tbuckley/cabot-search huggingface dataset:
S140 The role of transforming growth factor- activated kinase-1 (TAK-1) in the development of airway fibrosis
Authors: A. Gardner, M. J. Brodlie, D. A. Mann, L. A. Borthwick, A. J. Fisher
Journal: Thorax (2010)

<h3>Introduction and aims</h3> Fibrotic disorders of the lung are characterised by an increase in fibroblast numbers and excessive deposition of extra cellular matrix, resulting in loss of airway or alveolar function. Murine lineage tracing experiments have suggested that these fibroblasts may, in part, be derived from lung epithelium via epithelial to mesenchymal transition (EMT). Transforming Growth Factor-β1 (TGF-β1) has been shown to drive EMT both in vitro and in vivo. Previous work in our lab has shown that inflammatory stimuli such as Tumour Necrosis Factor-α (TNFα) can accentuate TGF-β1 driven EMT in primary bronchial epithelial cells (PBEC). This crosstalk between inflammatory and TGF-β1 signalling may have implications in the pathogenesis of fibrotic disorders of the lung including Bronchiolitis Obliterans Syndrome and Idiopathic Pulmonary Fibrosis. We hypothesised that TGF-β activated kinase-1 (TAK-1), a protein phosphorylated in response to both TGF-β1 and TNFα, may be a key convergent point and assessed its role in inflammatory accentuation of EMT. <h3>Methods</h3> PBEC isolated from stable lung transplant recipients were treated with TGF-β1 (10 ng/ml) and/or TNFα (20 ng/ml) and the phosphorylation and localisation of signalling molecules SMAD-3 and TAK-1 assessed (western blot, confocal microscopy). TAK-1 function was blocked using a selective inhibitor and by siRNA knockdown; effects on EMT marker expression were assessed (western blot, confocal microscopy). <h3>Results</h3> TAK-1 is phosphorylated in response to both TGF-β1 (161% <i>increase</i>) and TNFα (145%) with an accentuated phosphorylation upon co-treatment (516%, <i>n=3</i>). Co-treatment also resulted in pronounced nuclear localisation of phosphorylated TAK-1, which has not previously been reported. Chemical Inhibition of TAK-1 phosphorylation significantly reduced TGF-β1 driven down-regulation of E-cadherin (22% <i>inhibition</i>) and up-regulation of Vimentin (78%) and Fibronectin (39%, p&lt;0.05, n=4). Furthermore, TAK-1 inhibition significantly reduced TNFα accentuated TGF-β1 driven down-regulation of E-cadherin (39%) and up-regulation of Fibronectin (87%) and Vimentin (258%, p&lt;0.05, n=4). These findings were independently validated via siRNA knockdown of TAK-1. <h3>Conclusions</h3> These findings suggest that TAK-1 is an important convergent point for inflammatory and TGF-β1 signalling, controlling the accentuation of EMT in primary human airway epithelium. Examination of TAK-1 activation and function in animal models of lung fibrosis may provide information on the potential for TAK-1 inhibition as a therapeutic target.
Intestinal dilatation associated with phenothiazine therapy: a case report and literature review
Authors: D L Evans, J F Rogers, S C Peiper
Journal: American Journal of Psychiatry (1979)

The authors describe a fatal episode of intestinal dilatation associated with chlorpromazine therapy. A total of 26 similar cases associated with phenothiazine or tricyclic antidepressant therapy, including 9 fatalities, has been reported in the literature. The authors cite experimental evidence supporting this association. They emphasize the difficulty of recognizing this syndrome in the psychotic patient; careful evaluation is indicated in the constipated patient who exhibits vomiting, abdominal pain, distension, or tenderness.
Multiple Selective Responders Should Not be Confounded with Cross-Intolerance to Nsaids
Authors: Natalia Blanca-López, Diana Perez-Alzate, Inmaculada Doña, Maria Luisa Somoza, Cristobalina Mayorga, María José Torres, Jose A. Cornejo-Garcia, Miguel Blanca, Gabriela Canto
Journal: Journal of Allergy and Clinical Immunology (2016)
FRI0390 Therapeutic Plasma Exchange (TPE) for Refractory Autoimmune Diseases: Report of 60 Cases
Authors: O. Karadag, A. Soyuoz, U. Kalyoncu, T. Karaagac, L. Kilic, S. Kiraz, O. Ozcebe, I. Ertenli
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Therapeutic Plasma Exchange (TPE) is an effective therapeutic option for treating serious manifestations of systemic autoimmune diseases. More data about real life experience regarding outcomes of those patients are required. <h3>Objectives</h3> This study is aimed to investigate the main demographic and clinical characteristics as well as the outcome of patients with systemic autoimmune diseases treated with TPE at an university hospital. <h3>Methods</h3> Patients treated with TPE between 2002-2013 were included into the study. Indications for TPE, complications and outcomes were obtained from hospital records. <h3>Results</h3> A total of 60 patients (Female/male: 43/17) were treated with TPE. Mean age at the time of 41.0±16.5 (range: 15-73 years). Twenty-one (35.0%) patients had SLE, 14 (23.4%) patients had patients had vasculitis, 6 patients had Sjogren syndrome, 4 patients had dermato/polimyositis, 3 patients had primary antiphospholipide syndrome, 12 patients with other diagnosis. Indications for TPE were hematologic (28.4%), neurologic (28.3%), pulmonary (20.0%) and renal failure (23.4%), myopathy (5.0%), hepatic (5.0%) and dermatologic (3.4%) causes. In 9 (15%) of patients TPE had performed in case of concomitant leucopenia or infection. Fifteen of the patients (25%) had TPE required disease involvement as presenting feature. All patients were receiving corticosteroids at varying doses and all received a concomitant immunosuppressive drug. Outcome analysis had been done in 55 (91.6%) of patients. Totally 20 (33.3%) of patients had been died (17 of them during first treatment course, 3 of them after discharge from hospital). More than half of the patients with pulmonary (57.9%) and renal (63.6%) cause as TPE indication had been died whereas in neurologic and hematologic causes mortality were lower (26.7% and 18.8%, respectively). The median application regimen of TPE was 6 (range 2-33) sessions with alternate days. In 32.3% of patients TPE had been performed in more than 10 times. The major adverse events of TPE were occurred in 14 (23.3%) of patients (catheter related problems 6 patients, hypotension 3 patients, 1 catheter infection, 2 thrombocytopenia). One patient had died due to atrial fibrillation and myocardial infarction periprocedural period. <h3>Conclusions</h3> TPE is an effective therapeutic option for treating serious manifestations of systemic autoimmune diseases with less adverse events. TPE could be a valid option for those with refractory disease to conventional treatments and concomitant infection and/or leucopenia. Patients with pulmonary and renal indications had increased mortality compared to patients with hematologic and neurologic indications <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4876
Abstract 5284: EMMPRIN mediates VEGF activation of VEGFR-2 in melanoma cells
Authors: Farah Khayati, Samia Mourah
Journal: Cancer Research (2012)

Abstract EMMPRIN's expression in melanoma tissue was reported to be predictive of poor prognosis. Here we demonstrate that EMMPRIN up-regulated VEGF receptor-2 (VEGFR-2) in two different primary melanoma cell lines and consequently increased migration and proliferation of these cells while inhibiting their apoptosis. SiRNA inhibition of VEGFR-2 expression abrogated these EMMPRIN effects. EMMPRIN regulation of VEGFR-2 was mediated through the over-expression of HIF-2α and its translocation to the nucleus where it forms heterodimers with HIF-1β. These results were supported by an in vivo correlation between the expression of EMMPRIN with that of VEGFR-2 in human melanoma tissues as well as with the extent of HIF-2α localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2α/VEGFR-2 mediated mechanism, with an autocrine role in melanoma cell malignancy. As VEGF/VEGFR2 system has been implicated in regulation of melanoma cells migration, proliferation and apoptosis, the role of EMMPRIN in the regulation of these cellular properties was investigated. Blocking EMMPRIN by siRNA have shown that VEGF enhancement of melanoma cell migration requires EMMPRIN. The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor cell growth and invasion. 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 5284. doi:1538-7445.AM2012-5284
Abstract 848: Preclinical antitumor activity of S 49076, a novel MET / AXL / FGFR kinase inhibitor and molecular stratification for tumor sensitivity
Authors: Mike F. Burbridge, Celine Bossard, Carine Saunier, Imre Fejes, Alain Bruno, Alain Pierre, Nolwen Guigal-Stephan, Marianne Rodriguez, Jean-Pierre Galizzi, Brian P. Lockhart, Anne Jacquet-Bescond, Jean-Claude Ortuno, Francisco H. Cruzalegui, Stephane Depil
Journal: Cancer Research (2012)

Abstract Aberrant activity of receptor tyrosine kinases (RTKs) has been associated with tumor progression in a wide variety of human malignancies, making them promising drug targets for cancer therapy. Although, in some instances, specific inhibition of just one of these RTKs suffices for inhibition of tumor progression, in the majority of cases, targeting more than one RTK could be required for therapeutic efficacy. Moreover, increased expression or activation of RTKs is often associated with resistance to standard chemotherapy agents or signal transduction modulators. S 49076 is a novel, potent, ATP-competitive tyrosine kinase inhibitor of the RTKs MET, AXL and FGFR. S 49076 blocks autophosphorylation of these RTKs and their downstream signaling in cells with IC50 values of less than 50 nM in the case of MET and AXL, and at below 200 nM for FGFR1/2/3. In vitro, S 49076 inhibits the proliferation of MET- and FGFR2- dependent gastric cancer cells, blocks MET-driven migration of lung carcinoma cells and inhibits colony formation of hepatocarcinoma cells overexpressing FGFR2 and AXL. In vivo, oral administration of S 49076 inhibits MET autophosphorylation and tumor growth in subcutaneous GTL-16 human gastric carcinoma and U87-MG human glioblastoma at 6 mg/kg/day. In FGFR2-dependent SNU-16 gastric tumors S 49076 inhibits FGFR2 autophosphorylation, downstream signaling and tumor growth at 25 mg/kg/day. In a panel of 53 patient-derived tumors and 14 cell lines of diverse origin growing in three-dimensional in vitro culture, twenty-five (37%) were found to be sensitive to S 49076 at 1 µM or less. In the majority of cases, analysis of the expression, activation and mutation status of MET, AXL, FGFR1/2/3 and other target kinases of S 49076 as well as that of major signaling proteins enabled hypotheses to be made concerning the sensitivity or resistance to S 49076. Moreover, in many of these resistant tumors, a rationale for association of S 49076 with other targeted therapies emerged. Examples of the efficacy of such combined therapies will be shown. Based on these preclinical studies showing a favorable and novel pharmacological profile of S 49076, a phase I study is currently underway in patients with advanced solid tumors. 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 848. doi:1538-7445.AM2012-848
P13 * CHANGING DOSE BANDINGS TO IMPROVE COMPLIANCE WITH TEMOZOLOMIDE CONCOMITANT WITH RADIOTHERAPY FOR HIGH GRADE GLIOMA; AN ANALYSIS OF SAFETY
Authors: T. Mathew, S. Clenton, A. G. Bradshaw
Journal: Neuro-Oncology (2014)

INTRODUCTION: The current standard of care for the treatment of grade IV glioma is radiotherapy with concomitant temozolomide chemotherapy which conveys a 2.5 month improvement in overall survival and a 2.5 fold improvement in 2 year survival when compared to radiotherapy alone. The dose of concomitant Temozolomide, 75 mg/m2, often results in a complicated regimen of capsules of differing doses and has led to a clinical incident were the patient mixed up their different strength capsules resulting in an overdose. We changed the dose banding, rounding to the nearest 20 mg rather than 10 mg which was our previous practice, thereby eliminating the use of the 5 mg capsule. Using the previous dose banding the maximum potential dose received would be 78.6 mg/m2 however this increases to a potential 80.8 mg/m2 with the new dose banding. This is still below the maximum tolerated dose of 85 mg/m2 reported in the phase I trial. We audited the non-completion rate pre and post change and performed a root-cause analysis of any omitted doses to ensure tolerance of the new dose banding. METHOD: Retrospective case note analysis of all patients who underwent concomitant chemoradiotherapy for glioma 2 years before the dosage change and this was compared to those treated up to 20 months post change. RESULTS: Reasons for non completion were categorised as due to toxicity, clinical deterioration, logistics or co-morbidities. Pre dose change 102 patients were reviewed with 6.8% stopping their treatment due to toxicity. Post dose change 74 patients were reviewed with 2.7% stopping their treatment due to toxicity CONCLUSION: This comparison suggests that the newer dose banding is equally well tolerated when compared to the older dose.
A Hypophyseal Metastasis of Follicular Thyroid Carcinoma
Authors: NURIYE ÖZLEM KÜÇÜK, PELİN ARCAN, GÜLSEREN ARAS, KEMAL METIN KR
Journal: Clinical Nuclear Medicine (2002)

KÜÇÜK, NURIYE ÖZLEM M.D.; ARCAN, PELİN M.D.ı; ARAS, GÜLSEREN M.D.; KR, KEMAL METIN M.D.ı Author Information
Case 35-2013
Authors: Jeffrey A. Barnes, Jeremy S. Abramson, James A. Scott, Aliyah R. Sohani
Journal: New England Journal of Medicine (2013)

A 77-year-old man was admitted to this hospital because of confusion and malaise after resection of a papillary urothelial cancer. He reported abdominal pain, facial and jaw pain, anorexia, lethargy, weakness, and night sweats; imaging revealed generalized lymphadenopathy.
Real-time in vivo histologic examination using a probe-based endocytoscopy system for differentiating duodenal polyps
Authors: H. Neumann, S. Kudo, M. Vieth, M. Neurath
Journal: Endoscopy (2013)

Endocytoscopy is an emerging endoscopic imaging modality enabling real-time in vivo visualization of the superficial mucosal layer at a magnification up to 1400-fold. This allows analyzing ultrastructural features of a tissue, including the arrangement and density of cells, the nucleus-to-cytoplasm ratio, and the microvascular network [1]. Endocytoscopy is based on the principle of contact light microscopy and requires prestaining of the mucosa with either methylene blue or toluidine blue. Previous studies have shown the potential of endocytoscopy for in vivo diagnosis of esophageal squamous cell carcinoma, celiac disease, and colonic polyps. Moreover, recent data suggest the potential of endocytoscopy to differentiate between individual mucosal inflammatory cells during endoscopy [2] [3] [4].
Remote Ischemic Preconditioning for Cardiac Surgery
Authors: Anweshan Samanta, Buddhadeb Dawn
Journal: Circulation Research (2016)

E ver since its discovery more than 2 decades ago, re- mote ischemic preconditioning (RIPC) has generated tremendous interest among scientists and clinicians alike.However, two recent large, well-conducted, randomized controlled trials (RCTs) have failed to identify any significant benefit of RIPC during cardiac surgery.A reconciliatory yet objective review of cumulative evidence with regard to cardiac surgery reveals that RIPC in preclinical studies reduced infarct size after experimental myocardial infarction (MI), which is different from cardiac surgery; improved release of biomarkers, but not hard clinical end points, in proof-of-concept clinical trials with discordant results; and failed to produce significant improvement in outcomes in meta-analyses.This difficult journey of RIPC across the valley of death underscores the importance of scientific rigor and exercise of caution in interpreting data at every step of the way until efficacy of a purported therapy is proven conclusively in large RCTs.RIPC is a phenomenon, whereby brief episodes of ischemia in a distant vascular bed protect other organs in the body from subsequent ischemic injury.The concept that a noninvasive and simple procedure can protect organs during elective ischemic episodes has continued to generate tremendous interest among clinicians and scientists.Promising results from numerous basic studies led to many smaller clinical trials and meta-analyses, and then to two large, well-conducted RCTs.The recent results from Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA) and RIPHeart, however, have failed to identify any significant benefit of RIPC on hard clinical end points or surrogate markers of organ protection. 1,2Because hindsight is often 20/20, it is important to interpret these latest findings in light of relevant data accumulated over the past 2 decades.
Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1
Authors: Shengqing Gu, Wayne W. Chan, Golam Mohi, Joel Rosenbaum, Azin Sayad, Zhibin Lu, Carl Virtanen, Shaoguang Li, Benjamin G. Neel, Richard A. Van Etten
Journal: Blood (2016)
Neuroscientific evidence for contextual effects in decision making
Authors: Kaisa Hytönen
Journal: Behavioral and Brain Sciences (2014)

Abstract Both internal and external states can cause inconsistencies in decision behavior. I present examples from behavioral decision-making literature and review neuroscientific knowledge on two contextual influences: framing effects and social conformity. The brain mechanisms underlying these behavioral adjustments comply with the dual-process account and simple learning mechanisms, and are weak indicators for unintentionality in decision-making processes.
Abstract 4243: Potential protective role of phytoalexins derived from soybean by biotic elicitor on inflammatory mechanism
Authors: Hyo Jung Kim, Chae Lim Jung, Dae Hwan Nam, Ji Sun Lim, Min Young Han, Ye-Seul Hong, Jong-Sang Kim
Journal: Cancer Research (2011)

Abstract Given the preventive effect of soy intake against several chronic diseases, this study was conducted to investigate the inhibitory activity of phytoalexins glyceollins derived from soybean isoflavones by treating with biotic elicitor against LPS-induced inflammation in RAW 264.7 cell culture system. Our data showed that glyceollins effectively inhibited NO production, IL-6 release, and COX-2 expression induced by LPS. In particular, glyceollins suppressed the LPS-induced phosphorylation of NF-B p65, suggesting that the compounds inhibit the production of NO and transcriptional activation of COX-2 by regulating NF-B activity. In another experiment we found that glyceollins enhanced the expression of heme oxygenase 1 and repressed the phosphorylation of ERK1/2 and p38 but not JNK in LPS-treated RAW 264.7 cells. Glyceollins also reduced TPA-induced skin inflammation in mouse model, confirming the anti-inflammatory activity of glyceollins in vivo system as well as cell culture system. Taken together, glyceollins merit further study as potential therapeutic agents for inflammatory disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2011-4243
THU0175 T cell reactivity to β2 glycoprotein I in systemic lupus erythematosus and anti-phospholipid syndrome: Correlation with subclinical atherosclerosis
Authors: F.R. Spinelli, C. Alessandri, E. Marocchi, F. Ceccarelli, A. Capozzi, M. Sorice, M. Arca, M. Pacelli, B. Buttari, R. Riganò, E. Profumo, G. Valesini, F. Conti
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) patients present a high prevalence of atherosclerosis associated with both traditional and disease-related risk factors. β2 glycoprotein I (β2GPI), the main antigen in APS, seems to represent a link between autoimmunity and endothelial dysfunction which is the earliest atherosclerotic lesion. Recently, β2GPI reactive T cells have been identified; however, their role in the atherosclerosis is still unknown. <h3>Objectives</h3> Aim of this study was to evaluate early atherosclerosis in SLE and APS patients, correlate subclinical atherosclerosis with traditional and disease-related risk factors and investigate T cell reactivity to β2GPI and its relationship with the atherosclerotic process. <h3>Methods</h3> We enrolled 50 SLE and 18 primary APS patients and 25 controls. Demographic and clinical data, including traditional cardiovascular risk factors, were recorded. Blood samples were collected to investigate autoantibodies and lipid profile. Monocyte β2GPI and Tissue Factor (TF) expression and peripheral blood mononuclear cells (PBMCs) proliferation after β2GPI stimulation were evaluated. Brachial artery Doppler ultrasound for flow-mediated dilation (FMD) and carotid arteries ultrasound for intima-media thickness (IMT) were performed. <h3>Results</h3> We detected an increase in mean IMT (mIMT) (0.69 mm ± 0.12) and a decrease in FMD% (6.5±6.6) in SLE patients versus controls (p&lt;0.05 and p=0.0001, respectively) and a decrease in FMD% in APS patients (13.4±12.3) versus controls (p&lt;0.05). Univariate analysis demonstrated a correlation between atherosclerotic lesions and traditional and disease related risk factors; multivariate analysis confirmed as independent risk factors only total cholesterol levels, SLICC and steroid dose for SLE, anti-β2GPI and age for APS. Monocyte β2GPI and TF expression was higher in SLE (34.2±18.9 and 69.5±20.6) and APS (36.3±22.7 and 66.9±26.9) than in controls (18.6±13.7 and 18.6±13.7) (p=0.006 and p=0.001, respectively); no correlation between monocyte β2GPI and TF and IMT or FMD% was detected. β2GPI induced PBMC proliferation in 32% of SLE patients, 25% of APS patients and none in the controls. Proliferative response to β2GPI correlated with history of arterial thrombosis, thrombocytopenia and IMT &gt;0.9 mm. <h3>Conclusions</h3> β2GPI T cell reactivity and its correlation with IMT and arterial thrombosis suggest a role for β2GPI response in the pathogenesis of accelerated atherosclerosis described in SLE and APS patients. Our study shows a subclinical atherosclerosis in SLE and APS patients associated with traditional and disease-related risk factors. <h3>Disclosure of Interest</h3> None Declared