tbuckley/cabot-search huggingface dataset:
Abstract 959: Sulindac resistant colon tumors possess an altered molecular phenotype
Authors: Emily J. Greenspan, Frank C. Nichols, Daniel W. Rosenberg
Journal: Cancer Research (2010)

Abstract Although non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer (CRC), results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study we evaluated the effect of sulindac on colon tumorigenesis in the ApcMin/+ mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to ApcMin/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 vs. 1.6 tumors/mouse, respectively; P&amp;lt;0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. In the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 vs. 42.0 tumors/mouse, respectively; P&amp;lt;0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to have many non-COX targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins and PPARγ. Our goal was to determine whether alterations in these cellular mediators might be responsible for the observed increase in tumor multiplicity in the colon. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21WAF1/cip1 and PPARγ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for lack of response to sulindac. Together, these observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance. 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 959.
SP0075 The Multifaceted Role of Ubiquitination in Inflammation
Authors: R. Beyaert
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> The conjugation of ubiquitin to proteins is involved in the regulation of many processes. Although ubiquitination was initially identified as a signal that leads to proteasome-mediated degradation of the target protein, it has become clear that attachment of ubiquitin can lead to different outcomes depending on the type of this attachment. Aberrant ubiquitination promotes numerous disease states, but the mechanisms by which the ubiquitin system regulates cellular signaling and pathogenesis remain largely unknown. In this presentation I will highlight recent basic science advances in the field of ubiquitin research and the role of ubiquitination in cellular signaling, with a focus on enzymes and specific pathways related to arthritis. I will also discuss how deeper insights into the versatility of ubiquitination brings new excitement and hope for further successful drug development. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6301
SAT0213 Association of mannose-binding lectin gene polymorphisms with intima-media thickness (IMT) in primary antiphospholipid syndrome
Authors: A. Barrera-Cruz, A.M. Carmona-Becerril, Y.-M. Anguiano-Hernandez, C. Hernandez-Gonzalez, G. Medina-García, M. Saavedra-Salinas, M.I. Vega-Paredes, C. Gonzalez-Bonilla, L.J. Jara-Quezada
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Serum mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement with antimicrobial and anti-inflammatory actions. Several polymorphisms have been reported for the MBL2 gene. These variants are associated with low MBL serum concentration and are risk factors of infectious diseases, atherosclerosis and autoimmune diseases <sup>(1)</sup>.Systemic lupus erythematosus patients with associated antiphospholipid syndrome have a higher prevalence of MBL-deficient genotypes.<sup>(2)</sup>. Patients with primary antiphospholipid syndrome (PAPS) have carotid intima-media thickness, a marker of accelerated atherosclerosis. However, the role of MBL-deficient genotypes in PAPS is unclear. <h3>Objectives</h3> To investigate the prevalence of MBL-deficient genotypes in PAPS and its association with carotid intima-media thickness (IMT). <h3>Methods</h3> Blood samples were obtained from 48 patients with PAPS and matched with 111 healthy controls by age and gender, in a relation 1:2. Demographic, clinical data, cardiovascular risk factors and antibody profile were recorded. Total DNA was extracted from total blood with DNA isolation kit for mammalian blood (ROCHE). PCR-RFLP (Restriction Fragment Length Polymorphisms) reactions were performed on 50 ng of genomic DNA. MBL exon 1 PCR products were incubated with Mbo II, Ban I at 37°C, and Mwo I at 60°C for 1 h. MBL promoter gene region PCR products were incubated with Drd I and Btg I overnight at 37°C. The products were analyzed by electrophoresis using silver staining of polyacrylamide gel electrophoresis. Colour Doppler with high resolution B mode carotid ultrasonography was performed in patients to measure intima-media thickness (IMT). <b>Results:</b> <h3>Conclusions</h3> This study shows a high prevalence of MBL-deficient genotypes in the promotor region of the MBL2 gene (LX/LY, LXA/A) in patients with PAPS. However, MBL variant alleles were not significantly associated with carotid IMT. The accelerated atherosclerosis in PAPS could be consequence of genetic, immunological, and environmental risk factors. A prospective study is necessary in order to confirm these results. <h3>References</h3> Dommett R, et al. Tissue Antigens 2006;68:192-209. Font J, et al. Rheumatology 2007;46:76-80. <h3>Disclosure of Interest</h3> None Declared
VASCULAR HEALING RESPONSE OF CALCIFIED CORONARY LESIONS AFTER EVEROLIMUS ELUTING STENT IMPLANTATION: EVALUATION WITH OPTICAL COHERENCE TOMOGRAPHY
Authors: Yutaka Goryo, Shiro Uemura, Yoko Dote, Yu Sugawara, Tomoya Ueda, Makoto Watanabe, Yoshihiko Saito
Journal: Journal of the American College of Cardiology (2015)
Abstract 4532: Fluorine-18- carboplatin derivative for imaging and therapeutic applications.
Authors: Gajanan K. Dewkar, Purnima Jose, Narottam Lamichhane, Celina Thadigiri, Gobalakrishnan Sundaresan, Nicholas Farrell, Jamal Zweit
Journal: Cancer Research (2013)

Abstract DNA-damaging agents, such as cisplatin and other platinum drugs are the largest class of anti-cancer drugs. They are most important in the clinical use for the treatment of various cancers, although ovarian cancer cells often become resistant. Besides resistance, non-specific uptake in normal tissues and related toxicity is a dose limiting factor and affects their overall effectiveness. Knowledge of the drug concentration in the tumor as well as its overall concentration in the body of a patient will be helpful in accurately predicting the overall responsiveness of a patient to the drug. This type of knowledge can be accomplished by the development of a drug analog with positron emission tomography (PET) imaging capability, so that the accumulation of the drug in the tumor and normal organs can be tracked and quantified during the course of therapy to predict its effectiveness in a patient. Therefore, we developed a novel fluorinated carboplatin derivative, towards a hybrid agent for imaging and therapy. We synthesized 19F fluorinated carboplatin derivative using 2-(5-fluoro-pentyl)-2-methyl malonic acid by co-ordination with cis-platinum aqua complex. It was then used to treat various cell lines and compared with Cis-platin and Carboplatin at different concentrations ranging from 0.001 μM to 100 μM for 72 hrs and 96 hrs. LC50 values calculated from cell viability indicate that fluorinated carboplatin is a more potent drug than Carboplatin but less effective than Cisplatin. Table 1: LC50 values of fluorinated carboplatin and known platinum drugs Cell line Cisplatin (μM) Carboplatin(μM) Fluorinated Carboplatin (μM) 72 hrs 96 hrs 72 hrs 96 hrs 72 hrs 96 hrs COLO 205 28.78 1.35 &amp;gt;100 48.98 92.52 31.56 SK-OV-3 4.34 1.28 33.7 18.94 20.3 12.56 FaDu 2.77 &amp;lt;2 34.72 11.26 21.54 8.55 A549 11.01 3.07 56.56 31.78 41.18 24.8 A498 13.35 3.42 152.83 39.34 57.25 18.5 LNCaP 19.2 7.18 113.51 63.4 80.09 46.06 RWPE-1 6.27 &amp;lt;1 65.19 36.8 34.69 10.2 KB 3-1 4.13 2.04 59.82 26.08 22.76 13.46 We have also developed a microfluidic method to synthesize [18F]-2-(5-fluoro-pentyl)-2-methyl malonic acid, which will co-ordinate with cis-platinum aqua complex to yield 18F labeled carboplatin derivative. Our approach to synthesis various derivatives of 18F labeled fluorinated carboplatin will allow us to develop anticancer drugs with PET imaging capabilities. Citation Format: Gajanan K. Dewkar, Purnima Jose, Narottam Lamichhane, Celina Thadigiri, Gobalakrishnan Sundaresan, Nicholas Farrell, Jamal Zweit. Fluorine-18- carboplatin derivative for imaging and therapeutic applications. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4532. doi:10.1158/1538-7445.AM2013-4532
AB0543 Systemic Manifestations in the Primary SjÖGren's Syndrome: about 31 Cases
Authors: R. Hajji, C. Eya, D. Fatma, B.H. Lamia, K. Chakib
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Primary Sjögren9s syndrome (pSS) is a systemic disorder characterized by lymphocytic infiltration and progressivedestruction of exocrine glands. The inflammatory process extends beyond the exocrine glands and can potentially affect any organ.pSS patients may develop a large number of systemic manifestations including neurological, renal, pulmonary and hematologicalmanifestations. While sicca features primarily affect the quality of life and cause local complications in the mucosa involved,systemic involvement marks the disease prognosis. <h3>Objectives</h3> The goal of this work is to study the demographic, clinical, serologic features and outcomes of Tunisian patients withpSS. <h3>Methods</h3> It is a single-center retrospective study including all the cases of pSS diagnosed since 1998 until 2011 in InternalMedicine Department from Tunis in Tunisia. All the patients fulfilled the 2002 American-European Consensus Group (AECG)criteria for pSS. <h3>Results</h3> The study include 31 patients: 4 men and 27 women. The age average was 51 years. Dryness of the mouth and eyes wasobserved in all the cases. Immunological assays showed that the anti-SSA and anti-SSB antibodies were both positive in 96% ofpatients. Extra-glandular manifestations were found in 87% of cases, revealing the disease in 77% of patients. In 45% of pSS cases,the Sjögren9s syndrome was revealed only by systemic manifestations without any glandular symptom.Musculoskeletal manifestations, were the most frequent, observed in 67% of the cases. Leucocytoclastic vasculitis and neurologicalinvolvement was noted in 23% of patients each one. Raynaud9s phenomenon was observed in 13% of cases as was the pulmonaryinvolvement. Interstitial nephritis was diagnosed in 3 patients. Hematological manifestations were marked by autoimmune hemolyticanemia in 3 cases and thrombotic thrombocytopenic purpura (TTP) in one case.Corticosteroids were given in 10 of our patients. Non-steroidal anti-inflammatory drugs (NSAID) were used for 12 patients andantimalarial for 3 cases.The disease outcomes was marked by good evolution. But, malignant lymphoma occurs in a woman after 40 months of primary Sjögren9s syndrome past history. <h3>Conclusions</h3> During the pSS, the most common clinical manifestation is mouth and eyes dryness. But glandular manifestations arenot always in the foreground. pSS has no one specific clinical or biological sign that makes it diagnosis easy. Clinicians should notignore this condition. Because it displays the highest incidence of malignant lymphoproliferative disorders among autoimmunediseases, pSS should be diagnosed as early as possible. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4674
AB0625 Prevalence of post menopausal osteoporosis in patients with rheumatoid arthritis undergoing lower limb arthroplasty
Authors: S. Waliullah, V. Sharma, A. Kumar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid disorder is a common systemic disorder that causes joint destruction and frequently require joint replacement surgery. Osteoporosis is a recongnize complication of rheumatoid arthritis. Osteoporosis can affect the final outcome of any joint replacement surgery, if not diagnose and treated early. <h3>Objectives</h3> We have evaluated prevalence of post menopausal osteoporosis in Post menopausal female patients with Rheumatoid disorder awaiting for lower limb joint replacement surgery. <h3>Methods</h3> 87 patients, after satisfying inclusion and exclusion criterias, were enrolled in our study and bone mineral density was assessed by Dual Energy X-ray Absorptiometry (DEXA) scan and classified as per World Health Organisation classification. The logistic regression and multivariate analysis were used to find out the risk factors associated with osteoporosis in post menopausal female patients with rheumatoid arthritis. <h3>Results</h3> The overall rate of osteoporosis at any site was 39% and a further 41% of patients found to osteopaenic as per World Health Organization criteria. Significant risk factors associated with post menopausal osteoporosis in our study are Age, Body mass index, Onset of arthritis at younger age, History of prior fracture, Long term steroid intake and Co-morbidities. <h3>Conclusions</h3> High prevalence of osteoporosis found in our study suggests, BMD testing in post menopausal women should be made in patient undergoing arthroplasty surgery, to achieve successful functional outcome of arthroplasty surgery. <h3>Disclosure of Interest</h3> None Declared
LONG-TERM OUTCOMES OF PEDIATRIC CARDIAC PATIENTS SUPPORTED BY EXTRACORPOREAL MEMBRANE OXYGENATION
Authors: Matthew D. Elias, Barbara-Jo Achuff, Richard F. Ittenbach, Chitra Ravishankar, Thomas L. Spray, Stephanie Fuller, Lisa M. Montenegro, J. William Gaynor, Matthew J. O’Connor
Journal: Journal of the American College of Cardiology (2016)
FRI0168 Comprehensive Analysis of the Oral Microbiome in Axial Spondyloarthritis Reveals Associations with Disease Activity and Periodontitis: Table 1.
Authors: J.E. Bisanz, P. Suppiah, M. Thomson, T. Milne, N. Yeoh, A. Nolan, G. Ettinger, G. Reid, G.B. Gloor, J. Burton, M. Cullinan, S. Stebbings
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> A wealth of data supports a role for the microbiome in the pathogenesis of spondyloarthtritis (SpA). To date, studies have concentrated on the intestinal tract, which harbours the largest and most diverse microbiota. However, the oral microbiota is also notable in its diversity and has recently been the focus of interest as a potential factor in the pathogenesis of rheumatoid arthritis. Recent studies have demonstrated a higher prevalence of periodontitis in patients with ankylosing spondylitis, raising the possibility that exposure to the oral microbiome through a compromised mucosal barrier may be a factor in the pathogenesis of SpA. <h3>Objectives</h3> To investigate the oral cavity as a site of chronic inflammation in axial spondyloarthritis (AxSpA) and to compare profiles of microbial communities which colonise the oral cavity in health and AxSpA. <h3>Methods</h3> Thirty nine participants, 17 with AxSpA and 22 age and gender matched, disease free controls, were recruited. Disease activity in patients with AxSpA was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and CRP. All participants underwent a detailed dental examination including assessment of probing pocket depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), plaque index, oral mucosal conditions, and caries status. Plaque samples were obtained and their bacterial populations were profiled using Ion Torrent sequencing of the V6 region of the 16S rRNA gene. <h3>Results</h3> Patients with AxSpA had active disease (BASDAI Mean ± SD 4.1±2.1) and had significantly greater prevalence of both periodontitis (PPD≥4mm at ≥4 sites) and a higher plaque index than controls (P=0.008 and P=0.006 respectively). Analysis of bacterial communities showed no difference between AxSpA patients and healthy controls, either in their overall within sample organism diversity or in community structure between groups. However, analysis at the level of operational taxonomic units (OTU) demonstrated a significant association between AxSpA and several bacteria including <i>Campylobacter spp.</i> and <i>Actinomycetes spp</i>. Additionally, certain OTUs were present in higher relative abundances in patients with active AxSpA (see Table). <h3>Conclusions</h3> Patients with AxSpA have a higher prevalence of periodontitis. Analysis of plaque communities suggests that certain bacteria are more prevalent in the periodontal tissues of patients with AxSpA and associates with active disease. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3406
Abstract 1783: Trifluorothymidine incorporation into DNA strongly enforces the potential of TAS-102 and leads to remarkably prolonged survival of cancer patients
Authors: Nozomu Tanaka, Kei Oguchi, Ryoto Fujita, Takamasa Suzuki, Keisuke Yamamura, Akio Fujioka, Hiroyuki Okabe, Kazuharu Noguchi
Journal: Cancer Research (2012)

Abstract TAS-102 is a novel oral antitumor agent, consisting of trifluorothymidine (FTD) as the active component and thymidine phosphorylase inhibitor (TPI) which prevents degradation of FTD. In a double-blind randomized phase II study conducted in Japan, TAS-102 significantly improved overall survival of metastatic colorectal cancer patients, compared with placebo (TAS-102, n = 112; Placebo, n = 57; median OS, 9.0 vs. 6.6 months; HR, 0.56; p = 0.001). We investigated mechanisms of action of TAS-102 to understand how prognosis of cancer patients was improved. In vitro study, FTD was previously reported to have two mechanisms, FTD incorporation into DNA and thymidylate synthase (TS) inhibition. In this study, we show that FTD incorporation into DNA is the main mechanism of TAS-102 and the key to potentiate anti-tumor efficacy of FTD. We found that although TS inhibition of FTD reduced rapidly after drug removal, the cytotoxicity of FTD did not diminish. On the other hand, the cytotoxicity of FdUrd diminished after drug removal. As compared to FdUrd, FTD was incorporated into DNA to a greater extent by the time drug was removed. It is thought that the FTD retained in DNA contributes to sustained growth inhibition. Therefore, FTD incorporation into DNA is considered to be essential for enforcing the potential of FTD. Additionally, we investigated the in vivo potency of TAS-102 by using daily divided oral administration since this regimen was the most optimal to maximize FTD incorporation into DNA. Interestingly, TAS-102 showed marked tumor growth delay even after end of the administration and remarkable prolonged survival of mice implanted with KM20C derived from human colon cancer. Collectively, these data suggest that TAS-102 improved survival of cancer patients primarily due to FTD incorporation into DNA. FTD is previously reported to affect DNA structure, and we speculate that TAS-102 exerts its anti-tumor effects through interfering with DNA function once adequate amounts of FTD have been accumulated in the DNA. 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 1783. doi:1538-7445.AM2012-1783
Osteoporosis in Women with Anorexia Nervosa
Authors: Nancy A. Rigotti, Samuel R. Nussbaum, David B. Herzog, Robert M. Neer
Journal: New England Journal of Medicine (1984)

Because estrogen deficiency predisposes to osteoporosis, we assessed the skeletal mass of women with anorexia nervosa, using direct photon absorptiometry to measure radial bone density in 18 anorectic women and 28 normal controls. The patients with anorexia had significantly reduced mean bone density as compared with the controls (0.64 +/- 0.06 vs. 0.72 +/- 0.04 g per square centimeter, P less than 0.001). Vertebral compression fractures developed in two patients, and bone biopsy in one of them demonstrated osteoporosis. Bone density in the patients was not related to the estradiol level (r = 0.02). Levels of parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal despite low calcium intakes. The patients with anorexia who reported a high physical activity level had a greater bone density than the patients who were less active (P less than 0.001); this difference could not be accounted for by differences in age, relative weight, duration of illness, or serum estradiol levels. The bone density of physically active patients did not differ from that of active or sedentary controls. We conclude that women with anorexia nervosa have a reduced bone mass due to osteoporosis, but that a high level of physical activity may protect their skeletons.
Abstract 3966: Development of a fully-human chimeric antigen receptor against PSCA for the treatment of pancreatic cancer.
Authors: Daniel Abate-Daga, Kiran H. Lagisetty, Luca Gattinoni, Zhiya Yu, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan
Journal: Cancer Research (2013)

Abstract Pancreatic cancer represents the fourth leading cause of cancer-related death in developed countries. Despite remarkable advances in the understanding of its molecular pathophysiology, treatment options remain scarce, highlighting the need for novel therapies. Adoptive cell transfer (ACT) of lymphocytes engineered ex vivo to express chimeric antigen receptors (CAR) has come of age as a safe and clinically efficacious treatment for advanced cancers. We sought to develop a CAR specific for prostate stem cell antigen (PSCA), a glycoprotein with restricted expression in normal tissues that is over-expressed in pancreatic cancer cells starting at early stages of malignant transformation. In order to establish the optimal CAR design, we generated constructs containing antigen-recognition domains derived from mouse or human antibodies, and intracellular domains containing one or two co-stimulatory domains, in addition to CD3zeta. We compared multiple constructs and found that a CAR based on human monoclonal antibody Ha1-4.117 had greater reactivity in vitro. Using a murine model of ACT we observed that CAR-engineered human lymphocytes induced an antitumor effect on HPAC xenografts. Interestingly, unlike what has been described for other CARs, a second generation PSCA CAR (containing CD28 signaling domain) induced a more potent antitumor effect than its third generation counterpart (containing CD28 and 41BB domains). Our results provide evidence to support PSCA as a target antigen for immunotherapy of pancreatic cancer, using adoptively transferred autologous lymphocytes engineered to express an Ha1-4.117-based CAR. Citation Format: Daniel Abate-Daga, Kiran H. Lagisetty, Luca Gattinoni, Zhiya Yu, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan. Development of a fully-human chimeric antigen receptor against PSCA for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3966. doi:10.1158/1538-7445.AM2013-3966