tbuckley/cabot-search huggingface dataset:
P759Novel therapeutic approach to target endothelial dysfunction in type 2 diabetes
Authors: CM Sena, AM Pereira, R Fernandes, D Santos-Silva, A Faustino, R Ceica
Journal: Cardiovascular Research (2014)

Purpose: To determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions in endothelial dysfunction associated with type 2 diabetes in both aorta and mesenteric arteries. Methods: Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes and age-matched control Wistar rats were treated with or without PM (100 mg/kg/day) and /or SFN (1 mg/kg/day) during 8 weeks. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability, glycation, inflammation and vascular oxidative stress were also assessed. Results: Diabetic GK rats presented significantly lower levels of Nrf2 (p<0.001), antioxidant enzymes and concomitantly exhibits higher levels of oxidative stress, glycation, inflammation and endothelial dysfunction (associated with decrease NO bioavailability). PM and SFN were both capable of significantly improve endothelial dysfunction (by 20 and 25 %, respectively), inflammation and oxidative stress in aorta and mesenteric arteries. PM and SFN as monotherapy significantly decreased vascular oxidative damage (accumulation of anion superoxide and 3-nitrotyrosine in arteries) and inflammation (levels of monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1 in arteries). SFN up-regulated Nrf2 expression and transcription activity that was reflected by increased Nrf2 nuclear accumulation and phosphorylation as well as the protein expression of Nrf2 downstream antioxidants. Furthermore, both therapeutics in association proved more effective and were capable of reducing to a greater extent oxidative stress and inflammation improving endothelial function and metabolic profile in GK diabetic rats. Conclusions: We provide experimental evidence indicating that activators of Nrf2 can be used therapeutically in association with inhibitors of AGEs formation to improve metabolic profile and relieve endothelial dysfunction in type 2 diabetes.
A1.32 Alpha-enolase activates monocytes by CD14-dependent TLR4 signalling pathway
Authors: M Fréret, C Guillou, E Fondard, C Derambure, G Avenel, ML Golinski, M Verdet, O Boyer, F Caillot, P Musette, T Lequerré, O Vittecoq
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatism. Identification of autoantigens&nbsp;targeted by RA autoantibodies has been of major interest. Alpha-enolase (ENO1) is considered as a pivotal&nbsp;autoantigen in early RA. Whatever the nature of this molecule, its role in RA pathophysiology remains unknown. The main objective of this study was to investigate the <i>in&nbsp;vitro </i>effects of soluble ENO1 on peripheral blood mononuclear cells (PBMCs) from healthy donors and RA patients in order to determine the potential pathogenic role of ENO1. <h3>Materials and methods</h3> PBMCs of healthy donors or RA patients were cultured with ENO1 or control. ELISA and transcriptomic analysis were performed to assess the pro- or anti-inflammatory effect of ENO1. Moreover, flow cytometry analysis, experiments of receptor inhibition and ELISA were performed to determine the target cell population and receptor of ENO1. <h3>Results</h3> Firstly, we showed that ENO1 has the ability to induce the production of a&nbsp;large amount of pro-inflammatory cytokines and chemokines, and to activate the innate immune system on PBMCs from healthy donors. ENO1 also exhibits this pro-inflammatory effect on cells from RA patients. Then, we demonstrated that ENO1, which exclusively bound monocytes, exhibited a LPS-like action mediated by TLR4. More precisely, the effects of ENO1 specifically involved the CD14-dependent TLR4 pathway. <h3>Conclusions</h3> Together, these findings illustrate for the first time that ENO1 triggers <i>in vitro</i> an inflammatory response mediated by monocytes through the CD14-dependent TLR4 pathway and contribute to elucidate the role of this autoantigenin the RA pathophysiological mechanisms.
PM-19 * DEVELOPMENT OF A PANEL OF PATIENT-DERIVED XENOGRAFT (PDX) MODELS FROM BRAIN METASTASES
Authors: J. Sarkaria, D. Ma, M. Schroeder, B. Carlson, C. Giannini, I. Parney
Journal: Neuro-Oncology (2014)

BACKGROUND: Most common models of brain metastases are developed from established cell lines selected for brain tropism. We hypothesized that PDX models derived from brain metastases would maintain brain tropism and more faithfully maintain features of primary brain metastases. METHODS: Resected brain metastases were used to establish PDX models. Survival was assessed following intracranial or intracardiac injection of explant cultures. Radiation response was assessed using 20 Gy in 5 fractions. RESULTS: From January 1, 2013 to May 31, 2014, 41 brain metastases from 40 patients were implanted into athymic mice, and 25 of 34 (74%) models implanted more than 3 months ago could be serially transplanted. These include 9 melanoma, 7 non-small lung (NSCLC), 1 small-cell lung, 4 gastro-intestinal (pancreas, esophagus, colorectal), and 2 breast cancers. Intracardiac injection of 1E5 cells resulted in consistent development of multiple brain metastases in models from NSCLC (M5), melanoma (M2, M12, M15), but not esophageal (M7). In a titration study, intracardiac injection of 1E5, 1E4, and 1E3 cells resulted in a median survivals of: M12 - 31, 59, and 167 days; M15 - 70, 107 and 192 days, respectively. Direct intracranial injection of tumor cells resulted in large, unifocal brain tumors with histology similar to the original patient tumor. Median survivals were: M1 - 63 days, M2 - 46 days, M5 - 12 days, M7 - 43, M15 - 10 days, M20 - 14 days. Using established intracranial tumors, radiation significantly extended survival compared to sham irradiation in breast (M1: median survival >132 vs. 48 days) and esophageal (M7: 75 vs. 43 days) models but not in melanoma models (M2: 52 vs. 52 days; M12, 22 vs. 18 days). CONCLUSIONS: These brain metastasis PDX models may be useful for basic mechanistic studies of metastatic behavior and translational studies of novel therapeutic strategies.
Abstract B62: <i>WWOX</i> expression suppresses tumorigenecity by inducing apoptosis and attenuating migration of metastatic cells
Authors: Suhaib Abdin, Zaidoun Salah, Rami Aqeilan
Journal: Cancer Research (2009)

Abstract The WW domain-containing oxidoreductase (WWOX) spans one of the most active common fragile sites, FRA16D, involved in cancer. WWOX encodes a 46-kDa protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase (SDR) domain. Through its WW domain, Wwox interacts with its partners and modulates their functions; mainly by suppressing their transactivation functions through sequestering them in the cytoplasm. Wwox expression is absent or reduced in most cancer cells and its ectopic overexpression induces apoptosis in vitro and suppresses tumorigenecity in vivo suggesting tumor suppressor function of WWOX. Recently we demonstrated that targeted deletion of the Wwox gene in mice causes increased spontaneous tumor incidence confirming WWOX as a bona fide tumor suppressor. Furthermore, Wwox attenuates the migration and invasion ability of MDA-MB-231 breast carcinoma metastatic cells. In addition, its restoration results in reduced attachment and migration on fibronectin. By contrast, knocking down endogenous Wwox increases adhesion to fibronectin. Therefore, Wwox acts as a tumor suppressor not only by inducing apoptosis mediated by caspase activation but also through modulating the interaction between tumor cells and the extracellular matrix. Citation Information: Cancer Res 2009;69(23 Suppl):B62.
ASTRO Radiologists Find Fertile Prospects in Gene Therapy Research
Authors: J. McCann
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article ASTRO Radiologists Find Fertile Prospects in Gene Therapy Research Get access Jean McCann Jean McCann Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 22, 16 November 1994, Pages 1668–1669, https://doi.org/10.1093/jnci/86.22.1668 Published: 16 November 1994
THU0221 Lung physiology impairment in anca-associated vasculitis (AASV)
Authors: L.F. Flores-Suarez, S. Cardenas, L. Torre-Bouscoulet, S. Toral
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Although lung involvement in ANCA-associated vasculitis (AASV) is frequent, few studies<sup>1</sup> exist regarding assessment of lung function. <h3>Objectives</h3> To describe lung function in inactive AASV patients, relate them to previous lung damage as measured by respiratory items in the Vascular Index Damage (VDI) and explore cardiopulmonary exercise capacity. <h3>Methods</h3> Patients with AASV were prospectively studied with lung function tests (LFT), plethysmography, diffusing capacity for carbon monoxide (DLCO), six-minute walk (6MW), cardiopulmonary exercise test (CPX) and Saint George respiratory questionnaire (SGRQ) which evaluates patients in a 0 (minimal) to 100 (maximal impairment) scale. Normal values (corrected for Mexico City altitude): FEV1, FVC, corrected DLCO, VO<sub>2</sub> &gt;80% of predicted values, pO<sub>2</sub> decrease during exercise &lt;4 mmHg, 6MW &gt;300 meters. Inclusion criteria: age ≥18 years old, diagnosis of AASV according to ACR criteria and/or Chapel Hill Consensus nomenclature and signed informed consent. Exclusion criteria: active disease (BVAS &gt;0), concurrent infections. comorbidity which limited lung function evaluation. <h3>Results</h3> Out of 46 patients, 20 consented participation, 10 males, 10 females, all but one under maintenance treatment. Mean age: 53±15.6 years, median: 57 (20-72). 14 had granulomatosis with polyangiitis (GPA), 4 microscopic polyangiitis (MPA) and 2 Churg-Strauss syndrome (CSS). Overall results (mean ± SD): FEV1 91.3±27.2%, FVC 101.3±21.6, corrected DLCO 91±21.5%, VO2% 78.2±18.5, 6MW 449.5±78.4 meters, SGRQ 24.8±14.4, total VDI 2.6±2.08 (median 2, range 0-7), pulmonary VDI 0.7±0.97 (median 0, range 0-3). Only 5 patients had all tested parameters within normal (3 GPA, 2 MPA). Fourteeen patients had normal LFT; five patients had an obstructive pattern (3 GPA, 2 CSS), in 2 being severe, and one patient had an spirometric restrictive pattern, although plethysmography was normal. Seven had low DLCO, abnormal CPX was seen in 10 and in 4, decrease in pO<sub>2</sub> during exercise occurred. These changes did not relate with pulmonary VDI parameters, initial presentation or time since disease onset. In spite of this, only one patient had an abnormal 6MW (296 mts) and only two patients reported a SGRQ over 40 points, interpreted as inadequate quality of life perception. <h3>Conclusions</h3> As in a previous report<sup>1</sup>, lung impairment and diminished exercise capacity occurs in AASV, irrespective of adequate disease control, previous lung involvement and/or damage, concurrent treatment and total disease time. However, in our population, overall health status does not seem to be as affected as in that report. Intervention leading to early recognition of these phenomenae is needed, with the purpose to avoid permanent lung impairment. <h3>References</h3> Newall C et al. Rheumatology 2005;44:623-8. <h3>Disclosure of Interest</h3> None Declared
Ga-67 Citrate Imaging of a Primary Thymic Seminoma
Authors: JEAN M. LESCOUT, EMMANUEL BUSSY, JOEL GUIGAY, HERVÉ RAKOTONIRINA
Journal: Clinical Nuclear Medicine (1998)

The present case report illustrates the high affinity of primary thymic seminoma for Ga-67 citrate. This tumor is an uncommon anterior mediastinal germ cell neoplasm with generally high radiosensitivity. Only a few cases have been reported in the last 20 years, and their discovery is frequently accidental. The usual absence of increased uptake in the normal thymus in the adult makes Ga-67 SPECT and whole-body imaging helpful in the differential diagnosis, staging, and follow-up of anterior mediastinal tumors.
Abstract 1399: SRC-1 up-regulates CSF-1 expression to potentiate breast cancer metastasis
Authors: Li Qin, Yelin Wu, Dabing Li, Michael Joseph Toneff, Jean Ching Yi Tien, Yixiang Xu, Lan Liao, Zhen Feng, Yi Li, Jianming Xu
Journal: Cancer Research (2012)

Abstract Steroid receptor coactivator-1 (SRC-1/NCOA1) has been reported to be overexpressed in a subset of human breast cancer (BC) and its overexpression correlates with Her2 expression, disease recurrence and endocrine therapy resistance. To determine the role and underlying mechanisms of SRC-1 overexpression in BC progression and metastasis, a transgenic mouse model with overexpression of human SRC-1 in mouse mammary epithelial cells was created. In vivo data revealed that overxpression of SRC-1 potentiated BC metastasis to lung in both MMTV/Neu and MMTV/TVA/PyMT tumor models. While SRC-1 overexpression did not obviously accelerate tumor growth in these BC mouse models, the number of tumor cells invaded into blood vessels and metastasis index in lung tissue significantly increased in these mice. In addition to the elevated Twist expression and activation of Her2 and AKT driven by SRC-1 overexpression in the tumors, CSF-1 level was significantly increased in SRC-1 overexpressed tumors. We also found that CSF-1 expression was decreased in two PyMT/SRC-1 KO tumor cell lines compared with the two PyMT/WT control cell lines. Knockdown of SRC-1 in PyMT/WT cells or human BC cells reduced CSF-1 levels, while adenoviral-mediated expression of SRC-1 in PyMT/SRC-1 KO cells or human BC cells significantly promoted CSF-1 expression. Furthermore SRC-1 was found to interact with transcription factors, c-jun and c-fos, to activate the csf-1 promoter. Both SRC-1 and c-fos were found to associate with the csf-1 promoter at AP-1 binding sites in human BC cells. This study provided compelling evidence that overexpression of SRC-1 promotes BC metastasis. Targeting SRC-1 might be a potential therapeutic strategy for controlling BC metastasis. 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 1399. doi:1538-7445.AM2012-1399
A1.13 The prevalence of a raised interferon gene signature is increased in early ra and is associated with worse disease activity
Authors: FAH Cooles, AE Anderson, CMU Hilkens, JD Isaacs
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and Objectives</h3> An interferon gene signature (IGS) is present in 20–30% of established rheumatoid arthritis (RA) patients where it does not correlate with disease activity. However immunomodulatory treatment may mask underlying associations so we investigated both the prevalence of the IGS and associations with disease activity in early RA. <h3>Materials and Methods</h3> For steroid naïve patients with a new ACR/EULAR RA diagnosis we recorded: swollen joint count (SJC), tender joint count (TJC), patient visual analogue scale, DAS-28, CRP, ESR, rheumatoid factor, anti-CCP antibody, serum IL-6, IL-8, TNF-α, IFN-γ (MSD) and whole blood (Tempus, Life Technologies) RT-PCR expression of 5 interferon-α response genes, IRGs (MXA, IFI6, OAS-1, ISG-15, IFI-44L). Some patients had IRG expression repeated at 3 months. In addition established RA, SLE patients and healthy controls had the above IRGs quantified. Patients were defined as "high IGS" if the sum of their IRGs was ≥ 2 standard deviations above healthy control mean sum IRG expression. Statistics performed: linear regression/Mann Whitney-U (Graphpad Prism). Significance when p &lt; 0.05. <h3>Results</h3> Cohorts included 50 early RA (Male:Female 1:2, median age 57 [30–91]), 18 healthy controls (Male:Female 1:1, median age 22 [25–57]), 15 established RA (Male:Female 1:7, median age 73 [52–78]) and 24 SLE (Male:Female 1:10, median age 53 [33–69]). There was no significant association between age/sex and IRGs. In early RA 47% had a high IGS compared with 33% established RA. Total IRG expression was significantly upregulated in early RA compared with established RA and comparable to SLE. Furthermore after 3 months of treatment in early RA (n = 9) there was a significant fall in MxA, ISG15, IFI6 and IFI44L. At diagnosis MxA and OAS1 demonstrated significant associations with DAS-28, TJC and CRP. MxA also significantly associated with ESR and serum IL-6 and OAS1 with SJC. There were no other significant associations for remaining clinical parameters, cytokines or autoantibodies. <h3>Conclusions</h3> We report an increase in IRG expression in early RA which associates with increased disease activity and falls with time/treatment. Other autoimmune conditions, such as primary Sjogrens, suggest type 1 interferons are important in disease initiation, and we propose IFN-a may play a role in early RA pathophysiology. Further work is needed to determine its relative importance.
FRI0025 A crucial role for lectin-like oxidized ldl receptor-1 on joint inflammation in ra
Authors: M. Ishikawa, H. Ito, M. Furu, K. Murata, H. Shibuya, H. Yoshitomi, S. Matsuda, T. Nakmura
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is one of the immune-mediated inflammatory diseases. LOX-1 (Lectin-like oxidized low-density lipoprotein receptor 1), one of functional receptors for oxidized LDL (ox-LDL), is expressed in various cells, including endothelial cells and chondrocytes, and its expression is enhanced by oxidative stress, inflammatory cytokines (1). Several studies have reported that the ox-LDL/LOX-1 axis modulates cartilage degradation in RA (2) (3). Although the importance of LOX-1 in RA is apparent, little is known whether LOX-1 is expressed in the RA synovium, which is a major site of systemic inflammation in RA. <h3>Objectives</h3> In this study, we investigate the presence of LOX-1 protein in human synovium, and the functional roles of LOX-1 in the pathogenesis of RA. <h3>Methods</h3> Synovial tissues samples with RA patients were prepared at the total knee replacement. Ox-LDL was injected into the knee joints of mice with or without of anti-LOX-1 antibody. <h3>Results</h3> The ox-LDL and LOX-1 (Figure 1) protein were clearly identified and colocalized in the synovial tissues in RA joints, particularly in the lining layer and around blood vessels. To assess the role of ox-LDL and LOX-1 in the pathogenesis of arthritis <i>in vivo</i>, ox-LDL, native LDL, or PBS were injected into right knee joints for 7 days and evaluated joint inflammation. Hematoxylin-eosin staining revealed that treatment with ox-LDL caused massive synovial hyperplasia, compared with the controls (Figure 2). In contrast, joints pretreated with the anti-LOX-1 antibody significantly inhibited synovial hyperplasia induced by ox-LDL treatment. Immunohistochemistry study showed prominent LOX-1 and MCP-1 expression (Figure 3, 4) in the cartilage and synovium in the ox-LDL-treated group, whereas the control groups hardly displayed any positive staining. <h3>Conclusions</h3> These findings clearly demonstrated that ox-LDL/LOX-1 axis induces synovial inflammation. Therefore, blockade of LOX-1 signal would be beneficial for prevention of the synovial inflammation in the inflammatory arthritis, such as RA. <h3>References</h3> Sawarura T, et al. Nature 1997; 386 Nakagawa T, et al. Arthritis Rheum 2002; 46, 2486-94. Kakimuma T, et al. Arthritis Rheum 2004; 50, 3495-503. <h3>Disclosure of Interest</h3> None Declared
Abstract 277: Downregulation of the receptor tyrosine kinase cMet is impaired in pancreatic adenocarcinoma cells
Authors: Kristen S. Hill, Marta Lorinczi, Lisa A. Elferink
Journal: Cancer Research (2010)

Abstract Increased signaling from cMet, the receptor for Hepatocyte Growth Factor (HGF) has been implicated in the progression of many cancers, particularly pancreatic cancer, correlating with cellular transformation, tumor invasion and poor patient prognosis. In contrast to other cancers, receptor mutations that result in increased cMet signaling have yet to be detected in pancreatic cancers. This led us to hypothesize that post translational mechanisms such as impaired cMet down regulation, a process that normally functions to attenuate cMet signaling in vivo, could be a factor for increased cMet signaling in pancreatic tumors. To test this, we examined the lysosomal down regulation of cMet in a panel of pancreatic adenocarcinoma cell lines. Here we report that uncoupled cMet down regulation in pancreatic tumor cells correlates with increased cMet stability and signaling in response to HGF. In pancreatic Suit-2 cells, impaired binding of the E3 ubiquitin ligase Cbl to cMet, results in reduced receptor ubiquitination and increased cMet recycling to the cell surface. Conversely, transient HGF induced cMet ubiquitination in pancreatic BxPC-3 cells correlates with prolonged cMet stability and signaling, suggesting that the kinetics of cMet ubiquitination rather than receptor ubiquitination per se is critical for efficient cMet down regulation. These data mark the first evidence that disrupted cMet down regulation could be a contributing factor in the aggressiveness of certain pancreatic tumor cells and highlights the importance of the endocytic machinery as a novel therapeutic target. 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 277.
EUS-Diagnostics of Cystic Duodenal Dystrophy, Case Report
Authors: T Silina
Journal: Endoscopy (2011)

Materials: 29-year old man with the first attack of abdominal pains at the age of 6 years and with periodic attacks of pains since the age of 18 years, always after meals. Decrease in body weight from 113 to 88kg between 2000 and 2009yy when ultrasound showed cysts at the head of the pancreas. Since May 2009 there has been a further decrease in body weight, with fear of food intake, and constant and increasing pain.
Resurgence of Acute Rheumatic Fever in the Intermountain Area of the United States
Authors: L. George Veasy, Susan E. Wiedmeier, Garth S. Orsmond, Herbert D. Ruttenberg, Mark M. Boucek, Stephen J. Roth, Vera F. Tait, Joel A. Thompson, Judy A. Daly, Edward L. Kaplan, Harry R. Hill
Journal: New England Journal of Medicine (1987)

We describe an outbreak of acute rheumatic fever that occurred in the intermountain area centered in Salt Lake City, Utah. Seventy-four children meeting the modified Jones criteria for the diagnosis of acute rheumatic fever were evaluated by the staff at Primary Children's Medical Center, Salt Lake City, from January 1985 through June 1986. This represents an eightfold increase over the average annual incidence at this hospital during the past decade. Carditis, a dominant feature of the outbreak, was confirmed by auscultation in 53 of the patients (72 percent). An additional 14 patients were found to have mitral regurgitation by Doppler ultrasound examination, raising the total incidence of carditis to 91 percent. The children were predominantly from white (96 percent) middle-class families with above-average incomes and with ready access to medical care. There was no apparent increase in the incidence of streptococcal disease or other explanation for the marked increase in acute rheumatic fever. However, mucoid M type 18 and M type 3 group A streptococcal strains were isolated from several siblings of the patients and from schoolchildren (chosen at random) in the area. We conclude that acute rheumatic fever remains an important health problem in the United States. (N Engl J Med 1987; 316:421–7.)