tbuckley/cabot-search huggingface dataset:
Abstract 306: TWEAK functions as chemotactic factor for glioma cells via Lyn activation
Authors: Harshil D. Dhruv, Nathan Jameson, Falak Patel, Mitsutoshi Nakada, Brock Armstrong, Jeffrey A. Winkles, Michael E. Berens, Nhan L. Tran
Journal: Cancer Research (2012)

Abstract The long-term survival of patients with glioblastoma multiforme is compromised by the tumor's proclivity for local invasion into the surrounding normal brain. These invasive cells escape surgery and display resistance to chemotherapeutic- and radiation-induced apoptosis. We have previously shown that tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion and survival via binding to the fibroblast growth factor-inducible 14 (Fn14) receptor and subsequent activation of the Rac1/NF-kappaB pathway. In addition, we have reported previously that Fn14 is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Here we demonstrate that TWEAK can act as a chemotactic factor for glioma cells, a potential process to drive cell invasion into the surrounding brain tissue. Specifically, we detected a chemotactic migration of glioma cells to the concentration gradient of TWEAK using the Modified Boyden chamber assay. Because TWEAK has been shown to be expressed in normal astrocytes, microglia, and endothelial cells, we neutralized TWEAK using a recombinant soluble murine Fn14-Fc decoy receptor and examined the effect on glioma cell invasion in the ex vivo rat brain slice model. Incubation of the brain slice with the Fn14-Fc decoy receptor reduced glioma cell invasion as compared to control IgG treated brain slice. Since Src family kinases (SFK) have been implicated in chemotaxis, we next determined whether TWEAK:Fn14 engagement activated these cytoplasmic tyrosine kinases. Our data shows that TWEAK stimulation of glioma cells results in a rapid phosphorylation of Src as detected by Western blot analysis using a pan-Src phosphorylation antibody. To determine which SFK member is phosphorylated by TWEAK, we applied the multiplex Luminex assay and identified Lyn as a candidate SFK. Immunoprecipitation of Lyn from TWEAK-treated cells verified that Lyn is phosphorylated as determined by phosphotyrosine immunoblot analysis. Immunodepletion of Lyn by siRNA oligonucleotides suppressed the chemoattractive effect of TWEAK on glioma cells. We hypothesize that TWEAK secretion by cells present in the glioma microenvironment induce invasion of glioma cells into the brain parenchyma. Understanding the function and signaling of the TWEAK-Fn14 ligand-receptor system may lead to development of novel therapies to therapeutically target invasive glioma 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 306. doi:1538-7445.AM2012-306
THU0373 Pamidronate Treatment of SAPHO Syndrome: A Retrospective Study of 22 Cases
Authors: E. Delattre, X. Guillot, C. Prati, D. Wendling
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> There are no guidelines for the treatment of SAPHO (Synovitis, Acne, Pustulosis, Osteitis, Hyperostosis) syndrome, particularly in the situation of inadequate response to NSAIDs. Bone involvement (hyperostosis, osteitis) may legitimate the therapeutic use of bisphosphonates. <h3>Objectives</h3> The aim of this study was to evaluate efficacy and tolerance of intravenous (IV) pamidronate in patients with SAPHO. <h3>Methods</h3> Open monocentric retrospective study including patients with SAPHO syndrome (Benhamou "criteria") and treated with IV pamidronate. Main characteristics of the disease and the treatments were recorded. Pamidronate was administered IV, 60 or 120 mg (one or 2 infusions), eventually repeated evey 4 weeks. Efficacy was assessed by global patient VAS, % of improvement, physician9s judgment and biologic parameters (ESR, CRP). Side effects were recorded. <h3>Results</h3> 22 patients were evaluable: 19 women, mean age 48 years, mean disease duration 5.8 years. Skin involvement was present in 18 patients, 22 patients had osteitis, 4 hyperostosis and 13 a sterno clavicular involvement. Initial CRP was 16±22 mg/l, ESR 25 and VAS 67±21 mm. The mean number of infusions was 5.6 (1 to 23). A significant improvement is obvious at month 1 (VAS 44±18; p=0.01), no more significative at month 2 (p=0.06). Physician9s judgment was: efficacy (n=13), partial or transient efficacy (n=8), inefficacy (n=1). In case of efficacy, the mean duration of efficacy under treatment was 7 months. A non significant decrease in ESR was observed at month 1 (25 to 14 mm). Side effects were noted in 11 cases: flu-like syndrome (N=5), fever (3), hypocalcemia, conjunctivitis, headache, vein inflammation. No predictive factor for good response could be found in these patients. <h3>Conclusions</h3> This study suggests a modest global efficacy, variable and transitory, of IV pamidronate treatment in SAPHO syndrome. Analysis of the results remains difficult in the absence of validated response criteria in this heterogeneous disease. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1582
THU0149 Treat to target early rheumatoid arthritis clinic: High rates of remission and low disease activity on treatment with conventional disease modifying drugs:
Authors: O. Semenova, H. Thompson, S. Kallankara, O. Olabambo, Y. Patel, E. Baguley
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The Early Rheumatoid Arthritis Clinic (EAC) was established in 2010 to meet NICE recommendations (2009) for treatment of early rheumatoid arthritis [1]. <h3>Objectives</h3> Analysis of remission and low disease activity (LDA) rates in patients that have been followed up for 1 year. <h3>Methods</h3> Patients seen in EAC are adults (&gt;18 years of age) with a new diagnosis of RA (≤2 years) and active disease (DAS28&gt;3.2) at the first visit. Target of treatment was remission (DAS28 &lt;2.6) or LDA (DAS28 &lt;3.2). We used an agreed protocol for treatment escalation. Activity measure was DAS28-CRP. Patients were seen every 4-6 weeks. Treatment was escalated if DAS28 &gt;3.2. Therapy started with methotrexate (MTX) with rapid escalation from 15mg to 25 mg per week. If activity persisted, a combination of up to 3 disease modifying drugs (DMARDs) was given, hydroxychloroquine and then leflunomide. If this failed (still DAS28 &gt;3.2), treatment with biologic drugs was started as per NICE guidelines. <h3>Results</h3> 37 of 108 patients have completed 1 year of treatment in the EAC. Female:male ratio was 2.7:1. At the first visit, 81% (30/37) patients were seropositive and 38% (14/37) had high disease activity, DAS &gt;5.2. Results of treatment after 1 year in the EAC are shown in Table 1, as well as the type of treatment. <h3>Conclusions</h3> Targeted protocol-driven treatment of early RA with rapid escalation of therapy with conventional DMARDs has resulted in remission in 63% and LDA in 81% of patients. Obtained in the real-life clinical setting, these outcomes are comparable to the ones reported in rigorous clinical trials [2]. However, radiological outcomes remain to be analysed to see if this approach can also ameliorate bone erosions and joint damage. <h3>References</h3> NICE, February 2009. RA: The Management of RA in adults. Lancet 2008;37:375-82 <h3>Disclosure of Interest</h3> None Declared
Abstract 1342: Nuclear Apc suppresses colitis-associated tumorigenesis in mice
Authors: Maged Zeineldin, Kristi L. Neufeld
Journal: Cancer Research (2012)

Abstract Because mutation of tumor suppressor gene APC is the initiating step in most colorectal cancers (CRC), understanding the full spectrum of APC functions will illuminate better diagnostic, preventive and therapeutic strategies for the disease. Although APC shuttles between the cytoplasm and nucleus, testing proposed roles for nuclear APC in the context of a whole organism was only recently made possible using a mouse model compromised for nuclear Apc which we generated by introducing germline mutations that inactivate the Apc nuclear localization signals (ApcmNLS). Our previous analysis of ApcmNLS mice revealed a role for nuclear Apc in regulation of Wnt signal transduction and intestinal cell proliferation as well as in tumor suppression. In humans, chronic colitis significantly increases CRC risk and APC mutations occur late in this cancer progression. In the current study, we show increased expression of inflammatory mediators cyclo-oxygenase-2 (Cox-2) and macrophage-inflammatory-protein-2 (MIP-2) in colon epithelial cells from ApcmNLS/mNLS mice, suggesting a role for nuclear Apc in suppressing colitis-mediated colon cancer. To test this hypothesis, we initiated colon tumors with a single injection of the mutagen, azoxymethane (AOM) and promoted the tumors with repeated oral administration of dextran sodium sulfate (DSS) to induce colonic inflammation. When treated with AOM-DSS, ApcmNLS/mNLS mice developed more colonic tumors than treated wildtype mice. Tumors from treated ApcmNLS/mNLS and wildtype mice had the same spectrum of β-catenin mutations, proliferation rates and histopathological features, consistent with the ApcmNLS allele enhancing colitis-associated tumor initiation rather than progression. ApcmNLS/mNLS mice had increased weight loss and colonic lymphoid follicles implicating nuclear Apc in suppression of AOM-DSS-induced colitis. These findings reveal novel functions for nuclear Apc and also indicate a critical protective role for Apc early in inflammation-induced colon tumorigenesis. 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 1342. doi:1538-7445.AM2012-1342
Abstract 1486: The contribution of stromal caveolin-1 to breast cancer metastasis
Authors: Allan D. Burrows, Christina Restall, Erica K. Sloan, Robin L. Anderson
Journal: Cancer Research (2012)

Abstract In a previous study, our group has shown that the expression of caveolin-1 (CAV1) in normal tissue surrounding a primary breast cancer is a powerful prognostic indicator of subsequent metastatic disease. Whilst reports linking expression of CAV1 within breast tumour cells to clinical outcome have not led to any clear conclusions, our finding of a strong positive correlation between loss of CAV1 expression in breast tumour stroma and poor prognosis (p&amp;lt;0.0001) (Sloan et al, 2009, AJP 174: 2035-2043), is novel and exciting as it offers the potential of a reliable prognostic indicator of metastatic disease. Tumours arising from non- or weakly metastatic mammary cells grow at a faster or similar rate when co-injected with CAV1 null mammary fibroblasts. In contrast, co-injection with CAV1 expressing mammary fibroblasts has a suppressive effect on tumour growth. To mimic this phenotype observed in vivo, 3D co-culture assays are being developed, and although they have demonstrated a positive effect of fibroblasts on tumour cell migration and proliferation, no stromal CAV1 specific effect has been observed. To further understand the consequences of the loss of stromal CAV1, profiling of CAV1 expressing and null mouse mammary fibroblasts was conducted using cytokine arrays and cDNA microarrays. Differences in the secretion of known CAV1 associated cytokines such as RANTES, Gas6 and IL-6 were observed, with no significant changes in their expression. Based on these findings, CAV1 may be contributing directly to the progression of breast cancer and thus provide the basis of a stromal targeted therapy. An understanding of the mechanism by which CAV1 expression is lost from host cells, and how this loss leads to progressive disease, could allow a therapy that restores or substitutes for CAV1 activity in stromal cells or that targets the key cytokines involved in this paracrine signalling. 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 1486. doi:1538-7445.AM2012-1486
A9.13 TNF-Induced- Protein Tyrosine Phosphatase Nonreceptor Type 2 (PTPN2) as a Negative Regulator of Inflammation in Rheumatoid Arthritis
Authors: Borbala Aradi, Maria Filkova, Stephanie Kasper, Kerstin Klein, Michael Scharl, Beat A Michel, Renate E Gay, Edit I Buzas, Steffen Gay, Astrid Jüngel
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Protein Tyrosine Phosphatase Nonreceptor Type 2 (PTPN2) is a protein tyrosine phosphatase that plays a role in the development of autoimmune diseases. PTPN2 function has not been studied in rheumatoid arthritis (RA), although single nucleotide polymorphisms within the gene have been described to be associated with RA in genome wide association studies. Considering the involvement of PTPN2 in the regulation of key inflammatory pathways, our aim was to analyse the expression and function of PTPN2 in RA synovial fibroblasts (RASF). <h3>Materials and Methods</h3> The expression of PTPN2 was assessed in synovial tissue and fibroblasts (passage 4–10) from patients with RA and osteoarthritis (OA) using immunohistochemistry, real-time PCR (w/o tumour necrosis factor α (TNFα), IL1β, LPS and hypoxia) and Western blotting. PTPN2 was silenced with silencing RNA. Levels of IL-6 and IL-8 expression were measured by commercially available ELISA in cell culture supernatants after silencing PTPN2 in RASF w/o stimulation with tumour necrosis factor α (TNFα). Apoptosis of RASF was evaluated by AnnexinV staining using flow cytometry after stimulation with TNF-related apoptosis-inducing ligand (TRAIL, 20 ng/ml) for 24 hours. <h3>Results</h3> In RA synovial tissue, compared with OA, we observed a stronger staining of ptpn2 in both the lining and the sublining layer by immunohistochemistry. On mRNA level we confirmed this overexpression in RA synovial tissue (2.0 fold, n = 4–5). In isolated RASF the constitutive mRNA level of PTPN2 was higher than in OASF (1.6 fold, p &lt; 0.01, n = 10–16). Levels of PTPN2 were further upregulated in RASF after stimulation with inflammatory cytokines such as TNFα (10 ng/ml, 24 hours, 3.1 fold, p &lt; 0.05, n = 4), TNFα and IL-1β (1 ng/ml, 2.3 fold, n = 5), LPS (100 µg/ml, 24 hours, 1.9 fold, n = 5) and by 1% hypoxia (1.3 fold, n = 3). Accordingly, basal PTPN2 protein expression was 2.0 fold higher in RASF than in OASF (n = 4) and TNFα upregulated levels of PTPN2 (1.7 fold). ptpn2-deficient RASF produced 2.4 times more IL-6 than scrambled siRNA transfected cells (mean ± SD pg/ml 11412 ± 6313 versus 28133 ± 12734, n = 3). On the other hand, levels of IL-8 were not affected (35800 pg/ml versus 24330 pg/ml, n = 3). Furthermore, after silencing, 34% increase in TRAIL-induced apoptosis was detected in RASF (n = 5) compared to scrambled controls. <h3>Conclusions</h3> Our findings indicate that PTPN2, known to be involved in the pathogenesis of several autoimmune diseases, could be an important negative regulator of inflammation in RASF. <h3>Acknowledgement</h3> This work was supported by IMI BTCure, IAR and Masterswitch-FP7.
ABSENCE OF CORONARY ARTERY CALCIUM IDENTIFIES ASYMPTOMATIC DIABETIC INDIVIDUALS AT LOW SHORT-TERM BUT NOT LONG-TERM RISK OF MORTALITY
Authors: Valentina Valenti, Bríain ó Hartaigh, Heidi Gransar, Iksung Cho, Joshua Schulman-Marcus, Ran Heo, Tracy Callister, Leslee Shaw, Joseph Knapper, Anita Kelkar, Pratik Sandesara, Fay Lin, Quynh Truong, James Min
Journal: Journal of the American College of Cardiology (2015)
Complete and Readily Reversible Blocking of Striatal DaTscan Binding by Methylphenidate
Authors: Gang Cheng, James F. Morley
Journal: Clinical Nuclear Medicine (2013)

An 80-year-old man with Parkinson disease underwent DaTscan imaging, which showed no detectable uptake in the basal ganglia but normal background uptake in other parts of the brain and in the chest and abdomen. It was later found that the patient was taking methylphenidate. The second study performed 3 weeks later after discontinuing methylphenidate for 48 hours showed good uptake in the striatum. Our results indicate that methylphenidate may completely block physiologic uptake of DaTscan in the striatum and that this effect can be effectively reversed after discontinuing the medication for a short period.
Abstract LB-387: MYCN dependence of tumor propagating cells in an orthotopic model of medulloblastoma
Authors: Zai Ahmad, Amy Moore, Karen Barker, Lynsey Vaughan, Sergey Popov, Andrew DJ Pearson, Louis Chesler
Journal: Cancer Research (2010)

Abstract Medulloblastoma (MB) is the most common paediatric brain tumor and is a major cause of cancer death in children. MYCN expression is critical to cerebellar development, regulates the fate of neural progenitor cells (NPCs) and drives the expansion of tumor propagating cells (TPCs) thought to represent the cell-of-origin for this disease. To examine the role of MYCN in MB tumorigenesis, we established neurosphere cell lines enriched for putative TPCs from the cerebella of GTML mice (transgenic for doxycycline-regulable overexpression of MYCN and luciferase). These mice are predisposed to anaplastic/large-cell MB (AACR abstract LB-79). Neurospheres derived from GTML cerebella with positive luciferase imaging signals but no visible tumor tissue exhibited several characteristics consistent with enrichment for TPCs and/or NPCs. Spheroids proliferated efficiently in the absence of exogenous growth factor, exhibited self-renewal in clonal dilution assays, expressed high levels of Mycn protein and the NPC markers nestin and SOX2, and in response to serum, differentiated along neuronal and glial lineages (increased GFAP and III tubulin expression by immunofluorescence). Finally, orthotopic reimplantation at low titer (&amp;lt;250 cells) recapitulated anaplastic/large-cell MB tumor formation with short latency (&amp;lt;14 days) and complete penetrance. Suppression of MYCN with doxycycline (confirmed by loss of luciferase imaging) caused growth arrest via a G1 blockade of neurospheres in vitro. Pretreatment of implanted spheres significantly reduced tumor penetrance (&amp;lt;60%) and increased latency (2-3 months). Efficient regression of established tumors was observed with concomitant loss of nestin expression and increases in differentiated glial and neuronal markers. Taken together, these data suggest that MYCN expression drives MB tumor formation by maintenance or expansion of a population of relatively undifferentiatedTPCs present in normal cerebella. This model represents a significant tool for further investigation of the role of MYCN in MB initiation and progression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 LB-387.
Common Inheritance of Susceptibility to Colonic Adenomatous Polyps and Associated Colorectal Cancers
Authors: Lisa A. Cannon-Albright, Mark H. Skolnick, D. Timothy Bishop, Randall G. Lee, Randall W. Burt
Journal: New England Journal of Medicine (1988)

We studied 670 persons in 34 kindreds by flexible proctosigmoidoscopic examination (60 cm) to determine how frequently colorectal adenomas and cancers result from an inherited susceptibility. Kindreds were selected through either a single person with an adenomatous polyp or a cluster of relatives with coIonic cancer. The kindreds all had common colorectal cancers, not the rare inherited conditions familial polyposis coli and nonpolyposis inherited colorectal cancer. Likelihood analysis strongly supported the dominant inheritance of a susceptibility to colorectal adenomas and cancers, with a gene frequency of 19 percent. According to the most likely genetic model, adenomatous polyps and colorectal cancers occur only in genetically susceptible persons; however, the 95 percent confidence interval for this proportion was 53 to 100 percent. These results suggest that an inherited susceptibility to colonic adenomatous polyps and colorectal cancer is common and that it is responsible for the majority of colonic neoplasms observed clinically. The results also reinforce suggestions that first-degree relatives of patients with colorectal cancer should be screened for colonic tumors. This evidence of an inherited susceptibility to a cancer with well-recognized environmental risk factors supports the hypothesis that genetic and environmental factors interact in the formation and transformation of polyps. (N Engl J Med 1988; 319:533–7.)
Circulating Immune Complexes and Complement Activation in Primary Biliary Cirrhosis
Authors: Jack R. Wands, Jules L. Dienstag, Atul K. Bhan, Edward R. Feller, Kurt J. Isselbacher
Journal: New England Journal of Medicine (1978)

We evaluated 20 patients with primary biliary cirrhosis and seven controls with extrahepatic biliary obstruction for presence of circulating immune complexes, having found serologic evidence of alternate complement-pathway activation in eight of the 20. Immune complexes were isolated by cryoprecipitation from serum and measured directly by the sensitive Raji-cell radioimmunoassay. Cryoproteins, found in high concentrations in 90 per cent of the patients with cirrhosis but undetectable in the controls, were composed of IgM (60 per cent), IgG-IgM (25 per cent) and IgA-IgM (5 per cent) and were capable of activating the complement system in vitro. Immune complexes detected by the Raji assay were found in 95 per cent of the patients with cirrhosis and circulated in exceedingly high concentrations (474 microgram per milliliter; range, 16.2 to 2192) but were absent in the controls. Furthermore, the alternate complement pathway was activated in eight cirrhotic patients. These complement-fixing immune complexes differ from immune complexes isolated from other types of liver diseases and may be important in the pathogenesis of primary biliary cirrhosis.