tbuckley/cabot-search huggingface dataset:
THU0319 Disease course, outcome and predictors of outcome in an unselected cohort of individuals with juvenile chronic arthritis followed for 17 years
Authors: L. Bertilsson, B. Andersson-Gäre, A. Fasth, I.F. Petersson, H. Forsblad-d’Elia
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Juvenile chronic/idiopathic arthritis (JCA/JIA) is a heterogeneous disease. Some long-term studies are published, but few are population based and predictions of long-term outcome are incompletely defined. <h3>Objectives</h3> The aim of this study was to investigate disease course, outcome and predictors of outcome in an unselected population based cohort diagnosed with JCA followed for 17 years. <h3>Methods</h3> This cohort consists of 132 incidence patients identified 1984 to 1986 in southwestern Sweden according to EULAR criteria for JCA. At 5-year follow-up 129 individuals were examined with joint assessment, laboratory measurements, radiographic examinations, as well as medication and functional assessment. At 17-year follow-up the individuals were examined with joint assessment, laboratory measurements, medication, Health Assessment Questionnaire (HAQ), Keitel functional test (KFT) and short form 36 health survey (SF-36). <h3>Results</h3> At 17-year follow-up 86 out of 132 individuals (65%) were examined. The individuals lost to follow-up did not significantly differ with respect to baseline and 5-year data from the individuals examined at 17 years. Forty percent of the individuals were in remission. The median HAQ score was 0.0 (0.0 – 1.5) and the median KFT 100 (54 – 100). Fifty one (59%) individuals had HAQ score &gt;0 and/or KFT &lt;100. SF-36 was significantly lower in all domains compared to a reference group. During the 17 years 44% changed subgroups. Thirty-nine percent of the individuals in remission at 5-year follow-up were not in remission at 17-year follow-up. In multivariate analyses, remission at 17-year follow-up was predicted by remission at 5-year follow-up (OR 4.8, 95% CI 1.8 – 12.5). At 17-year follow-up disability defined by HAQ &gt;0 was predicted by RF-positivity at 5-year follow-up (OR 3.6, 95% CI 1.0 – 13.3) and disability defined by KFT&lt;100 was predicted by non-remission at 5-year follow-up (OR 11.3, 95% CI 2.7 – 47.9) and RF-positivity at 5-year follow-up (OR 5.6, 95% CI 1.0 – 30.6). At 17-year follow-up the physical summation score in SF-36 better than the average of the reference group was predicted by remission at 5-year follow-up (OR 5.8, 95% CI 2.2 – 15.4). Long-term outcome was not predicted by any baseline variables in multiple logistic regression. <h3>Conclusions</h3> In a population based cohort of patients with JCA, 40% were in remission but more than half of the individuals had some physical disability and the cohort had lower health related quality of life compared to a reference population. Many individuals changed subgroups and disease activity. Long-term outcome was best predicted by and associated with characteristics at 5-year follow-up and not by onset variables. <h3>Disclosure of Interest</h3> None Declared
A8.8 Mesenchymal stromal cells suppress synovial fluid-derived T cells from juvenile idiopathic arthritis patients<i>in vitro</i>
Authors: J Wienke, J Swart, A Martens, N Wulffraat, B Prakken, S De Roock
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Mesenchymal stromal cells (MSC) are multipotent cells with an immunosuppressive capacity. In the last decade the feasibility and safety of MSC therapy has been established in various inflammatory diseases. MSC are known to suppress T cell function and modulate T helper 17 (Th17) cells and regulatory T cells (Tregs), which play an important role in the pathogenesis of juvenile idiopathic arthritis (JIA). MSC may therefore serve as a new treatment option for JIA patients refractory to conventional therapies. However, it is unknown whether MSC are capable of suppressing the highly inflammatory synovial fluid mononuclear cells (SFMC), which have been shown to be resistant to suppression by Tregs. Furthermore, the effect of the inflammatory environment on MSC function is largely unknown, though it has been suggested that proinflammatory cytokines can enhance the suppressive potential of MSC. We aimed to study the <i>in vitro</i>immunomodulatory effects of MSC on SFMC from JIA patients, with a focus on T cell function. In addition, we assessed the influence of the inflammatory micro-environment, i.e. proinflammatory cytokines, on the suppressive potential of MSC. <h3>Materials and methods</h3> MSC were cocultured with either peripheral blood mononuclear cells (PBMC) or synovial fluid mononuclear cells (SFMC) from JIA patients (paired samples) or PBMC from healthy controls. We analysed the effect of MSC on T cell proliferation and Th17 and Treg numbers by flow cytometry. Cytokine production was analysed in culture supernatants by Multiplex Immunoassay. Furthermore, we blocked the proinflammatory cytokines TNFα, IFNγ, IL-1β and IL-6 to assess the result on MSC-mediated suppression. <h3>Results</h3> MSC suppressed proliferation of PB T cells and SF T cells from JIA patients dose-dependently, but patient-derived T cells were less susceptible to suppression than healthy donor-derived T cells. MSC reduced Th17 numbers and increased Treg numbers in PBMC, but not in SFMC. Addition of MSC did not clearly affect IL-17 levels in the supernatant, but TNFα production was suppressed in both PBMC and SFMC. Contrary to previous reports, blockade of TNFα, IFNγ, IL-1β and IL-6 during <i>in vitro</i>culture did not reduce suppression, but rather enhanced suppression in PBMC from JIA patients. <h3>Conclusions</h3> MSC suppress proliferation of synovial fluid T cells from JIA patients in a dose-dependent manner. However, patient-derived T cells are less susceptible to immunomodulation than healthy donor T cells. We propose that reduction of proinflammatory stimuli in conjunction with MSC therapy may benefit the suppressive effects of MSC in JIA.
Case 6-2013
Authors: Leigh H. Simmons, Alexander R. Guimaraes, Lawrence R. Zukerberg
Journal: New England Journal of Medicine (2013)

A 54-year-old man was admitted to this hospital because of recurrent diarrhea, vomiting, and weight loss. The initial episode of diarrhea occurred 2.5 years before admission. Diagnostic procedures were performed.
Abstract 185: Protein expression of DNMT1, DNMT3a, and DNMT3b in human hepatocellular carcinoma
Authors: Kanenori Endo, Takanori Miyake, Soichiro Honjo, Shunichi Tsujitani, Yasuaki Hirooka, Masahide Ikeguchi
Journal: Cancer Research (2010)

Abstract Background/Aims: DNA methylation plays an important roles in the regulation of gene expression. Gene silencing by aberrant hypermethylation of CpG islands in gene promoter regions in frequently found in human cancers. By the assistance of DNA methyltransferases (DNMTs), methyl groups are transferred to promoter CpG islands, many tumor suppressor gene can be silenced by promoter CpG islands methylation. However, studies on DNMTs in hepatocellular carcinoma (HCC) are rare, and there are no immunohistochemical studies on the correlations with these expressions and HCC patient's suvival. Methods : We immunohistochemically examined the expression of DNMT1, DNMT3a and DNMT3b and the relationships between these expressions and histological grade, clinicopathological parameters and patient's survival in 95 patients with HCC. Results : DNMT1, DNMT3a and DNMT3b immunoreactivities were presented in nuclei of HCC cells. In the tumorous lesion, the number of positive immunoreactivities was 95/95 (100%) for DNMT1, 87/95 (92%) for DNMT3a and 81/95 (85%) for DNMT3b. The degree of each protein expression significantly correlated with tumor differentiation and intrahepatic metastasis, and only DNMT3a protein expression significantly correlated with portal vein imvolvement of tumor. Though there were no relations between the DNMTs expression and tumor size, over-expressions of DNMT3a and 3b proteins were associated with poor prognosis of HCC's patients. Moreover, the overall survival rate of patients group that showed over-expression of three DNMTs in tumorous lesion was significantly lower than it of other patients groups. Conclusion : DNMTs are involved in HCC progression, and their overexpression is associated with poor prognosis. 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 185.
Langerhans'-Cell Histiocytosis (Histiocytosis X) -- A Clonal Proliferative Disease
Authors: Cheryl L. Willman, Lambert Busque, Barbara B. Griffith, Blaise E. Favara, Kenneth L. McClain, Marilyn H. Duncan, D. Gary Gilliland
Journal: New England Journal of Medicine (1994)

The lesions of Langerhans'-cell histiocytosis (histiocytosis X), a proliferative histiocytic disorder of unknown cause, contain histiocytes similar in phenotype to dendritic Langerhans' cells. The disease ranges in severity from a fatal leukemia-like disorder to an isolated lytic lesion of bone. Intermediate forms of the disease are usually characterized by multiorgan involvement, diabetes insipidus, and a chronic course.
Abstract LB-352: Functional significance of Zic1 and hsa-miR-23a over-expression in malignant mesothelioma
Authors: Yuen Yee Cheng, Hong Chuan Jin, Michaela Kirschner, Nico van Zandwijk, Glen Reid
Journal: Cancer Research (2011)

Abstract Background: Epigenetic inactivation of tumour suppressor genes plays a crucial role in the progression of malignant mesothelioma (MM). Previous research has shown epigenetic gene silencing, through DNA methylation or through control of mRNA expression by microRNAs, to be important in MM. Our previous work indicated that Zic1 silencing in MM lines is only partially explained through DNA hypermethylation. Interestingly, miRNA microarray analysis revealed that hsa-miR-23a is over-expressed in MM cell lines, and that this miRNA has target sites in the 3′UTR of the Zic1 mRNA. The aim of the current study was to investigate the functional significance of Zic1 silencing and hsa-miR-23a over-expression in MM. Methods: We first confirmed DNA hypermethylation of Zic1 in human MM specimens using MSP, MS-HRM and COBRA. The expression level of hsa-miR-23a was also confirmed in MM using qPCR. To investigate the functional significance of Zic1 silencing, Zic1 was re-expressed in MM cell lines and effects on proliferation, migration and growth in soft agar were assessed. The relationship between hsa-miR-23a and Zic1 expression was investigated by the use of an antagonist of hsa-miR-23a. Results: Our results indicated that Zic1 is hypermethylated and ectopic expression of Zic1 inhibited cell migration and cell proliferation in MM cell lines. Hsa-miR-23a overexpression in MM is closely linked to the expression of Zic1. Our results suggest that Zic1 is a functional tumour suppressor gene that is silenced by a combination of hypermethylation and hsa-miR-23a-mediated inhibition in MM. These findings suggest that hsa-miR-23a is a potential therapeutic target for MM deserving further pre-clinical study. 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 LB-352. doi:10.1158/1538-7445.AM2011-LB-352
THE SIGNIFICANCE OF PULMONARY ARTERIAL HYPERTENSION PRE- AND POST-TRANSFEMORAL AORTIC VALVE IMPLANTATION FOR SEVERE AORTIC STENOSIS
Authors: Diego Medvedofsky, Robert Klempfner, Paul Fefer, Fernando Chernomordik, Ashraf Hamdan, Ilan Hay, Ilan Goldenberg, Ehud Raanani, Victor Guetta, Amit Segev
Journal: Journal of the American College of Cardiology (2014)
Prelaminated Free Flap for Auricular Reconstruction
Authors: Ryan M Collar, Patrick J Byrne
Journal: New England Journal of Medicine (2013)

A 42-year-old woman presented with nearly complete defects of the left auricular and lateral temporal bone as a result of advanced basal-cell carcinoma. She did not want an adhesive auricular prosthesis and was not a candidate for traditional repair techniques because of trauma and irradiation damage to the postauricular skin. A prelaminated radial forearm free flap was selected for reconstruction.
AB0586 Short and Long-Term Anti-TNF-Alpha Therapy in Refractory Uveitis. Study of 40 Adult Patients from A Single Universitary Center
Authors: F.M. Ortiz-Sanjuán, V. Calvo-Río, R. Blanco, J. Cañal-Villanueva, J. Ventosa, J. Loricera, M. Santos-Gόmez, T. Pina, M.A. González-Gay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To assess the efficacy and safety of anti-TNFα drugs in refractory uveitis to conventional synthetic immunosuppressive drugs (CSISDs). <h3>Methods</h3> Study of refractory uveitis from a single Universitary hospital who had failed to at least one CSISD. The degree of ocular inflammation was established according to SUN-2005. Macular thickness was evaluated by OCT. We compared data between baseline 1st month, and 1st, 2nd, 3rd and 4th year (Wilcoxon test). <h3>Results</h3> We studied 40 adult patients/62 affected eyes (16 men/24 women); mean age, 39.3±11.5 years. The underlying pathologies were Spondyloarthritis-HLA-B27+ (n=7), Behçet disease (n=6), sarcoidosis (n=6), VKH (n=2), Birdshot (n=1), serpinginous (n=1), sympathic opthalmopathy (n=1), Juvenile Idiopathic Arthritis (n=1) and idiopathic uveitis (n=15). Besides oral corticosteroids and before anti-TNFα, patients had received methylprednisolone i.v. (n=9), methotrexate (n=16), cyclosporine A (n=13) and azathioprine (n=10). The first anti-TNFα was: adalimumab (n=18; 45%) (40 mg/sc/2 weeks) and infliximab (n=22; 55%) (5 mg/kg/i.v./every 4-8 weeks. Anti-TNFα drugs were used as monotherapy (n=8), or combined with methotrexate (n=18), azathioprine (n=10), Cyclosporine A (n=3) and salazopyrine (n=1). Adalimumab was switched to golimumab (50 mg/sc/week) (n=2) and to tocilizumab (n=2). Infliximab was switched to adalimumab (n=8) and to golimumab (n=2). Visual acuity (VA), Tyndall, vitritis and OCT experienced significant improvement at the 1st month, and 1st, 2nd and 3rd year. The mean OCT in cases of cystoid macular edema (OCT&gt;300 μ) (n=11 eyes) improved from 382.2±98.4 (baseline) to 195.5±38.9 microns (1st year). After a mean follow-up of 40.7±25 months anti-TNFα drugs was well tolerated in most cases. The most important side effects were pulmonary TBC (n=1), herpes zoster (n=2), urinary tract infection (n=3) and elevation of liver enzymes during treatment (n=2). <h3>Conclusions</h3> Anti-TNFα therapy seems effective and relatively safe in refractory uveitis. <h3>Acknowledgements</h3> This study was supported by a grant from "Fondo de Investigaciones Sanitarias" PI12/00193 (Spain). This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from "Instituto de Salud Carlos III" (ISCIII) (Spain). <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3369
Abstract B32: Telomerase activity confers growth and DNA damage survival advantages in telomerase-negative transformed human cells
Authors: Helen B. Fleisig, Judy M.Y. Wong
Journal: Cancer Research (2011)

Abstract Constitutively high telomerase activity is detected in more than 85% of human cancers. Together with the activation of oncogenic growth through RAS-oncogene-associated signal transduction pathways and the inactivation of tumor suppressor pathways regulated by p53 and Rb, telomerase reverse transcriptase expression promotes tumorigenic transformation of human cells. The prevalence of telomerase, rather than a homologous recombination-based mechanism, for telomere length maintenance in human cancers, suggests that telomerase has auxiliary roles in tumorigenesis. Here, we investigate growth advantages provided by the telomerase enzyme in oncogene-transformed human cells that do not require telomerase activity for telomere length control. We employed retroviral vector directed expression of telomerase components in human cell models that utilize the alternate lengthening of telomeres (ALT) mechanism for telomere maintenance. Forced expression of telomerase in ALT cells did not abolish the ALT mechanism, and ALT molecular characteristics were maintained in the resultant cell lines. Our data indicates that in these oncogene-transformed ALT cells, telomerase activity accelerates cell growth kinetics and promotes anchorage-independent growth. Co-culture experiments demonstrated that this growth advantage conferred by telomerase activity is not transferable by cytokine exchange and not likely the result of increased cellular crosstalk. Growth advantages provided by telomerase required all functional aspects of the enzyme. Dissociation-of-activities telomerase mutants and other functionally defective versions of telomerase were unable to promote oncogene-transformed cell growth, implying that canonical telomerase activities may be involved. Telomerase-positive ALT cells pass through the cell division phases of the cell cycle with increased kinetics, suggesting that the observed cell growth advantage is cumulative over cycles of proliferation. In addition, telomerase-positive ALT cells displayed an increased tolerance to the cytotoxic effects of DNA damaging agents that cause double-stranded DNA breaks. We conclude that telomerase expression provides growth and survival advantages to oncogene-transformed human cells; this supports the development of telomerase-based anticancer chemotherapies targeting these growth-promoting effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B32.
Abstract 2717: Reolysin: A novel reovirus-based agent that induces endoplasmic reticular stress in RAS-activated pancreatic cancer
Authors: Jennifer S. Carew, Claudia M. Espitia, Kevin R. Kelly, Matt Coffey, James W. Freeman, Steffan T. Nawrocki
Journal: Cancer Research (2012)

Abstract Mutations in the RAS oncogene are associated with transformation and proliferation and are prevalent in many tumor types. Since RAS is frequently hyperactivated in pancreatic cancer and plays an essential role in tumor progression, it is an ideal therapeutic target. Reoviruses are naturally occurring viruses that are non-pathogenic and have been reported to specifically replicate in cancer cells with an activated RAS pathway, but not in normal tissue. To take advantage of this observation therapeutically, the reovirus-based anticancer agent Reolysin was recently developed. Reolysin has already progressed into clinical trials, but its mechanisms of action have not been fully elucidated. We hypothesized that Reolysin exposure would result in the production of viral products, stimulate endoplasmic reticular (ER) stress, and induce apoptosis. Reolysin treatment triggered the selective replication of reoviruses as visualized by immunocytochemistry and electron microscopy in KRAS-transformed immortalized human pancreatic duct epithelial cells and in a panel of pancreatic cancer cell lines. Reovirus accumulation was associated with an increase in the expression of ER stress-related genes as assessed by microarray and quantitative RT-PCR analyses, cleavage of caspase-4, and induction of apoptosis. In support of our hypothesis that Reolysin induces ER stress-mediated apoptosis, co-treatment with tunicamycin or brefeldin A further augmented Reolysin-induced cell death. Previous studies have demonstrated that the proteasome inhibitor bortezomib causes ER stress-mediated apoptosis. Here we show that co-treatment with bortezomib and Reolysin stimulates the simultaneous accumulation of ubiquitinated and viral proteins resulting in enhanced levels of ER stress-related gene expression, caspase-4 cleavage, and apoptosis. The role of caspase-4 as a regulator of therapeutic sensitivity to these agents was investigated by targeting caspase-4 expression with siRNA. Knockdown of caspase-4 blunted apoptosis stimulated by Reolysin, bortezomib, and the combination. Importantly, bortezomib also dramatically augmented the anticancer activity of Reolysin in xenograft models of pancreatic cancer in vivo. Analysis of tumor specimens from mice treated with Reolysin and bortezomib displayed reovirus accumulation, enhanced expression of GRP78/Bip, a marker of ER stress and increased levels of apoptosis. Collectively, our results demonstrate that the abnormal protein accumulation induced by Reolysin and bortezomib promotes heightened ER stress and apoptosis in pancreatic cancer cells. 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 2717. doi:1538-7445.AM2012-2717
Tryptase Levels as an Indicator of Mast-Cell Activation in Systemic Anaphylaxis and Mastocytosis
Authors: Lawrence B. Schwartz, Dean D. Metcalfe, Jeffrey S. Miller, Harry Earl, Timothy Sullivan
Journal: New England Journal of Medicine (1987)

Better methods are needed to assess mastcell activation In vivo and to distinguish the activation of mast cells from that of basophils. Tryptase, a neutral protease selectively concentrated in the secretory granules of human mast cells (but not basophils), is released by mast cells together with histamine and serves as a marker of mast-cell activation. In 17 patients with systemic mastocytosis, concentrations of tryptase in plasma were linearly related to those of histamine (P<0.01). Eleven of the 17 patients had tryptase levels of 4 to 88 ng per milliliter, indicating ongoing mast-cell activation. In each of six patients who experienced corresponding anaphylactic reactions after penicillin, aspirin, or melon ingestion, a wasp sting, exercise, or antilymphocyte globulin injection, tryptase levels in serum ranged from 9 to 75 ng per milliliter, indicating mast-cell activation during each of these events. In contrast, serum tryptase levels were less than 5 ng per milliliter in all patients presenting with myocardial disease (n = 8, 6 with hypotension) or sepsis (n = 6, 3 with hypotension) and in the controls (n = 20). One patient had a myocardial infarction after anaphylaxis in response to a wasp sting and an elevated tryptase level of 25 ng per milliliter. Thus, the plasma or serum tryptase level is a diagnostic correlate of mast-cell-related events. (N Engl J Med 1987; 316: 1622–6.)
IATROGENIC INFERIOR VENA CAVA SYNDROME SECONDARY TO DELAYED PARTIAL EMBOLIZATION OF AN ATRIAL SEPTAL DEFECT OCCLUDER DEVICE: CHALLENGING CLINICAL SCENARIO
Authors: Marwan Saad, Alaa Roushdy, Ashraf A.H. Elmidany, Addi Suleiman
Journal: Journal of the American College of Cardiology (2015)
Bile acid diarrhea as the leading symptom of misplacement of a biliary stent into the colon
Authors: G. Dworschak, E. Dulic-Lakovic, M. Dulic, C. Neumann, K. Glaser, A. Holzäpfel, M. Gschwantler
Journal: Endoscopy (2011)

Biliocolonic fistulas are usually associated with severe clinical symptoms including recurrent cholangitis, sepsis, and abdominal pain [1] [2]. To the best of our knowledge, this is the first case in which misplacement of a biliary stent was associated with a mild clinical course, bile acid diarrhea being the leading symptom.