making news for quite a while now. The film marks the directorial debut of a famous Nigerian director. The first look of the movie was shared by the hero of the movie on his Facebook page.
The movie is going to release on 8th November 2019. It is going to face a lot of competition because a lot of good movies from Hollywood and Bollywood are going to release on the same day. The film features a lot of Tamil actors and almost the whole team of the movie is Tamil. This is going to be the biggest release of a Tamil based movie in Hindi cinema.
The film stars Saubin Shahir in the lead role. Saubin is a Malayalam director and actor. He started off as an assistant director in the Malayalam film industry and after a few years started directed solely. He made his acting debut with the hit movie Annayum Rasoolum. The movie wasn't a big hit but he still managed to get good critical reviews by the public and critics. The movie also stars Navin Nazim who plays an important character in the movie.
Read More: Kung Fu Panda 4 All News: Release Date, Rumors, Cast, And Director
The movie revolves around a villager and his son who are quite lonely and distressful with their life. The hero of the movie is very poor and earns his day to day living in a small village. His wife is already dead and he has to meet the everyday needs of his son and his parents. The family comes under the biggest crisis of their life when the head of the family loses his job and is forced to leave his house.
His son gets bullied at school and gets kicked out of school because his father is not able to provide for his school fees. They move out of the village and move to a new city. The life of father and son changes when a robot enters their life. He changes their life for the better and brings a lot of happiness and relief. How the robot solves their problem and how luck comes on their side is how the movie proceeds. The movie has a lot of humorous moments and the comic element remains strong in the movie.
Read More: X-The Exploited Full Movie Leaked Online Download On Tamilrockers
Android kunjappan version 5.25 leaked by Tamil rockers
Tamil rockers the famous piracy site has done it again and this time they have got their hands on the recent Tamil flick Android kunjappan. The movie got leaked even before its release and the movie is now expected to open with a cold response. The trailer of the movie did not grab many eyeballs and now with the leak of the movie the amount that was expected to go to the theaters is also going to watch it for free. Tamil rockers is a piracy website that provides movies for free download to all its users.
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Teodora Torrendo is an investigative journalist and is a correspondent for European Union. She is based in Zurich in Switzerland and her field of work include covering human rights violations which take place in the various countries in and outside Europe. She also reports about the political situation in European Union. She has worked with some reputed companies in Europe and is currently contributing to USA News as a freelance journalist. As someone who has a Masters' degree in Human Rights she also delivers lectures on Intercultural Management to students of Human Rights. She is also an authority on the Arab world politics and their diversity.

redpajama_set_name: RedPajamaCommonCrawl


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April 23, 2009 . Leave a comment.
The nice chaps at NorthWestEngland PerlMongers have organized a technical meeting on 5th May, at the Manchester Digital Development Agency.
I'll be doing a 3rd version of my Functional Pe(a)rls talk, about Haskell-inspired craziness in Pure Perl. And Matt Trout and Ian Norton will be talking about OO Database design, and Maildir migration, so there's something for everyone.


text:
module Network.Bluetooth (
      module Network.Bluetooth.Addr
    , module Network.Bluetooth.Device
    , module Network.Bluetooth.Exception
    , module Network.Bluetooth.Protocol
    , module Network.Bluetooth.SDP
    , module Network.Bluetooth.Socket
    , module Network.Bluetooth.UUID
    ) where

import Network.Bluetooth.Addr
import Network.Bluetooth.Device
import Network.Bluetooth.Exception
import Network.Bluetooth.Protocol
import Network.Bluetooth.SDP
import Network.Bluetooth.Socket
import Network.Bluetooth.UUID

redpajama_set_name: RedPajamaGithub


The regulation applies to majors and universities that have not received official accreditation in education quality.
It specifies that if an educational institution has 90 per cent of graduates finding employment within one year of graduation, they can choose either to keep the recruitment quota from the previous school year or raise it by no higher than 10 per cent.
But if this percentage is achieved by forcing non-performing students to leave school, they are only allowed to raise the recruitment quota by no higher than 25 per cent of the number of students they had forced to leave over the previous four years.
Dr Nguyễn Thị Kim Phụng, head of MoET's Department of Higher Education, said the regulation would help bridge the gap between labour supply and demand.
"There has been a drastic increase in the number of universities and their educational scope as we are striving toward having 450 students for every 10,000 people by 2020," she said.
"But we have not been able to ensure teaching quality at these institutions, so a lot of students have been unable to find jobs after getting their Bachelor or Master's degrees, or having to work as manual labourers or in professions unrelated to their majors.
Dr Vũ Thu Hương, a lecturer at Hà Nội National University of Education, said one year after graduation was not a realistic indicator of a student's employability.
"Graduates often have a lot of choices after they finish studying, such as going to study abroad, getting another degree, pursuing advanced study or getting married. In some instances personal situations prevent them from doing so.
Professor Nguyễn Văn Minh, principal of Hà Nội National University of Education, said he was concerned about the transparency of statistics provided by educational institutions.
He said: "Many universities have provided similar percentages [of students finding jobs within a year after graduation]. This should be tackled as soon as possible otherwise there would be no point in making student data public.
The accuracy and trustability of statistics has also raised concerns among educators.
Although statistics from the HCM City University of Education last year showed 100 per cent of its French majors were employed after graduation, only 15 of the 35 graduates responded to the school's survey.
The statistics also showed 93.3 per cent of the school's Japanese majors found employment, but that was taken from only 30 of 104 graduates who responded to the survey, of which 27 landed jobs.


How you envision yourself in your mind is how you are going to blossom and manifest throughout your life. You will not grow any higher than you are if your perception doesn't allow you to be. You have complete and total control of your mind and emotions do have the capacity to determine what path you are taking in life. Did you know that you can completely reprogram your mind? You can do so the following ways.
Learn how to meditate. When you are relaxed you are more likely to make decisions that contribute to what you actually want in life. You are less likely to take actions based on negative emotions.
Surround yourself with people and places that contribute to your mood and your effectiveness. Keep negative energy away as much as you can.


Two Greater Victoria men face arson charges after setting a fire on the Lochside Regional Trail early Sunday morning.
Saanich police were alerted of the fire, located on the trail just west of Quadra Street, around 3 a.m. Two men were seen adding fuel – pieces of wood and pallets – to the large fire, which was estimated at four feet in diameter.
Both men were arrested. Police say they were "highly intoxicated" at the time of the incident.
A 24-year-old Central Saanich man and a 27-year-old Esquimalt man each face charges of arson and mischief.
Mike MacIntyre, operations manager with CRD Parks, says the trail will be repaired, but crews need to wait until the weather improves to fix the asphalt. He estimates it will cost $2,000 for the repairs.


text:
Jean Debourges, né le  à Boussac (Creuse), mort le , est un homme politique français.

Biographie
Avocat dans son pays natal lors du déclenchement de la Révolution, il est juge au tribunal de district et président de l'administration de la Creuse, puis député de ce département à la Convention nationale le .

Siégeant parmi les modérés, il vote en faveur de l'appel au peuple et ne se prononce pas sur la peine à infliger lors du procès de Louis XVI. Hostile aux pétitionnaires du faubourg Saint-Antoine le , il s'oppose à la fixation d'un maximum sur les denrées de première nécessité. Membre du comité des travaux publics, il se tient à l'écart du débat politique sous la Terreur, avant de s'engager en faveur de la réaction thermidorienne.

Élu député de la Creuse au Conseil des Anciens le 23 vendémiaire an IV, il vote en faveur du droit de radiation des émigrés par le Directoire et contre l'impression du discours de Portalis, qui voulait accorder ce droit aux Conseils. Auteur de divers rapports, il est élu secrétaire de l'assemblée le  frimaire an V (), avant de quitter le Conseil en l'an VI ().

Après le coup d'État du 18 brumaire, il est nommé président du tribunal de Chambon-sur-Voueize le 18 floréal an VIII, fonctions qu'il occupe jusqu'à son élection à la Chambre des députés par l'arrondissement de Boussac, le , pendant les Cent-Jours.

Il abandonne la vie publique lors de la Seconde Restauration.

Sources
 , de Debelleyme à Defermon des Chapelières,  à 290
 Eugène Ernest Desplaces, Joseph Francois Michaud, Louis Gabriel Michaud, Biographie universelle ancienne et moderne, Paris, Firmin Didot frères, 1852, tome 10,
 Fiche sur Assemblée nationale

Député de la Creuse
Naissance en février 1747
Naissance à Boussac (Creuse)
Décès en juillet 1825
Député de la Convention nationale
Membre du Conseil des Anciens
Député des Cent-Jours
Avocat français du XVIIIe siècle
Magistrat français du XVIIIe siècle
Magistrat du Premier Empire
Décès à 78 ans
Décès à Boussac

redpajama_set_name: RedPajamaWikipedia


Dr. Edward Burns is the Executive Dean of the Albert Einstein College of Medicine of Yeshiva University. In this capacity, he has responsibility for the support of clinical and basic science research, the College's Doctoral and Post-Doctoral programs, the clinical and scientific relationships with the College's Hospital Affiliates, the development of scientific discoveries into biomedical technology and the licensing of these technologies to pharmaceutical and biotechnology partners. He also oversees the College's policies relating to the responsible conduct of research and biomedical ethics. He is spearheading the College's strategic plan for diversity enhancement.
Dr. Burns is a graduate of Yeshiva University and received his M.D. degree from Einstein. Over a more than thirty year period he has been a faculty member of the College and is a Professor in the Departments of Medicine and Pathology. He served as Director of Clinical Hematology at Einstein Hospital and Vice-Chairman and Director of Laboratories at Einstein and Montefiore Hospitals. He has over 50 publications, has authored two textbooks and holds five U.S. patents for his own inventions.
Since joining the Einstein faculty Dr. Burns was awarded the Sam Rosen Award for Outstanding Clinical Teaching and the Harry Eagle award for excellence in basic science teaching. He has been awarded the Einstein Alumni Association's Lifetime Service Award. In 2015 he was awarded Einstein's Lifetime Achievement Award in Excellence of Teaching.
Burns ER: Predictive value of the bleeding time in coronary artery bypass grafting. J Thorac Cardiovasc Surg 100:174-5,1991.
Burns ER: Mechanism of thrombocytopenia in the May-Hegglin anomaly.
Am J Ped Hematol/Onc 13:431-6, 1991.
Wenz B, Burns ER: Rapid removal of heparin from plasma by affinity filtration.
Am J Clin Pathol 96:385-389, 1991.
Burns ER, Lee V, Rubinstein A: Treatment of septic thrombocytopenia with immune globulin J Clin Immunol 11:363-368, 1991.
depleted red cell concentrate using flow cytometry. Transfusion 31:829-34, 1991.
heparin neutralization. Clin Lab Sci 8:113-117, 1995.
Markowitz GS, Brignol F, Burns, ER, Konigsberg M, Folkert V: Renal vein thrombosis treated with thrombolytic therapy. Am J Kidney Dis 25:801-806, 1995.
Murthy VV, Ali F, and Burns ER: Differentiation and resolution of erythrocyte and muscle adenylate kinase activities in serum by electrophoresis. J Clin Lab Analysis 11:235-7, 1997.
Burns ER, Kale A, Murthy VV: Diagnosis of the Hemolytic State using Serum Levels of Erythrocyte Adenylate Kinase. Am J Hematol 64:180-183, 2000.
Badve S and Burns ER: D-dimer measurements unhelpful for ruling in DIC. Laboratory Medicine 31:383-386, 2000.
Burns ER Lou Y, and Patek A: Morphologic diagnosis of thrombotic thrombocytopenic Purpura. Am J Hematol 75:18-21, 2004.
C. Velez, P.F. Palamara, L. Hao, T. Karafet, J. Guevara-Aguirre,A. Pearlman1, C.Oddoux, M. Hammer, E.R. Burns, I. Pe'er, G. Atzmon, H. Ostrer: The Impact of Converso Jews on the Genomes of Modern Latin American. Hum Genet. 2012 Feb;131(2):251-63.
Campbell CL, Palamara PF, Dubrovsky M, Botigué LR, Fellous M, Atzmon G, Oddoux C, Pearlman A, Hao L, Henn BM, Burns E, Bustamante CD, Comas D, Friedman E, Pe'er I, Ostrer H. North African Jewish and non-Jewish populations form distinctive, orthogonal clusters. Proc Natl Acad Sci USA 2012 Aug 21;109(34):13865-70.
2. Burns ER: The Harper Collins Medical Dictionary, New York 2006, 525 pgs.
WNYC Radio interviews Dr. Edward Burns about the planned budget deal that could restore some funding to the National Institutes of Health.
The New York Times ran a letter to the editor by Dr. Edward Burns, suggesting patients use physicians' expertise to guide their medical decisions.


text:
Gilles Bader / Le Pictorium -
high Karabakh -
23/11/2021 - Armenia / syunik / Agarak -
high Karabakh
Gilles Bader
17/11/2021 - Armenia / Armenia / Erevan -
21/11/2021 - Armenia / Nagorno Karabakh / Stepanakert -
24/11/2021 - Armenia / syunik / Kapan -
18/11/2021 - Armenia -
Nicolas Cleuet / Le Pictorium -
Lebanon 12 months later -
07/05/2021 - Lebanon / Beirut / Beirut - Ground Zero, August 4, 2020, at 6:07 p.m., 2,750 tons of ammonium nitrate explode in warehouse number 12 at the foot of the Silos, destroying half of the city and leaving 216 dead and more than 7,500 dead
Lebanon 12 months later
Nicolas Cleuet
Lebanon - Explosion at the port in honor of the fallen firemen - -
30/04/2021 - Lebanon / Beirut / Beirut - Vue de la Place des Martyrs
Lebanon - Explosion at the port in honor of the fallen firemen -
08/05/2021 - Lebanon / Beirut / Beirut - Carlem Hitti lost on the same day her husband, her brother and a cousin, all three firemen of the team sent to the port before the explosion. Widow at 28, she has to stand up for her daughter, her parents, her aunts and uncles, to face her own tragedy and to lead the fight to know the truth within the collective of the victims of the explosion.
13/06/2021 - -
IRAN -
18/06/2021 - Iran / Tehran / Tehran - Park e Shahr, monument for Peace with a fresco in memory of the war with Iraq in the 80s. (from left to right), Sina, 19 years old singer of the group. Like more than a million Iranians, he will attempt the National University Entrance Examination at the end of June, which will decide his life and his city of residence for the next four years. Ziba, 16 years old, high school student, painter in her spare time. Ziba does not plan to live anywhere else but Iran. They met in a skateboard store. They all live in the conservative neighborhoods of southeast Tehran. April 21, 2021. Photography by Nicolas Cleuet / Hans Lucas.
Iranian Elections -
18/06/2021 - ? IRANIRAN ? / ? TEHRANTEHERAN ? / ? TEHRANTEHERAN ? - Tajrish Imam Zadeh Saleh mosquee polling station. 18 June 2021.
Iranian Elections
? IRANIRAN ?
14/06/2021 - ? IRANIRAN ? / ? TEHRANTEHERAN ? / ? TEHRANTEHERAN ? - North of Tehran, four other elections are taking place on June 18. One of them is the municipal elections, for which Iranians are getting more information. April 14, 2021.
France - Philippe Martinez - CGT -
03/02/2021 - France / Ile-de-France (region) / Montreuil - February 3, 2021, interview with Philippe Martinez general secretary of the CGT
France - Philippe Martinez - CGT
Marine Le Pen travelling to Normandy -
07/06/2021 - France / Normandy / NESLE-HODENG - Marine Le Pen travelling to Normandy to support the Rassemblement Nationale list led by Nicolas Bay. Nesle-Hondeg, Seine Maritime. 7 June 2021
Marine Le Pen travelling to Normandy
rally against the closure of cultural places in Belgium -
26/12/2021 - Belgium / Brussels / Brussels - 5000 people (source police) 15000 (source organization) gathered today (under the rain and the cold) in the Belgian capital to protest and to act of resistance to the decision of the Belgian government to order the closing of the majority of the cultural places of the country in order to contain the contaminations due to the coronavirus (variants delta and ommicron). Many places had already announced that they would remain open despite the closure decision.
rally against the closure of cultural places in Belgium
Nicolas Landemard
Paris FC - Olympique Lyonnais -
17/12/2021 - France / Ile-de-France (region) / Paris - Paris FC / Olympique Lyonnais / Coupe de France, 32eme de Finale Logo of the Coupe de France before the 32eme de fin de la coupe de France, at the Stade Charléty, opposing Paris FC to Olympique Lyonnais, on December 17th 2021.
Paris FC - Olympique Lyonnais
17/12/2021 - France / Ile-de-France (region) / Paris - Paris FC / Olympique Lyonnais / Coupe de France, Jean-Michel Aulas during the 32nd final of the Coupe de France, at the Stade Charléty, between Paris FC and Olympique Lyonnais, December 17, 2021.
17/12/2021 - France / Ile-de-France (region) / Paris - Paris FC / Olympique Lyonnais / Coupe de France, Paris FC on the attack during the 32nd final of the Coupe de France, at the Stade Charléty, between Paris FC and Olympique Lyonnais, December 17, 2021.
17/12/2021 - France / Ile-de-France (region) / Paris - Paris FC / Olympique Lyonnais / Coupe de France, Lyon on the attack during the 32nd final of the Coupe de France, at the Stade Charléty, between Paris FC and Olympique Lyonnais, December 17, 2021.
17/12/2021 - France / Ile-de-France (region) / Paris - Paris FC / Olympique Lyonnais / Coupe de France, Celebration of Moussa Dembele during the 32nd final of the Coupe de France, at the Stade Charléty, between Paris FC and Olympique Lyonnais, December 17, 2021.


text:
Entermission Sydney- A Summary
Do you remember the days of one dimensional game play with a simple wheel control or a joystick? Now jump forward to today's video games consoles and their games. There is everything from games intended for adults only and ones design to help kids learn before they start school. Entermission Sydney – Virtual Reality Escape Rooms – escape room in sydney is one of the authority sites on this topic.
When it comes to the new age game consoles there is one that leaves the rest in the dust. Because of the virtual reality games offered by the manufacture. Yes you guessed it! The Nintendo Wii. With games like Rapala tournament fishing and Brunswick pro Bowling. With a little practise anyone can feel like a professional angler on the open waters. Or like a weekend bowler at your local lanes.
Don't be fooled by the Wii, it's not all new age virtual reality to make you feel like you are really doing the activity you are playing. Like all Nintendo's in the past the Wii offers a jam pack line up of classics. With games like super Mario galaxy and Mario kart you are sure to feel like a kid again when enjoying the game play.
There are many great features to the Nintendo Wii, from its great looks and its compact size, to its wireless controller nicknames the "Wiimote". With attachments for the remote like the nunchuck, the classic controller found on the previous versions of the Nintendo's consoles, and the Wii wheel prefect for all you driving / racing game fans. One of the Wii features that has the competition beaten is its ability to connect wireless to the web via a Wi-Fi connection. The great thing about this. Is with this wireless Wi-Fi connection you can download media and play it on your Wii. This media includes anything from Wii games to television shows, movies and music. With all these possibilities from one machine you can call is a home entertainment system and not just a video game console.
Business, Games, Technology, Virtual Reality


text:
Video: How VFX Made *Snow White and the Huntsman'*s Man in the Mirror
Angela Watercutter
Charlize Theron really doesn't need anyone or anything to tell her she's pretty. (Obviously.) But when she asked who was fairest of them all in Snow White and the Huntsman, she wasn't asking her mirror, mirror -- she was asking a prop.
Angela Watercutter is a senior editor at WIRED covering pop culture. She also serves as the publication's deputy bureau chief in New York. Prior to joining WIRED she was a reporter for the Associated Press. Watercutter was also a senior editor of Longshot magazine and a contributor to Pop-Up Magazine.... Read more
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Našli jsme další záznamy k osobě Lipót Altdorffer.
Lipót Altdorffer je pohřben(a) na hřbitově Ondrejský cintorín v místě zobrazeném na níže uvedené mapě. Tyto informace o GPS jsou k dispozici POUZE na stránkách BillionGraves. Naše technologie vám pomůže najít umístění hrobu a také další členy rodiny, pohřbené poblíž.
Lipót Altdorffer was 11 years old when Susan B. Anthony and Elizabeth Cady Stanton founded the National Woman Suffrage Association, breaking away from the American Equal Rights Association which they had also previously founded. Susan B. Anthony was an American social reformer and women's rights activist who played a pivotal role in the women's suffrage movement. Born into a Quaker family committed to social equality, she collected anti-slavery petitions at the age of 17. In 1856, she became the New York state agent for the American Anti-Slavery Society.
Lipót Altdorffer was 19 years old when Thomas Edison announces his invention of the phonograph, a machine that can record and play sound. Thomas Alva Edison was an American inventor and businessman, who has been described as America's greatest inventor. He developed many devices that greatly influenced life around the world, including the phonograph, the motion picture camera, and the long-lasting, practical electric light bulb. Dubbed "The Wizard of Menlo Park", he was one of the first inventors to apply the principles of mass production and large-scale teamwork to the process of invention, and is often credited with the creation of the first industrial research laboratory.
Lipót Altdorffer was 31 years old when The Eiffel Tower is officially opened. The Eiffel Tower is a wrought iron lattice tower on the Champ de Mars in Paris, France. It is named after the engineer Gustave Eiffel, whose company designed and built the tower.
Lipót Altdorffer was 35 years old when Electrical engineer Nikola Tesla gives the first public demonstration of radio in St. Louis, Missouri. Nikola Tesla was a Serbian American inventor, electrical engineer, mechanical engineer, physicist, and futurist who is best known for his contributions to the design of the modern alternating current (AC) electricity supply system.
Lipót Altdorffer was 47 years old when Albert Einstein publishes his first paper on the special theory of relativity. Albert Einstein was a German-born theoretical physicist who developed the theory of relativity, one of the two pillars of modern physics. His work is also known for its influence on the philosophy of science. He is best known to the general public for his mass–energy equivalence formula E = mc2, which has been dubbed "the world's most famous equation". He received the 1921 Nobel Prize in Physics "for his services to theoretical physics, and especially for his discovery of the law of the photoelectric effect", a pivotal step in the development of quantum theory.
Lipót Altdorffer was 59 years old when Tsar Nicholas II of Russia was forced to abdicate in the February Revolution, ending three centuries of Romanov rule. Nicholas II or Nikolai II, known as Saint Nicholas in the Russian Orthodox Church, was the last Emperor of Russia, ruling from 1 November 1894 until his forced abdication on 15 March 1917. His reign saw the fall of the Russian Empire from one of the foremost great powers of the world to economic and military collapse. He was given the nickname Nicholas the Bloody or Vile Nicholas by his political adversaries due to the Khodynka Tragedy, anti-Semitic pogroms, Bloody Sunday, the violent suppression of the 1905 Russian Revolution, the executions of political opponents, and his perceived responsibility for the Russo-Japanese War (1904-1905). Soviet historians portray Nicholas as a weak and incompetent leader whose decisions led to military defeats and the deaths of millions of his subjects.
Lipót Altdorffer was 71 years old when Babe Ruth becomes the first baseball player to hit 500 home runs in his career with a home run at League Park in Cleveland, Ohio. George Herman "Babe" Ruth Jr. was an American professional baseball player whose career in Major League Baseball (MLB) spanned 22 seasons, from 1914 through 1935. Nicknamed "The Bambino" and "The Sultan of Swat", he began his MLB career as a stellar left-handed pitcher for the Boston Red Sox, but achieved his greatest fame as a slugging outfielder for the New York Yankees. Ruth established many MLB batting records, including career home runs (714), runs batted in (RBIs) (2,213), bases on balls (2,062), slugging percentage (.690), and on-base plus slugging (OPS) (1.164); the latter two still stand as of 2018. Ruth is regarded as one of the greatest sports heroes in American culture and is considered by many to be the greatest baseball player of all time. In 1936, Ruth was elected into the Baseball Hall of Fame as one of its "first five" inaugural members.