tbuckley/cabot-search huggingface dataset:
SP0193 Physiologic Functions of Innate Immunity in Metabolic Homeostasis
Authors: A. Chawla
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Macrophages take residence in nearly all tissues, where they function as sensors and integrators of environmental and metabolic stress. In metabolic tissues, tissue resident macrophages sense their local and systemic environment to coordinate parenchymal cell metabolism. In this context, previous work from our laboratory has focused on the transcriptional regulation of the inducible program of alternative macrophage activation, and its importance in adaptations to dietary and environmental stress. In addition to the homeostatic functions of inducible macrophage activation, we postulated that innate immune responses might be regulated in an anticipatory manner, allowing organisms to anticipate and adapt to changes in their environment. Here, we present evidence that Ly6C<sup>hi</sup> inflammatory monocytes exhibit diurnal variation, which controls their trafficking to sites of inflammation. This cyclic pattern of trafficking confers protection against <i>Listeria</i><i>monocytogenes</i> and is regulated by the repressive activity of the circadian gene <i>BMAL1</i>. Accordingly, myeloid cell-specific deletion of <i>BMAL1</i> induces expression of monocyte-attracting chemokines and disrupts rhythmic cycling of Ly6C<sup>hi</sup> monocytes, predisposing mice to development of pathologies associated with acute and chronic inflammation. These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6C<sup>hi</sup> monocytes that enhances organismal fitness. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6271
P59 Utility Of Fib4 Score And Liver Disease In Alpha-1 Antitrypsin Deficiency (a1atd)
Authors: D. Bruce-Hickman, A. Saleh, B. Gooptu, D. Lomas, D. Thorburn, J. Hurst
Journal: Thorax (2014)

<h3>Introduction</h3> A1ATD is an autosomal co-dominant condition where homozygosity for the Z-allele results, classically, in emphysematous lung involvement, and liver fibrosis dependant on polymerisation rate of aberrant protein.<sup>1</sup> The FIB4 score non-invasively estimates risk of liver fibrosis,<sup>2</sup> but has not previously been investigated in A1ATD. We completed preliminary assessment of the utility of FIB4 in our A1ATD cohort. Whilst the standard of care in A1ATD should be joint respiratory-hepatology services, not all patients are able to access this. A simple tool to guide referral to hepatology services could therefore be clinically useful to the respiratory community. <h3>Methods</h3> We report data from 30 PiZZ patients with ultrasound (USS) characterisation of liver disease. An abnormal USS was considered as any abnormality other than cysts, thus including features of cirrhosis and fatty infiltration. FIB4 was calculated as [Age (years)xAST(U/l)]/[Platelets (10<sup>9</sup>)xALT(U/l)]. The most recent lung physiology was recorded as FEV1 (%predicted), diffusion coefficient (KCO,%predicted) and residual volume (RV,%predicted). Body mass index (BMI) was calculated. <h3>Results</h3> The 30 patients had a mean age of 54 ± 12.4 years, 14 were male. Lung function showed mean FEV1 1.85 ± 1.12 L (61.3 ± 30.9%), KCO 1.05 ± 0.40 mmol/min/kPa/L (66.4 ± 22.2%) and RV 3.58 ± 1.36 L (171.8 ± 50.4%). The mean FIB4 was 1.76 ± 1.36. Eight (26.7%) patients had liver disease on USS. FIB4 cut-off values of 1.45 and 3.25 were utilised, as they are widely validated.<sup>3</sup> Of patients &gt;3.25, 100% had abnormal scans (PPV 100%), and of patients &lt;1.45, 15.8% had abnormal scans (NPV 82%). FIB4 enabled correct identification of patients with abnormal USS with an area under a ROC curve of 0.642. We demonstrate a relationship between liver involvement in A1ATD and BMI. Those with higher FIB4 had higher BMI (r = 0.453, p = 0.008). We found no relationship between FIB4 and severity of lung involvement. <h3>Conclusions</h3> The FIB4 score, calculated from routine laboratory variables and age, may be useful to rule in and out significant liver involvement in A1ATD with reasonable sensitivity and specificity. Further work is required for validation against biopsy, the gold-standard assessment. We confirm a previously noted lack of association between liver disease and emphysema severity,<sup>4</sup> and highlight the association between higher BMI and higher fibrosis risk in A1ATD.
THU0021 Cartilage zone specific proteins: A quantitative proteomic analysis
Authors: P. Fernández-Puente, L. Lourido, V. Calamia, J. Mateos, C. Ruiz-Romero, M. Lotz, F.J. Blanco
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by degradation of the matrix and cell death, resulting in a gradual loss of articular cartilage integrity. Despite its high prevalence, disease-modifying therapies are not available and this is in part related limited sensitivity of current methods for the assessment of disease progression. <h3>Objectives</h3> To identify and localize proteins in normal cartilage, and compare them to the OA tissue using quantitative proteomic techniques. <h3>Methods</h3> Cartilage samples were obtained from OA patients undergoing joint replacement and normal donors without history of joint disease. For the localization studies, independent normal cartilage samples (n=3) were sectioned into three layers (superficial, intermediate and deep). Cartilage proteins were extracted with Urea 6M, 2% SDS using a mixer mill. Then, proteins were quantified, digested with trypsin and differentially labelled with iTRAQ isobaric tags. The peptide mixture was separated by two-dimensional LC coupled to MALDI-TOF/TOF mass spectrometry. Identification and relative quantification of the proteins were performed using ProteinPilot 3.0 software. <h3>Results</h3> We could identify more than 260 different proteins in articular cartilage. 47% of them were intracellular, and the rest were ECM components. When comparing between tissue layers, we found an increased abundance of type VI collagen and small proteoglycans (mimecan, lumican or PRG4) in the superficial layer. Several proteins involved in cell adhesion processes were also increased in this layer (gelsolin, vitronectin, tenascins). The intermediate layer was characterized by a high presence of type II, V, IX and XXVIII collagens, cartilage intermediate layer proteins (CILPs), COMP, vitrin and decorin. Finally, the deep layer exhibited an increased abundance of type I and XI collagens, aggrecan and bone-related proteins (bone sialoprotein 2, osteomodulin, and bone morphogenetic protein 3). Comparison of this normal cartilage proteome with that from OA tissue led to the identification of 23 proteins increased in the pathologic tissue, including aggrecan, COMP, complement factors or thrombospondin 1. We could also identify 36 proteins that were decreased in OA cartilage, such as type I, II and VI collagens, proteoglycans (biglycan, PRG4), tenascins or actin. <h3>Conclusions</h3> In summary, we have mapped more than 250 different human normal articular cartilage proteins according to their presence in the three different tissue layers, and identified 59 different proteins that are altered in OA cartilage when compared to normal tissue. This information would be of high relevance in the search of tissue-specific OA biomarkers. <h3>Disclosure of Interest</h3> None Declared
FRI0544 Self-experienced risk for loss of work productivity among patients with ra seen in rheumatology outpatient clinics in finland
Authors: K. Puolakka, T. Sokka, H. Kautiainen, S. Järvenpää, V. Rantalaiho, K. Eklund
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> We have shown in a population-based study that the risk of permanent work disability has decreased after the turn of millennium among incident patients with rheumatoid arthritis (RA) (1), but the risk among patients with established RA is not known. <h3>Objectives</h3> To investigate the risk for lost workdays in patients with RA in daily clinical practice. <h3>Methods</h3> In 12 rheumatology outpatient clinics in Finland, consecutive patients filled in a questionnaire. Data on age, sex, and work status were gathered. Employed patients estimated physical demand and psychological stress associated with work in a numeric scale from 0 to 10, and they were asked to assess, whether they were felt (yes or no) they would lose workdays because of rheumatic disease during the following 6 months and whether they felt they would lose their working ability. Their physician filled in the patient’s ICD-10 code and recorded any use of biologic drugs. Data on 2220 patients were obtained. Patients with RA (codes M05 and M06) were analysed. <h3>Results</h3> A total of 993 patients had RA diagnosis, 754 (76%) were seropositive. Of these, 529 (378 RF+ and 151 RF-) were 23 to 63 years of age and were employed during the preceding 6 months. 383 (72%) were biologic naïve. These patients had a shorter disease duration, 6.8 years (SD 8.2), compared to patients with history of biologics, 12.3 years (SD 8.3) (p&lt;0.001). No other differences between the groups appeared. Proportion of females was 76% and 79%, age 48.0 (SD 10.3) and 47.5 (SD 10.0) years, RF present in 74% and 66%, self-assessed physical work load 5.3 (SD 2.8) and 4.9 (SD 2.9), and self-assesses work related stress 6.3 (SD 2.3) and 6.6 (SD 2.3), in Bio- and Bio+ groups, respectively. The self-experienced risk for days off work was equal: in Bio- 42% (95% CI: 37 to 47) and in Bio+ 45% (95% CI: 37 to 53); p=0.48, adjusted for age, gender, RF, and disease duration. Neither was difference found in the experienced risk for permanent work disability: Bio- 27% (95% CI: 23 to 31), Bio+ 32% (95% CI: 24 to 39), adjusted p=0.67. <h3>Conclusions</h3> Self-experienced risk for temporary or permanent loss of work productivity is still substantial among patients with RA seen in daily clinical practice irrespective of the use of biologic agents. The longer disease duration of Bio+ patients, however, may suggest channelling bias. <h3>References</h3> Rantalaiho V et al. Decline in work disability caused by early rheumatoid arthritis: Results from a nationwide Finnish register, 2000-8. Ann Rheum Dis in press <h3>Disclosure of Interest</h3> None Declared
Abstract 1550: Supernatant of NIH3T3/Src(Y527F) cell line induced Ana-1 macrophages to tumor-associated macrophages by IL-6.
Authors: Lechuang Chen, Chenfei Hu, Qing Xu, Kai Ma, Mei Liu, Hongxia Zhu, Ningzhi Xu
Journal: Cancer Research (2013)

Abstract Macrophages (Mф) is the major components of the solid tumors. Tumor-associated macrophages (TAM) play an important role in the development of tumor inflammation. The tumor microenvironment could induce macrophages differentiation into TAM, and the TAM could regulate tumor growth and invasion. However, the mechanisms that by which signaling pathways contribute to cell differentiation are not well deﬁned. As we known, the tumor microenvironment in vivo is complex and integrated by a variety of cells and factors. In this study, we chose NIH3T3 cell line to construct a stable Src(Y527F) expression system. We found that its supernatant could induce macrophages differentiation into TAM in vitro. When we injected the cell mixture of Ana-1 macrophages and NIH3T3/Src(Y527F) cells into nude mice, the volume of tumors increased more quickly than the control group that just injected NIH3T3/Src(Y527F) cells only. And, we also found that the tumors became more invasive than control tumors. Furthermore, 62 cytokines were tested by using Cytokine Antibody Array, the result showed that 13 of them significantly changed in the supernatant of NIH3T3/Src(Y527F) cells compared with NIH3T3. Strikingly, IL-6 was 71-fold up-regulated. When we added IL-6 in the supernatant, it could also induce Ana-1 macrophages differentiation into a TAM phenotype. Our findings indicated that IL-6 might play an important role in the differentiation of Ana-1 from macrophages to TAM by using the supernatant of NIH3T3/Src(Y527F) cell line. Citation Format: Lechuang Chen, Chenfei Hu, Qing Xu, Kai Ma, Mei Liu, Hongxia Zhu, Ningzhi Xu. Supernatant of NIH3T3/Src(Y527F) cell line induced Ana-1 macrophages to tumor-associated macrophages by IL-6. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1550. doi:10.1158/1538-7445.AM2013-1550
Abstract 1580: A novel C. elegans animal model for human RET receptor function.
Authors: Jordan D.S. Zelt, Ian D. Chin-Sang, Lois M. Mulligan
Journal: Cancer Research (2013)

Abstract RET (Rearranged in Transfection) is a receptor tyrosine kinase mutated in the cancer syndrome multiple endocrine neoplasia 2 and linked to many other cancers, including medullary thyroid carcinoma and cancers of the adrenal gland. There are two distinct isoforms of RET, RET9 and RET51, with in vitro evidence indicating isoforms induce unique phosphorylation patterns on select tyrosine residues, possess different cell transforming and differentiation abilities, and bind/activate a unique set of substrates. However, these processes are challenging to dissect in complex organisms because both RET isoforms are ubiquitously co-expressed. We have generated a novel Caenorhabditis elegans model for RET expression to dissect the role of individual RET isoforms. C. elegans do not encompass a homologue of RET, thus we injected chimeric constructs in which human RET isoform sequences were fused to a N-terminal myristoylation signal for membrane targeting and expressed under the control of the C. elegans mechanosensory neuron-specific promoter, mec-4. The resultant transgenic animals were scored for phenotypes of RET-expressing neurons. We found that RET9 expressing animals have near WT phenotype, while RET51 expressing animals exhibited an axon termination phenotype where the PLM mechanosensory neuron of the tail fails to migrate to its correct location. This is indicative of early neuron terminal differentiation attributed to RET downstream signalling. Furthermore, strains harboring constitutively active oncogenic versions of RET9 or RET51 had severe PLM axon defects, with the RET51 phenotype being significantly more penetrant. Through generating strains with point mutations at select tyrosine residues and assessing the resulting phenotype, we have determined Y1062 and Y1096 to be main signalling hubs contributing to the RET-mediated phenotype in C. elegans. We are currently testing known kinase inhibitors, assessing efficacy and toxicity of potential RET inhibiting therapeutics. Using C. elegans as a platform to model RET is a quick and efficient system to gain insight on RET isoforms, delineate molecular events contributing to cancer progression, and investigate therapeutic agents that can be used to treat RET associated cancers. Citation Format: Jordan D.S. Zelt, Ian D. Chin-Sang, Lois M. Mulligan. A novel C. elegans animal model for human RET receptor function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1580. doi:10.1158/1538-7445.AM2013-1580
CLINICAL OUTCOMES OF PATIENTS WITH INDUCIBLE MICROVASCULAR DISEASE DURING REAL TIME PERFUSION ECHOCARDIOGRAPHY IN THE ABSENCE OF ANGIOGRAPHIC CORONARY DISEASE
Authors: Shelby Kutty, Mary Craft, Irsa Shoiab, Charles M. Kelly, Kevin Nalty, Valerie Shostrom, Thomas Porter
Journal: Journal of the American College of Cardiology (2016)
Acute Cytokine Response to Systemic Adenoviral Vectors in Mice Is Mediated by Dendritic Cells and Macrophages
Authors: Yi Zhang, Narendra Chirmule, Guang-ping Gao, Ruth Qian, Maria Croyle, Bindu Joshi, John Tazelaar, James M. Wilson
Journal: Molecular Therapy (2001)

We investigated the cellular basis for secretion of inflammatory cytokines in mice following intravenous administration of adenoviral vectors (Ad). Serum inflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-alpha (TNF-α) were detected as early as 6 h following intravenous injection of Ad-expressing Escherichia coli β-galactosidase (Ad-lacZ). Ad-lacZ readily accumulated in the splenic marginal zone 1 h after intravenous infusion, where both dendritic cells (DCs) and macrophages were transduced and activated within 6 h. Flow cytometric analyses showed that the expression of Ia and CD86 antigens was markedly enhanced on splenic DCs indicating their activation in vivo by Ad-lacZ. Upon ex vivo culture, these early-activated splenic DCs spontaneously produced high levels of IL-6 and IL-12. By contrast, activated splenic macrophages spontaneously secreted only IL-6. Elimination of tissue macrophages and splenic DCs in vivo considerably reduced the early release of IL-12, IL-6, and TNF-α and significantly blocked the specific cellular immune response to Ad and the transgene product in vivo. Our findings indicate that preferential activation of DCs and macrophages may account for Ad-triggered acute inflammatory response in vivo in mice. Moreover, DCs and macrophages may play different roles in this process in terms of their abilities to produce distinct patterns of inflammatory cytokines. We investigated the cellular basis for secretion of inflammatory cytokines in mice following intravenous administration of adenoviral vectors (Ad). Serum inflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-alpha (TNF-α) were detected as early as 6 h following intravenous injection of Ad-expressing Escherichia coli β-galactosidase (Ad-lacZ). Ad-lacZ readily accumulated in the splenic marginal zone 1 h after intravenous infusion, where both dendritic cells (DCs) and macrophages were transduced and activated within 6 h. Flow cytometric analyses showed that the expression of Ia and CD86 antigens was markedly enhanced on splenic DCs indicating their activation in vivo by Ad-lacZ. Upon ex vivo culture, these early-activated splenic DCs spontaneously produced high levels of IL-6 and IL-12. By contrast, activated splenic macrophages spontaneously secreted only IL-6. Elimination of tissue macrophages and splenic DCs in vivo considerably reduced the early release of IL-12, IL-6, and TNF-α and significantly blocked the specific cellular immune response to Ad and the transgene product in vivo. Our findings indicate that preferential activation of DCs and macrophages may account for Ad-triggered acute inflammatory response in vivo in mice. Moreover, DCs and macrophages may play different roles in this process in terms of their abilities to produce distinct patterns of inflammatory cytokines.
A memorable patient: The evidence and Audrey
Authors: R. Camidge
Journal: BMJ (2001)

This is a tale of two extraordinary people, one a professor of evidence based medicine, the other a retired schoolteacher with advanced ovarian cancer. I was a house officer to the famous professor when Audrey, the teacher, was an inpatient under our care.

One night, although not on call, I was still tidying things up on the wards when I heard someone call my name. Looking up I saw Audrey beckoning me. She had been suffering from pneumonia arising from a metastasis of the lung, and I assumed she was asking me for some assistance. As I approached, however, she told me breathlessly that I worked too hard, I wasn't being paid for it, and that I should go home. She was that sort of person.

Audrey recovered from her pneumonia …
Abstract 18321: Impact of Single Catheter Ablation of Atrial Fibrillation on Appropriate and Inappropriate Implantable Cardioverter Defibrillator Therapies in Patients with Cardiomyopathy
Authors: Jerzej Kosiuk, Sotirios Nedios, Angeliki Darma, Sascha Rolf, Arash Arya, Christopher Piorkowski, Thomas Gaspar, Philipp Sommer, Gerhard Hindricks, Andreas Bollmann
Journal: Circulation (2012)

Background: Atrial fibrillation (AF) is associated with frequent appropriate and inappropriate ICD therapies. Catheter ablation of AF has been shown to reduce AF burden and improve left ventricular function in heart failure patients but the impact on ICD therapies has not been studied. Here, we tested the hypothesis that AF ablation reduces ICD therapies in patients with cardiomyopathies. Methods: In 73 consecutive patients (mean age 59 ± 10 years, 85 % male) with previously implanted ICD due to ischemic (n=30) or dilated cardiomyopathy (n=43) undergoing AF catheter ablation, the frequency of appropriate and inappropriate ICD therapies before and after AF ablation were compared. Results: During mean follow-up of 3.3 ± 3 years prior to AF ablation, 4.5 ± 14.7 therapies per patient-year were delivered as opposed to 1.5 ± 10.9 in period of 1.1 ± 0.9 years after ablation. Therefore, catheter ablation of AF reduced the frequency of all ICD therapies by a factor of 3 (p=.002). Both, inappropriate therapies decreased from 2.7 ± 10.9 to 1.4 ± 10.9 per patient-year (p=.02) and appropriate therapies decreased from 1.7 ± 10.9 to 0.1 ± 0.9 per patient-year (p=.028). While heart failure medication and use of antiarrhythmic drugs was comparable during entire follow-up period, left ventricular ejection fraction (LVEF) was significantly improved from 36 ± 11 to 42 ± 13% (p=.004) after AF ablation. Conclusions: In patients with ischemic or dilated cardiomyopathy, catheter ablation of AF reduces inappropriate and appropriate ICD therapies and improves LVEF.