tbuckley/cabot-search huggingface dataset:
PWE-256 Intestinal inflammation regulates retinoic acid dependent imprinting of gut tropism by dendritic cells independently of RALDH expression
Authors: T J Sanders, N E McCarthy, E Giles, J O Lindsay, A J Stagg
Journal: Gut (2012)

<h3>Introduction</h3> In the mouse, tissue-specific expression of retinaldehyde dehydrogenase (RALDH) enzymes by CD103+ intestinal dendritic cells (DC) enables them to generate all-trans retinoic acid (RA) and thereby imprint a gut-tropic phenotype on T cells via induction of homing receptors including α4β7 integrin. In health, RA from CD103+ also enhances their generation of Treg, contributing to intestinal homeostasis. In murine models of inflammatory bowel disease (IBD) RALDH expression by CD103+ DC is reduced but little is known about the function of RA in the human intestine. The aim of this study was to determine whether factors present in the healthy and inflamed human intestine regulate RA generation and activity. <h3>Methods</h3> Conditioned media (CM) were generated by culture of intestinal biopsies from healthy individuals and IBD patients (inflamed/non-inflamed regions). DC were differentiated from monocytes using GM-CSF and IL-4 in the presence or absence of CM. Expression of RA-generating enzymes was assessed by qRT-PCR and RALDH activity determined using the Aldefluor assay. Induction of α4β7 following activation of naïve allogeneic CD4+ T cells was determined by flow cytometry. <h3>Results</h3> Activation of naïve CD4+ T cells by human monocyte-derived DC resulted in RA-dependent upregulation of α4β7. These DC possessed retinal-inhibitable Aldefluor activity and expressed both alcohol dehydrogenase (<i>RDH10</i>) and RALDH (<i>RALDH1,2,3</i>) enzymes required for the generation of RA from retinol via retinal. Aldefluor activity was regulated by GM-CSF and RA, and reflected predominately the activity of RALDH2 as suggested by qRT-PCR analysis of sorted Aldefluor+ DC. CM significantly suppressed Aldefluor activity (p&lt;0.0001) irrespective of whether generated from healthy or IBD tissue (inflamed or non-inflamed). The inhibitory effect of CM generated from healthy tissue could be partially reversed with the prostaglandin E2 (PGE2) EP-2 receptor antagonist AH6809 but this effect was less marked with CM from IBD tissue suggesting the involvement of distinct RALDH regulators. Although the effects of inflamed and non-inflamed CM on Aldefluor activity were similar, DC differentiated in the presence of inflamed CM induced significantly higher (p&lt;0.05) levels of CD4 T cell α4β7 expression. <h3>Conclusion</h3> Factors generated in the human intestinal mucosa limit RALDH activity in DC and may thereby impact upon their generation of RA. Factors other than PGE2 are involved particularly in inflamed tissue. Intestinal mediators influence the imprinting of gut tropism independently of effects on RA-generating enzymes. Manipulation of RA availability may offer new therapeutic options in IBD. <h3>Competing interests</h3> None declared.
1108 SELECTION OF HCV GENOTYPE 1 PATIENTS FOR DUAL THERAPY WITH PEGINTERFERON ALFA-2A/RIBAVIRIN WITH A HIGH PROBABILITY OF SUSTAINED VIROLOGIC RESPONSE ACCORDING TO BASELINE CHARACTERISTICS ALONE
Authors: P. Ferenci, R. Aires, I. Ancuta, A. Arohnson, H. Cheinquer, D. Delic, M. Gschwantler, D. Larrey, L. Tallarico, M. Schmitz, F. Tatsch, D. Ouzan
Journal: Journal of Hepatology (2012)
SAT0321 Is radiographic knee osteoarthritis more severe when hand osteoarthritis is present and conversely? A cross-sectional study in 1371 knee osteoarthritis patients
Authors: E. Maheu, C. Cadet, F. Berenbaum
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The association between hand (HOA) and knee osteoarthritis (KOA) has been questioned. Current evidence is contradictory. <h3>Objectives</h3> To study the prevalence of radiographic HOA in a large KOA population, and its cross-sectional association to knee OA radiographic severity. <h3>Methods</h3> Baseline data were obtained from an international 3-year prospective, multicenter, randomized, controlled trial comparing the structural effect of strontium ranelate to placebo in KOA. Inclusion criteria were: a diagnosis of OA according to ACR criteria, knee pain &gt;40mm on a visual analog scale, OA atmedial compartment witha Kellgren-Lawrence (KL) grade 2 or 3and a minimal joint space width (JSW) of 2.5 to 5mm. Fixed-flexion postero-anterior (PA) radiographs of both knees in standing position every year and PA radiographs of each hand at baseline and endpoint were performed. Minimal JSW was centrally measured using a semi-automated standardized method. Hand radiographs were graded by 2 readers using KL (range 0-128), Kallman (0-204) and Verbruggen scoring methods. Radiographic HOA was defined as 2 or more joints at a KL2 or more. Statistics: Student T test, and Pearson correlation coefficient.Only the 1371 patients having at least 2 knee radiographs were analyzed. <h3>Results</h3> 1360 patients had hand radiographs at baseline. 999 (73%) had HOA (HOA+). In HOA+, the mean age was 64 years, 71% were female, mean body mass index 29.6. HOA+ were older (5yrs), with a higher percentage of female (p=0.04), with no difference on BMI compared to non HOA patients (p=0.12). Mean knee JSW was 3.44 versus 3.66mm (p&lt;0.001), and there was slightly more KL3 knees (40% vs 34%; p=0.047) in HOA+ compared to non HOArespectively. Conversely, global hand KL and Kallman scores were higher in KL3 KOA patients (22.5 vs 20.2; p=0.01 and 27.0 vs 23.6; p=0.02respectively), compared to KL2 patients. There was no difference for the Verbruggen score (14.7 vs 13.6, p=0.32). Pearson analyses did not showed linear correlations between knee JSW and hand KL score (r=0.123) or between knee and hand KL scores (r=0.085). <h3>Conclusions</h3> Our data indicates a very high prevalence of radiographic HOA in a symptomatic KOA population, much more than expected. KOA is radiographically more severe in case of HOA. Conversely, HOA is more severe in the more severe KOA patients (KL3). <h3>Disclosure of Interest</h3> E. Maheu Grant/Research support from: from Institut de Recherche International Servier, C. Cadet Grant/Research support from: from Institut de Recherche International Servier, F. Berenbaum Grant/Research support from: From Institut de Recherche International Servier
Abstract PL04-02: Ras and Raf signaling: From biology to therapeutics
Authors: Richard M. Marais
Journal: Cancer Research (2012)

Abstract The protein kinase BRAF is mutated in about 50% of human melanomas and the small G-protein NRAS is mutated in another 20% of cases. We have developed mouse models of melanoma driven by oncogenic BRAF, NRAS and KRAS. These studies have established that acquisition of BRAF, NRAS or KRAS mutations can be founder events in melanomagenesis and we are currently using these models to investigate gene-gene and gene-environment interactions in cutaneous melanoma. We are also investigating other targets of BRAF in melanoma cells and have shown that BRAF drives melanoma cell migration and invasion by down-regulating expression of the cyclic GMP phosphodiesterase PDE5A. 2011 was a landmark year in melanoma research with the registration of vemurafenib and ipilimumab, drugs that show clinical benefit in patients with advanced disease. Critically, BRAF inhibitory drugs achieve objective clinical responses in about 80% of melanomas that harbour mutations in BRAF. Surprisingly however, these drugs also drive paradoxical activation of CRAF in melanoma cells that harbour mutations in NRAS, or in cells in which RAS is activated due to increased upstream signalling. This is due to the induction of BRAF/CRAF heterodimers and CRAF homodimers and importantly, activation of the pathway by this paradox can drive tumourigenesis in some circumstances. We have used a two-stage skin carcinogenesis model to show that BRAF inhibitors are not tumour promoters pre se, but rather that they work by accelerating the growth of tumours carrying pre-existing mutations in HRAS. Thus, we conclude that BRAF inhibitors appear to accelerate the inevitable in susceptible patients, but do not induce these lesions de novo. Notably, concurrent administration of a MEK inhibitor with a BRAF drug blocks the development of these skin lesions, providing a rationale for combining BRAF and MEK inhibitors in melanoma patients. Unexpectedly, we have also found that the ABL/CKIT inhibitor nilotinib also drives paradoxical activation of the RAF pathway because it possesses weak off-target activity against BRAF and CRAF. The consequence of this paradoxical activation is that nilotinib provides a survival advantage to chronic myeloid leukaemia (CML) cells that are resistant to nilotinib, but also provides an Achilles heel to these cells because they become dependent on MEK signalling in the presence of nilotinib. Thus, MEK inhibitors cooperate with nilotinib to drive synthetic lethality in nilotinib-resistant CML cells. Thus, paradoxical activation of the RAF proteins by small molecular weight drugs can have important consequences to patient responses, creating specific clinical problems in some circumstances, but therapeutic opportunities in others. 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 PL04-02. doi:1538-7445.AM2012-PL04-02
P418LRP5 modulates the Wnt signalling pathway to protect damaged cardiac cells
Authors: M Borrell-Pages, C Romero, L Casani, G Vilahur, L Badimon
Journal: Cardiovascular Research (2014)

Purpose: LDL receptor-related protein 5 (LRP5) triggers the canonical Wnt pathway which participates in cell function regulation, spanning from tissue regeneration to lipid metabolism. However there is little understanding on the role of LRP5 in the heart. The aim of this study was to investigate the expression and function of LRP5 and the canonical Wnt signalling pathway in cardiac pathology. Methods: Myocardial damage and LRP5 and Wnt signalling proteins expression levels were measured in in vivo myocardial infarction (MI) models in LRP5-/- mice and in human dyslipidemic hearts from heart transplants. To characterize the role of LRP5 and the different metabolic pathways involved in myocardial damage post-MI cultured cardiomyocytes, myofibroblasts and endothelial cells were challenged with lipids and hypoxic treatments. Results: We show that LRP5-/- mice have an increased infarct size after MI with respect to WT mice, indicating a protective role of LRP5 in injured myocardium. Furthermore, administration of a GSK3 inhibitor that activates the Wnt pathway downstream LRP5, induced smaller infarcts in WT and LRP5-/- mice indicating that an active Wnt pathway plays a protective role in injured myocardium. Proteins members and targets of the canonical Wnt signalling pathway were downregulated in the ischemic myocardium of WT mice in the acute phase of MI and regained physiological values after GSK3 inhibitor treatment. Hypoxic treatments induced LRP5 overexpression in isolated cardiomyocytes and endothelial cells indicating that the protective role of LRP5 is produced through these cell types. Administration of hypercholesterolemic diets induced bigger infarcts in WT and LRP5-/- mice. LRP5 overexpression/silencing experiments in isolated cardiomyocytes induced Wnt pathway activation only in lipid-loaded hypoxic cardiomyocytes whereas LRP5-silencing blocked the pathway. Finally, an increased LRP5 and Wnt regulated gene expression in human ischemic failing hearts of dyslipidemic patients, was observed. Conclusions: Our results demonstrate that the modulation of LRP5 and the canonical Wnt pathway in LRP5-/- mice, in hypoxic cardiomyocytes and in human ischemic myocardium is a defensive pro-survival process of the damaged myocardium triggered to restore cell viability. Therapeutic interventions targeting LRP5 may favour cardiac healing post-MI.
Skeletal Scintigraphy in Acquired Adult Fanconi Syndrome
Authors: Vincent M Brandenburg, Markus Ketteler, Ursula Blum, Jochen Riehl, Juergen Floege
Journal: Clinical Nuclear Medicine (2002)

BRANDENBURG, VINCENT M. M.D.,*; KETTELER, MARKUS M.D.,*; BLUM, URSULA M.D.,†; RIEHL, JOCHEN M.D.* AND; FLOEGE, JUERGEN M.D.* Author Information
Over-the-scope clip used to control bleeding from a duodenal ulcer
Authors: M. Peters, P. Meyer, J. Martin, A. Poerschke, S. Rupp, K.-H. Kirschstein
Journal: Endoscopy (2012)

The over-the-scope clip (OTSC) is a new device that was initially developed for the closure of perforations of the gastrointestinal tract, but has since been used for a variety of indications including closure of fistulas [1] [2]. We report the use of an OTSC to control persistent bleeding from a duodenal ulcer.
INTRAVASCULAR ULTRASOUND ARTERIAL MEASUREMENTS PREDICT VASCULAR ACCESS SITE COMPLICATIONS IN TRANSFEMORAL AORTIC VALVE REPLACEMENT
Authors: Juliet Blakeslee-Carter, David Dexter, Paul Mahoney, Sadaf Sadie Ahanchi, Samuel Steerman, Brandon Cain, Jean Panneton
Journal: Journal of the American College of Cardiology (2016)
Leading the Transformation of Health Care Delivery — The Launch of NEJM Catalyst
Authors: Thomas H. Lee, Edward W. Campion, Stephen Morrissey, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2015)

Health care delivery is in a period of historic transition. The pressure for major improvements in quality and efficiency exists everywhere — and thus is not driven by the Affordable Care Act alone. The real driver is the medical progress of recent decades, which has dramatically enhanced what medicine can do but has also increased its potential for creating waste, disappointing quality, and chaos for patients. Even if costs were not an issue, the need to reorganize health care would be compelling. Given economic realities, that need is an imperative. To support the decision makers and clinical leaders in our . . .
Abstract 4013: Transcriptional regulation of EGR1 by EGF and the ERK signaling pathway in prostate cancer
Authors: Jennifer L. Gregg, Gail C. Fraizer
Journal: Cancer Research (2011)

Abstract The early growth response gene 1, EGR1, is an important transcriptional regulator and acts as the convergent point between a variety of extracellular stimuli and activation of target genes resulting in diverse responses such as cell growth, proliferation, and apoptosis. Unlike other tumor types, in prostate tumor tissues EGR1 expression is elevated relative to normal tissues. However, the mechanism(s) of regulation of EGR1 in prostate tumor cells are unknown. As EGR1 expression and epidermal growth factor (EGF) signaling are frequently upregulated in prostate tumors, we tested the hypothesis that EGF induces EGR1 expression in prostate cancer cells. Using real-time PCR to quantify EGR1 transcripts, EGF induced EGR1 expression levels in a dose and time-dependent manner; and kinase inhibitors, PD98059 and wortmannin, abrogated the EGF-mediated EGR1 response. Analysis of the EGR1 promoter using reporter constructs identified an EGF-responsive region in the proximal promoter containing three potential serum response element (SRE) sites. In vivo chromatin immunoprecipitation assays demonstrated that EGF enhanced Elk-1 binding at the SRE sites of the EGR1 promoter in PC3 cells, and Elk-1 also bound in the absence of stimulus. Overexpression of Elk-1 enhanced activation of the EGF-responsive region indicating that Elk-1 is sufficient to activate EGR1 in PC3 cells. Similarly, a dominant-negative Elk-1 suppressed EGR1 promoter activity indicating that Elk-1 is necessary for EGF-induced EGR1 transcription in both PC3 and LNCaP cells. Taken together, these results demonstrate that EGR1 expression in prostate cancer cells is mediated through an EGF-ERK-Elk-1 signaling cascade. Since elevated EGF and EGF receptor are associated with prostate cancer progression, these results may explain elevated EGR1 in high-grade prostate tumors. 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 4013. doi:10.1158/1538-7445.AM2011-4013
Treatment of infected pancreatic pseudocysts using a novel, dedicated covered self-expandable metal stent (CSEMS) with an effective antimigration system
Authors: I. Tarantino, M. Traina, L. Barresi, M. Di Pisa, G. Curcio, A. Granata
Journal: Endoscopy (2012)

Endoscopic ultrasound (EUS)-guided treatment has become the preferred approach for managing pancreatic pseudocysts because it is associated with a lower morbidity rate compared with surgical and percutaneous approaches [1]. The disadvantages of the endoscopic approach are the need for multiple revisions because of obstruction of plastic stents, patient discomfort, and dislodgment of stents after placement of a nasocystic catheter. The most appropriate type of stent for drainage is currently a major area of interest. Covered self-expandable metal stents (CSEMSs) have recently been used for drainage of pseudocysts [2] [3] [4] [5]. Use of CSEMSs allows creation of a larger-diameter access fistula, an increase in the final success rate, and a reduction in the time for resolution, even in complicated cysts [3] [4] [5]. One problem with using a CSEMS is the risk of stent migration.
Abstract 1416: An animal model to study the effects of primary tumor excision on metastatic potential and organ-tropism of residual breast cancer cells
Authors: Yun Zhang, Danielle Jernigan, Mercedes Lioni, Fernando Garcia, Alessandro Fatatis
Journal: Cancer Research (2012)

Abstract Because of constant improvements in early detection, the majority of breast cancer patients are diagnosed when still in a localized or regional stage and considered to be viable candidates for breast-conserving surgery or lumpectomy. As only 37% of breasts are found tumor-free following initial lumpectomy, between 22 and 59% of patients currently need re-intervention because positive or close margins are detected. In addition, re-excision or adjuvant therapies, such as local irradiation, are normally started several weeks or even months after primary surgery. During this period, the stroma at the site of tumor removal, which is characterized by altered angiogenesis, immune cells infiltration and activation of cancer-associated fibroblasts, may be selecting for cancer stem phenotypes, increasing metastatic potential and promoting the dissemination to specific secondary organs. This study aims to: 1) establish whether surgery on primary breast tumors leads to the emergence of cellular phenotypes with higher malignancy, associated with an increase in local growth, invasiveness and metastatic potential; 2) determine whether breast surgery alters the organ-tropism of residual cancer cells. For our experiments, BALB/c mice were inoculated in the mammary fat pad with 4T1 murine breast cancer cells and developed tumors that were either allowed to progress or surgically excised. Approximately 50% of animals in the surgery group presented with local recurrence, although all the excised tumors had positive margins. Local recurrences showed higher Ki-67 staining compared to their respective primary tumors and these data were in agreement with human samples of primary and recurrent breast tumors. Interestingly, the overall survival of mice in the control and surgery with recurrence groups were similar. Furthermore, macroscopic lung metastases were detected in the control and local recurrence groups, whereas mice without post-surgery recurrence failed to develop lung metastatic lesions. Finally, differences in the dissemination and growth of 4T1 cells to brain and bone between control, surgery plus recurrence and surgery without recurrence groups were investigated. 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 1416. doi:1538-7445.AM2012-1416
FRI0262 Differences in serum microrna profile in active systemic lupus erythematosus and healthy controls
Authors: M. Fojtikova, R. Svobodova, D. Tegzova, J. Zavada, M. Olejarova, H. Ciferska, E. Simickova, P. Novota, M. Remakova, J. Vencovsky
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The microRNAs (miRNA) are small, non-coding RNA with a role in regulation of gene expression at post-transcriptional level and some of them are suggested to be involved in the adaptive and innate immunity regulation. MiRNA have been identified not only intracellularly, but in body fluid as well. Some of the serum miRNA serve as biomarkers of various diseases particularly autoimmune like systemic lupus erythematosus (SLE). <h3>Objectives</h3> The aim of our work was to identify differences in serum miRNA profile in SLE patients and healthy individuals. <h3>Methods</h3> Altogether, 11 patients suffering from active SLE without active lupus nephritis (average SLEDAI: 14,63, average age 41,36 years) and 16 healthy individuals (average age 39,81 years) as control group were investigated. Serum miRNA was isolated from serum by trisol-acid phenol precipitation. The expression of 1347 to date known miRNA was tested using microarray analysis. Paired comparisons between experimental groups were performed by the nonparametric Mann-Whitney U test. Pearson's and Spearman's correlation coefficients were calculated to determine the correlation between miRNA expression levels of two genes. The statistical analyses were performed using WinSTAT® software. <h3>Results</h3> Total 106 miRNA of all tested miRNA show significant differences in expression between SLE patients and healthy controls. Only 8 miRNA show significantly decreased expression in SLE whereas 98 of all miRNA were upregulated in SLE. Interestingly, only in a part of the identified SLE - associated miRNA have been known their immunological functions, the other miRNA have a role in apoptosis, cell proliferations, drug resistance or their function have not been identified yet. <h3>Conclusions</h3> Our work demonstrated the differences between serum miRNA profile in active SLE patients and healthy controls. The serum miRNA profile is different than miRNA profile of peripheral mononuclear cells and may reflect the intercellular communication. This pilot study identifies potential SLE - associated miRNA, which are connected to higher risk of active SLE with severe organ manifestation. The next step of our work is to quantify potential risk miRNA and establish some serum miRNA as biomarker of active SLE. <h3>References</h3> Wang G, et al. Serum and urinary free microRNA levels in patients with systemic lupus erythematosus. Lupus 2011, 20: 493-500. Shen N, et al. MicroRNAs – novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 2012, 8: 701-9 <h3>Acknowledgements</h3> This study is supported by research project of Czech Ministry of Health IGA NT 13707. <b>Disclosure of Interest</b>: None Declared