tbuckley/cabot-search huggingface dataset:
THU0054 Role of Fra-2 in TLR8-Mediated TIMP-1 Production in Systemic Sclerosis
Authors: M. Ciechomska, J. van Laar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterised by fibrosis, vascular dysfunction and abnormal activation of immune cells. We and others have shown that monocytes along with fibroblasts play an important role in the production of pro-fibrotic factors such as IL-6 and TIMP-1 (tissue-inhibitor of metalloproteinase-1). Importantly, the balance between TIMP-1 and MMPs is altered in SSc leading to abnormal ECM formation. However, the exact factors which drive pro-fibrotic TIMP-1 in monocytes have not been fully established. Previous studies showed that AP-1 transcription factors including Fra-2 and JunD are involved in TIMP-1 gene expression in hepatic stellate cells contributing to liver fibrosis. Also Fra-2 transgenic mice develop a proliferative vasculopathy of the lung and skin fibrosis resembling similar disease manifestations seen in SSc patients. <h3>Objectives</h3> The aim of this study is to determine the role of Fra-2 in TIMP-1 production. We also plan to determine if TIMP-1 is a direct target gene of Fra-2 upon TLR8 stimulation in SSc monocytes. Additionally, we want to investigate if altered Fra-2 signalling results in enhanced TIMP-1 production thus contributing to ECM deposition and fibrosis development observed in systemic sclerosis. <h3>Methods</h3> 20 patients with SSc, one IRAK4 deficient patient and 20 HC (healthy control) were included in this study. Peripheral blood monocytes were further separated by CD14+ microbeads. Expression of TIMP-1 and Fra-2 by monocytes was determined by ELISA, qRT-PCR in response toTLR8 agonists (ssRNA). <h3>Results</h3> The results from our group demonstrated that circulating monocytes from SSc patients contribute to the imbalance between TIMP-1 and MMPs and to an increased pro-fibrotic IL-6 production upon TLR8 agonist stimulation (ssRNA). Interestingly, monocytes from an IRAK-4 (a key kinase in TLR-signalling) deficient patient did not produce IL-6 and TIMP-1. In addition, the results showed that the basal gene expression level of Fra-2 in SSc monocytes is higher than in healthy or IRAK-4 deficient monocytes. Interestingly, TLR8 activation induced even stronger Fra-2 gene expression and correlated with increased expression of TIMP-1 in SSc monocytes, suggesting that the TLR signalling pathway may be involved in Fra-2 mediated TIMP-1 induction and therefore promotes fibrosis. Also, we plan to pre-treat monocytes with the chemical AP-1 inhibitor (T-5224) and assess both gene and protein level of TIMP-1 upon TLR8 activation. <h3>Conclusions</h3> This study helps to understand the molecular mechanisms of Fra-2 mediated fibrogenesis in SSc. <h3>Disclosure of Interest</h3> None Declared
Pancreatic stent placement for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: do we need further evidence? No, the defense rests
Authors: A. Rao, T. Baron
Journal: Endoscopy (2010)

The exact mechanisms that contribute to the development of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) have not been fully elucidated. However, several factors are known to promote PEP, the most important of which appears to be manipulations of the ampulla, which result in decreased outflow of secretions through the main pancreatic duct, either by inducing sphincter of Oddi spasm or by causing mechanical obstruction by edema formation. The latter concept is supported by data suggesting that a patent minor papilla in the absence of pancreas divisum is protective against PEP [1], presumably because pancreatic drainage can be sustained in the face of relative obstruction at the level of the major papilla. Thus, the idea of placing a temporary pancreatic duct stent to prevent PEP is supported by its role in maintaining the integrity of pancreatic outflow.
P1290 EARLY VIROLOGIC RESPONSES AND ADVERSE EVENTS FROM THE COMPARATIVE ASSESSMENT OF EFFECTIVENESS OF ANTIVIRAL THERAPIES IN HEPATITIS C STUDY (CMPASS)
Authors: M. Buti, S. Mauss, S. Ryder, V. Isakov, R. Paraná, A. Kalsekar, G. L'italien, S. Sapra
Journal: Journal of Hepatology (2014)
Pooled Analysis of Cardiac Safety in Patients Treated with Pertuzumab.
Authors: T. Suter, M. Brammer, G. Ross, D. Lenihan
Journal: Cancer Research (2009)

Abstract Background: Pertuzumab, a monoclonal antibody, is a human epidermal growth factor receptor 2 (HER2)-dimerisation inhibitor directed to the dimerisation epitope of HER2, with promising activity when given with trastuzumab to patients with HER2-positive metastatic breast cancer following progression on trastuzumab.1 As anti-HER2 treatment has been associated with cardiac dysfunction, we investigated the incidence of reduced left ventricular ejection fraction (LVEF) and congestive heart failure (CHF) in patients treated with pertuzumab as single agent or in combination with cytotoxic or anti-HER therapy.Methods: We analysed patients in completed Phase II studies with pertuzumab. Cardiac dysfunction was defined as: 1) reduced LVEF (baseline normal: LVEF reduced ≥10% absolute and to below 50%); 2) symptomatic CHF: any symptoms suggestive of CHF counted (severity then classified according to New York Heart Association).Results: In 554 patients analysed, the overall incidence of reduced LVEF was 5.8% and of CHF 0.7%. Individual data for patients in different treatment protocols are shown in Table 1. PatientsReduced LVEFCHF (n)(n/%)(n/%)Pertuzumab as single agent (24% with prior anthracyclines)30221/7.01/0.3Pertuzumab with cytotoxic therapy1756/3.42/1.1Pertuzumab with trastuzumab (71% with prior anthracyclines)775/6.51/1.3 The majority of patients with reduced LVEF or symptomatic CHF had significant improvement or return to baseline function on follow-up or with standard cardiac medication.Conclusions: Overall, the incidence of cardiac dysfunction in Phase II studies of patients treated with pertuzumab was low. When combined with trastuzumab in selected patients, there is no apparent indication that pertuzumab exacerbates the known risk of reduced LVEF and CHF with trastuzumab.2 These data suggest that the combination of pertuzumab with trastuzumab or chemotherapy for HER2-positive breast cancer appears safe from a cardiac perspective with appropriate monitoring in ongoing studies.References1. Gelmon K et al. Poster 1026 presented at the 44th ASCO Annual Meeting, Chicago, Illinois, USA, 30 May-3 June, 20082. Muehlbauer S et al. Abstract presented at SABCS 2008; abs 6136 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5088.
AB0085 Macrophages are modulated by factors secreted by adipocytes
Authors: I. Klein-Wieringa, S. Andersen, J. Kwekkeboom, B. de Lange, M. Kloppenburg, R. Toes, A. Ioan-Facsinay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Obesity has been associated with development and progression of osteoarthritis. Although the biological mechanisms underlying this association are unknown, several studies have indicated that adipose tissue secretes a large variety of soluble factors that can influence whole-body metabolism. We have recently shown that the infrapatellar fat pad (IFP), an adipose tissue organ in the knee joint, is a source of inflammatory mediators that could influence joint pathology. Moreover, we identified obesity-related changes in cytokine release by IFP. Both adipocytes and immune cells present in IFP could constitute the source of these inflammatory mediators. Among the IFP-infiltrating immune cells, macrophages are the most abundant and previous studies have indicated that cytokine release by adipose tissue macrophages depends on adiposity. However, the mechanism underlying this association is unknown. In the present study, we explored the possibility that adipocytes modulate the phenotype of macrophages, thereby contributing to obesity-induced changes in adipose tissue. <h3>Methods</h3> Adipocyte conditioned media (ACM) were generated by culturing adipocytes from IFP (OA patients) or subcutaneous adipose tissue (ScAT, healthy donors) for 24hrs. Protein and lipid fractions of ACM were isolated using TBME and resuspended in medium. Macrophages were obtained by differentiating purified CD14<sup>+</sup> monocytes of healthy individuals in the presence of GM-CSF for 7 days. ACM or different fractions were added for the last 48h, while LPS was added during the last 24hrs of culture. IL-12 and TNFα cytokine secretion was measured by ELISA. The T cell stimulatory capacity of ACM-conditioned macrophages was measured in a 4-day mixed lymphocyte reaction. T cell proliferation was measured by tritium-thymidine incorporation. <h3>Results</h3> Treatment of macrophages with ACM resulted in a strong reduction in IL-12 secretion upon LPS stimulation, whereas TNFα remained unaffected. In addition, ACM–conditioned macrophages had an increased T cell stimulatory capacity. These effects were observed with both IFP- and ScAT-derived ACM. Interestingly, the inhibition of IL-12 release correlated to the Body Mass Index (BMI) of the IFP adipocyte donor. Separation of protein and lipid fractions of ACM indicated that the IL-12 inhibition was mediated by the lipid fraction. Current research investigates the lipid(s) responsible for the observed effects. <h3>Conclusions</h3> Soluble factors secreted by adipocytes modulate macrophage function and this effect seems to reside in the lipid fraction of ACM. Interestingly, the inhibition of IL-12 release correlates with BMI of the adipocytes donor, indicating that obesity-related changes in macrophage phenotype could be mediated by adipocytes. <h3>Disclosure of Interest</h3> None Declared
OP38 * ROBOT-ASSISTED CONVECTION-ENHANCED DELIVERY OF CARBOPLATIN FOR PROGRESSIVE DIPG - A SAFETY AND FEASIBILITY REPORT OF 5 CASES
Authors: N. U. Barua, S. P. Lowis, M. Woolley, D. Cronin, R. J. Edwards, S. S. Gill
Journal: Neuro-Oncology (2014)

INTRODUCTION: Convection-enhanced delivery is a method of drug delivery to the brain through implanted microcatheters. There has been significant research focus on applying CED to the treatment of DIPG, where prognosis remains poor. METHOD: 5 paediatric patients with tumour progression after radiotherapy were treated on compassionate grounds. Up to 4 catheter trajectories per patient were planned on pre-operative 3T MRI scans using custom-made planning software. Catheters were implanted using a robot-assisted technique. Infusions of carboplatin (0.18 mg/mL) were performed on 2 consecutive days. Serial T2W MRI was used to determine drug distribution. RESULTS: No adverse events related to implantation of catheters were observed. High volume (9mL/day), high flow rate infusions (10 µL/min) were performed. During infusions patients exhibited worsening of pre-existing neurological dysfunction, which was transient in all except one patient who required a prolonged period of non-invasive respiratory support. Real-time MRI indicated drug distribution throughout the majority of targeted tumour in 4 patients. Reduction in the volume of enhancing tumour was seen in 2 patients on follow-up imaging. CONCLUSION:Robot-assisted catheter insertion was safe and achieved satisfactory targeting. Satisfactory drug distribution was achieved in 4 out of 5 patients. Reduction in tumour enhancement was seen in 2 patients. Infusions were associated with only transient worsening of neurological function in all but one patient. This initial experience in 5 patients represents a strong foundation for a clinical trial of CED of carboplatin for DIPG.
THE METABOLIC SYNDROME, CORONARY ARTERY CALCIUM SCORE AND CARDIOVASCULAR RISK RECLASSIFICATION
Authors: Marat Fudim, Devin K. Patel, Sandip Zalawadiya, Anupama Kottam, Issa Alesh, Shaun Cardozo, Luis Afonso
Journal: Journal of the American College of Cardiology (2015)
PTH-115 Prevalence Rates And Risk Factors For Osteoporosis In Patients With Coeliac Disease
Authors: J Schembri, P Torpiano, N Azzopardi, M Vassallo, P Ellul
Journal: Gut (2014)

<h3>Introduction</h3> The optimal timing for performing a baseline bone mineral density (BMD) in Coeliac disease (CD) patients is controversial. European guidelines published in 1998 recommended a baseline BMD at diagnosis. One study in 2005 demonstrated a low incidence of BMD abnormalities amongst patients with CD<sup>1</sup> and the British Society of Gastroenterology guidelines state that DEXA should only be done after introduction of a gluten-free diet on the subgroups of patients in whom the risk of osteoporotic fracture is high<sup>2</sup>. This was however followed up by a guidance document in 2010 stating that BMD assessment should always be performed at diagnosis. Meanwhile the American guidelines suggest testing for vitamin and micronutrient deficiencies<sup>3</sup>. The aims of this study were to determine, the prevalence of osteopenia and osteoporosis among patients who are newly diagnosed with CD, and any risk factors which would increase patients9 risk of osteopenia and osteoporosis. <h3>Methods</h3> We carried out a prospective cohort study, where newly diagnosed CD patients were recruited. DEXA scanning was done at diagnosis. Data with regards to smoking, BMD and histology was entered into a database and analysed using SPSS software package. <h3>Results</h3> 137 patients with a histological diagnosis of CD were recruited. 76.6% were females. Mean age at diagnosis was 37.1 years (95% CI: ±3.19 years). 21.9% (n = 30) of patients were osteoporotic and another 51.1% (n = 72) were osteopenic at diagnosis. A total of 14.9% (n = 17) had a previous history of fracture/s prior to diagnosis. Osteoporosis at the spine was significantly associated with the female gender (p = 0.04) and with an older age at diagnosis (50.3 years <i>p = 0</i>.01; 95% CI: ±6.6 years). Patients with Marsh 3c disease at diagnosis were also more likely to have an abnormal BMD at the spine than patients with Marsh 3a or 3b (<i>p = 0</i>.04). Mean BMI between osteopenic (24.15 kg/m<sup>2</sup> 95% CI: ±1.29) and osteoporotic (23.37 kg/m<sup>2</sup> 95% CI: ±2.81) patients was slightly different but not statistically significant (p<i> = 0</i>.07). <h3>Conclusion</h3> This data demonstrates a high rate of osteopenia and osteoporosis among CD patients at diagnosis. DEXA scanning should therefore be considered at diagnosis. This is of greater importance in female patients diagnosed at or above the age of 50 years and with Marsh 3c disease. <h3>References</h3> Lewis NR, Scott BB. Should patients with coeliac disease have their bone mineral density measured? E<i>ur J Gastroenterol Hepatol</i> 2005 Oct;17(10):1065–70 NR Lewis, BB Scott. Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease. <i>British Society of Gastroenterology</i> June 2007 American Gastroenterological Association medical position statement: Guidelines on osteoporosis in gastrointestinal diseases. <i>Gastroenterology</i> - March 2003;124(3): 791–794) <h3>Disclosure of Interest</h3> None Declared.
Abstract 1304: Induction of pericyte migration by autotaxin in angiogenesis
Authors: Chi-yen Lin, Joshua Leinwand, Cheryl Maier, Jordan Pober, William Chang, Demetrios Braddock
Journal: Cancer Research (2010)

Abstract Angiogenesis is essential for tumor cell growth and progression. Recent studies have shown that autotaxin (ATX) is a critical angiogenic factor since ATX knock-out mice exhibit severe vascular defects. ATX also has the ability to stimulate tumor cell motility by enzymatically generating lysophosphatidic acid (LPA). To form a new and stable blood vessel, interactions between pericytes and endothelial cells play important roles. A previous study has shown that endothelial cells can be induced to generate ATX; however little is known about how ATX and LPA are involved in these interactions. The focus of our study is to define the role of ATX in angiogenesis by examining pericyte and endothelial cell response to ATX. To test the effects on cell migration, we treated pericytes and endothelial cells with ATX and other angiogenic factors (including Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF)). Pericytes responded strongly to ATX and LPA stimulation, but human umbilical vein endothelial cells (HUVEC) and skin microvescular cells (HDMEC) showed little or no effect. PDGF elicits a qualitatively similar response. In contrast, endothelial cells migrated when treated with VEGF, but pericytes showed no such stimulation. Pericytes treated with ATX and PDGF together show an additive response. Moreover, in a checkerboard assay the migratory response to ATX or LPA is chemokinetic, whereas PDGF is chemotactic. We then utilized RT-PCR to examine the mRNA levels of four major LPA receptors in pericytes when treated with angiogenic factors. Treatment with PDGF increases LPAR1 mRNA levels and decreases LPAR4 levels. Treatment with ATX also increases LPAR1, but shows no change in LPAR4 levels. By contrast, VEGF treatment has no effect on the LPAR1 mRNA level, but increases the LPAR4 mRNA level. The amount of migration appears to correlate with an increase of LPAR1 and perhaps a decrease of LPAR4. As such, certain angiogenic factors might affect cell motility, in part, through the differential expression of various LPA receptors. These studies suggest that the ATX/LPA signaling pathway effects the formation of mature blood vessels by promoting the pericyte coverage of immature blood vessels. The role of the ATX/LPA pathway in the formation of mature blood vessels provides the scientific rationale for targeting the pathway in the development of novel anti-angiogenic compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1304.
ADVANCED PARAMETERS OF CARDIAC MECHANICS IN CHILDREN WITH CHRONIC KIDNEY DISEASE: THE 4C STUDY
Authors: Marcello Chinali, Alessio Franceschini, MariaChiara Matteucci, Doyon Anke, Claudia Esposito, Gabriele Rinelli, Giacomo Pongiglione, Franz Schaefer
Journal: Journal of the American College of Cardiology (2014)
Peritoneal Linear Uptake of Ga-67 Caused by Tuberculous Peritonitis
Authors: T Hashimoto, K Koizumi, T Saguchi, H Kakiuchi, S Inoue, K Abe
Journal: Clinical Nuclear Medicine (2000)

Ga-67 imaging showed diffuse abdominal uptake and linear uptake inferiorly in the pelvic cavity in a 54-year-old man with severe tuberculous peritonitis. This linear uptake might be a result of the peritoneal accumulation observed from a tangential direction.
Abstract 2416: Neuropilin-2 is upregulated during EMT in lung cancer
Authors: Patrick Nasarre, Joelle Roche, Vincent A. Potiron, Joyce Nair-Menon, Robert M. Gemmill, Harry A. Drabkin
Journal: Cancer Research (2012)

Abstract Neuropilins (NRP1 and NRP2) are high affinity receptors for the class-3 semaphorins, cell guidance molecules involved in tissue development, immune responses, angiogenesis and cancer. Semaphorins affect cell protrusion, spreading and adhesion, and can trigger migratory responses often in a repulsive manner depending on the cellular context. Interestingly, neuropilins are also receptors for galectin-1 and growth factors including VEGF, PlGF, EGF and TGFβ. We previously cloned the SEMA3F gene from chromosome 3p21.3, which undergoes homozygous deletion and frequent loss of heterozygosity in lung cancer. We found that SEMA3F levels were inversely correlated with tumor aggressiveness in human lung cancer and confirmed its tumor suppressor activity in experimental xenograft models. We subsequently discovered that SEMA3F is directly downregulated by ZEB1, a transcription factor involved in the epithelial to mesenchymal transition (EMT). In the present study, we asked whether SEMA3F specific receptor, NRP2, was also regulated during the EMT process. TGFβ, a physiologic EMT inducer, stimulated NRP2 expression in two NSCLC cell lines. Forced expression of ZEB1, but not Snail, also induced NRP2. Conversely, ZEB1 and Snail inhibition blocked NRP2 upregulation by TGFβ. Importantly, inhibiting NRP2 or ZEB1 expression reduced TGFβ-induced migration in an equivalent manner. In lung cancer tissue microarrays, NRP1 and NRP2 were preferentially expressed in the tumor compartment, whereas the EMT-related transcription factors, ZEB1 and Snail, were predominantly expressed in the stroma. Of note, NRP2 was also expressed in stromal cells and was significantly associated with both ZEB1 and a higher (worse) tumor grade. Since NRP2 is the highest affinity receptor for SEMA3F, our results suggest that loss of SEMA3F coupled with increased NRP2 would facilitate the binding of growth factors to NRP2 to further promote EMT and metastasis. Therefore, targeting NRP2 could be an important therapeutic approach against EMT in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2416. doi:1538-7445.AM2012-2416
Abstract 2459: Early changes in gene expression induced by tobacco smoke: Evidence for the importance of estrogen within lung tissue
Authors: Sibele I. Meireles, Gustavo H. Esteves, Roberto Hirata, Suraj Peri, Karthik Devarajan, Michael Slifker, Stacy L. Mosier, Manicka V. Vadhanam, Harrell E. Hurst, E. Jordao Neves, Luiz F. L. Reis, C. Gary Gairola, Ramesh C. Gupta, Margie L. Clapper
Journal: Cancer Research (2010)

Abstract Lung cancer is the leading cause of cancer deaths in the U.S., surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/day; 5 days/wk for 3, 8 and 20 wk). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15 K cDNA microarray. Cytochrome P450 1b1 (Cyp1b1), a Phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17β estradiol, was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed between control and smoke-exposed animals at 3, 8 and 20 wk (P &amp;lt; 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure including estrogen metabolism. In addition, 17β-estradiol was detected within murine lung tissue by gas chromatography coupled mass spectroscopy and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of 17β-estradiol within lung tissue when combined with the modulation of Cyp1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer. (Supported by fellowships from the AACR-Pennsylvania Department of Health and the ASPO/CRPF, the Estate of Jane Villon, the Jerome M. Spencer and Arnold Zaslow Family Foundation and NIH CA-96310). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2459.