tbuckley/cabot-search huggingface dataset:
AB0227 PSGL-1 deficiency develops systemic sclerosis in mice
Authors: A. Urzainqui, A. Perez-Frias, R. Gonzalez-Tajuelo, N. Nuñez-Andrade, R. Tejedor, C. Muñoz-Calleja, S. Castañeda, E. Vicente, C. Gamallo, J. Fraga, A. García-Diez
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Previous studies in our lab have established that PSGL-1 signaling in human monocyte-derived dendritic (DC) cells induces a tolerogenic program that enables them to promote the differentiation of naïve T cells to T regulatory cells (Treg). We have also found that PSGL-1 modulates the immune inflammatory response in the murine enteric lamina propria, indicating that this adhesion receptor plays a role in the control of peripheral tolerance, acting as a tolerogenic receptor. <h3>Objectives</h3> To study the spontaneous disease developed in PSGL-1 deficient mice and and analyze its evolution with aging <h3>Methods</h3> Inmunological study of skin infiltrate, Serological analysis and histological studies of skin, lungs and kidney of C57/Bl6 WT and PSGL-1 deficient mice <h3>Results</h3> we have observed that 30% of PSGL-1 deficient mice at the age of 3 months present skin ulcers in their back that get more severe as the animals get older. The immunological studies show an inflammatory environment in the skin of the PSGL-1 KO mice, with activated and pro-inflammatory DC and macrophage populations, increased populations of granulocytes and B lymphocytes and increased Teff/Treg ratio. In addition, these animals cannot maintain the back legs extended, suggesting muscle weakness, and do not gain weight after the age of 1 year, probably due to intestinal absorption problems. The serum analysis shows the presence of connective tissue disease-related autoantibodies that accumulate as the mice get old. By histological studies we have found that the skin of PSGL-1 deficient mice is altered, with loss of the fat layer and thickening of the dermis by collagen accumulation, a major criterion supporting a diagnosis of Scleroderma. We have also found that the old PSGL-1 deficient mice have infiltrating leukocytes in the lungs and in the kidneys, indicating systemic autoimmune disease. <h3>Conclusions</h3> All these data indicate that PSGL-1 has an important role in maintaining the homeostasis of the immune system and controlling the development of systemic sclerosis <h3>Disclosure of Interest</h3> None Declared
SAT0539 Novel Bifunctional Inhibitors of Xanthine Oxidase and URAT1 Induce Profound Hypouricemia in Human Subjects:
Authors: R.P. Warrell, A. Klukovits, K. Barnes, C. Satyanarayana, C. Cheeseman, J. Piwinski
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> We have shown that a prototype anticancer drug (RLBN1001) induced marked hypouricemia in studies comprising &gt;350 human subjects. Preliminary exploration suggested dual effects on uric acid (UA) production and excretion. <h3>Objectives</h3> Given the unusual clinical potency, we sought to: (1) identify mechanism(s) of hypouricemia; (2) clarify structure-activity relationships (SARs) to targets of UA metabolism and genotoxicity; and (3) use these insights to develop analogs that would enhance the hypouricemic effects and eliminate genotoxic effects, thereby discovering potentially useful treatments for gout. <h3>Methods</h3> Clinical proof-of-concept (POC) was verified by examining biochemical effects in 50 human subjects treated with RLBN1001. Recursive chemical syntheses were then conducted by exploring SARs using four principal bioassays: renal UA transporters URAT1 (SLC2A22) and splice variants of GLUT9a/b (SLC2A9); xanthine oxidase (XO); and <i>in vitro</i> mouse micronucleus (MMN) assays (to detect genotoxicity). <h3>Results</h3> Over a 15-fold clinical dosing range with RLBN1001, nadir levels of hypouricemia (≤1.0 mg/dL) were not dose-related, indicating the minimal effective dose was below the lowest dose examined (100 mg/m<sup>2</sup>/d x 5d). At low and high doses, hypouricemia was associated with increased urinary excretion of both UA and total oxypurines. This drug was a potent inhibitor of URAT1 but not GLUT9a, a modest inhibitor of XO, and a potent clastogen in the MMN assay. We iteratively synthesized a library of novel analogs and identified new compounds that are potent inhibitors of both XO (i.e., 2-to-3 fold more potent than allopurinol) and URAT1 (5-to-45 fold more potent than lesinurad), but devoid of genotoxicity. One compound showed potent inhibition of GLUT9a, but other compounds showed minimal effects (data not shown). Data for reference and selected new compounds are shown in the table. <h3>Conclusions</h3> Having established compelling clinical POC with the RLBN1001 prototype, we have synthesized a series of unique compounds with strongly enhanced activities that both reduce UA production and enhance UA excretion. A lead compound is expected to enter clinical trials as a novel, potential first-line treatment for hyperuricemic patients with gout. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2265
Abstract 1316: N-acetyl-L-cysteine sensitizes pancreatic cancer therapy by targeting NFκB pathway: Translation into animal model
Authors: Suparna Qanungo, Joachim de Klerk Uys, Anne Distler, John J. Mieyal, John J. Lemasters, Danyelle M. Townsend, Anna-Liisa Nieminen
Journal: Cancer Research (2012)

Abstract Pancreatic cancer has the worst prognosis of all major cancers with 97% treatment failure. First-line systemic therapy for pancreatic cancer is the antimetabolite gemcitabine. Although, tumors may initially respond to the gemcitabine treatment, soon tumor resistance and excessive toxicity develops leading to treatment failure. Efforts to optimize and improve the efficacy of gemcitabine therapy through combination with other agents have little success. Previously, we demonstrated that N-acetyl-L-cysteine (NAC), a glutathione (GSH) precursor prevents NFκB activation and promotes pancreatic cancer cell death. The mechanism of inactivation of NFκB by NAC supplementation is a post-translational sulfhydryl modification called S-glutathionylation on p65-NFκB that inhibits its DNA-binding capacity and thus prevents activation of the survival genes. Mass spectrometric analysis indicated that four of the 9 cysteines of p65 are potentially S-glutathionylated. Our hypothesis is that chemoresistance against gemcitabine arises from a combination of hypoxia- and gemcitabine-induced NFκB activation. The objective of this study is to test the hypothesis and investigate if thiol donors like NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Here we determined the anti-tumor effect of gemcitabine and NAC on pancreatic tumors in mice. MIA PaCa-2 pancreatic cancer cells were injected into nude mice to grow subcutaneous tumors. Treatment groups were untreated, NAC, gemcitabine and gemcitabine+NAC. Results indicated that neither gemcitabine nor NAC by itself was effective in decreasing tumor growth. However, NAC and gemcitabine in combination inhibited tumor growth by 33%. Gemcitabine activates NFκB, although the mechanism for this phenomenon is unclear. NFκB activity was indeed increased in gemcitabine-treated tumors (3-fold) and combination with NAC treatment blunted this effect (p&amp;lt;0.005). The results confirm gemcitabine-induced NFκB activation and NAC bioavailability in tumors. To assess whether combined treatment of gemcitabine and NAC induces apoptosis, we performed TUNEL staining in tissues. Gemcitabine plus NAC increased apoptosis by 35-fold compared to gemcitabine alone. Taken together, our data suggest that NAC first inhibits NFκB activation arising from hypoxic regions of tumors and secondarily block gemcitabine-activated NFκB in hypoxic and normoxic regions of tumors, and therefore sensitizes cells to gemcitabine-induced killing. This could be used as an effective adjunct to gemcitabine chemotherapy of pancreatic cancer. 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 1316. doi:1538-7445.AM2012-1316
THU0094 Incidence and Predictors of Morphometric Vertebral Fractures in Patients with Ankylosing Spondylitis
Authors: K.Y. Kang, Y.S. Hong, S.-H. Park
Journal: Annals of the Rheumatic Diseases (2014)

Background Ankylosing spondylitis (AS) is associated with an increased incidence of vertebral fractures (VFs). Previous studies report the prevalence of morphometric VFs; however, the actual incidence and predictors of morphometric VFs in AS remains unclear. Objectives The present study examined the incidence and predictors of new VFs in a large AS cohort. Methods Two hundred and ninety-eight AS patients who fulfilled the modified New York criteria were enrolled and spinal radiographs were evaluated biennially. Clinical and laboratory data and radiographic progression were assessed according to the BASDAI, ESR, CRP, and the Stoke AS spine score (SASSS). VF was defined according to the Genant criteria. The incidence of VFs at 2 years and 4 years was evaluated using the Kaplan-Meier method. The age-specific standardized prevalence ratio (SPR) for AS patients in comparison with the general population was calculated. Results Of 298 patients, 31 (10.8%) had previous VFs at baseline. Thirty new VFs occurred in 26 patients over 4 years. The incidence of morphometric VFs was 4.7% at 2 years and 13.6% at 4 years. Multivariate logistic regression analysis showed that previous VFs at baseline and increased CRP levels at 2 years were predictors of new VFs (OR =12.8, 95% CI =3.6–45.3 and OR=5.4, 95% CI =1.4–15.9). The age-specific SPR of morphometric VFs in AS was 3.3 (95% CI 2.1–4.5). Conclusions The incidence of morphometric VFs increased in AS. Previous VFs and increased CRP levels predicted future VFs. An appropriate anti-inflammatory therapy may prevent the incidence of new VFs in AS patients with and without previous VFs. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2430
Abstract 4583: Multiplex mass spectrometric immunoassays
Authors: Dobrin Nedelkov
Journal: Cancer Research (2010)

Abstract Targeted proteomics approaches can facilitate the study of the human protein variations and their association with cancer. In Mass Spectrometric Immunoassays, affinity interactions are utilized to selectively retrieve specific proteins from complex biological fluids, and are followed by mass spectrometric analysis of the targeted proteins. These assays are similar to traditional enzyme immunoassays in that they use antibodies as reagents for affinity retrieval of specific proteins, but instead of enzymatic reaction for indirect protein detection, mass spectrometric analysis is used for direct identification of the proteins and their modifications. This rather straightforward concept is realized through affinity pipette devices that enable high-throughput integration and assaying of thousands of samples per day. Described here is the development of several multiplex mass spectrometric immunoassays toward cancer-related proteins. The project is part of the NCI's Clinical Proteomic Technologies for Cancer initiative to assess and apply proteomic technologies and data resources to solve critical problems in cancer research. Antibodies to several proteins (including one that serves as an internal reference standard - IRS) were immobilized in various ratios in the affinity pipettes, and following analysis of human plasma spiked with constant amount of the IRS, the ratio of the peaks representing the proteins were monitored to determine the optimal ratio of antibodies in the affinity pipettes. Detailed assaying protocols were developed and optimized, including pre-and post-sample rinses, and elution matrix composition. Increasingly-diluted plasma samples were analyzed and a decrease of the protein signals in reference to the IRS signal was observed, indicating non-saturating conditions for the assays. The assays were tested with numerous human plasma samples, and the intra- and inter-assay CVs were determined to be &amp;lt;10%. The results obtained with the MSIA assay were also compared to commercially available ELISA assays. The introduction of mass spectrometric-based assays and platforms into clinical laboratories will facilitate the ongoing biomarker discovery, evaluation, and validation efforts. The multiplex mass spectrometric immunoassays are idealy suited for analysis of protein biomarkers exhibiting post-translational modifications because this protein microheterogeneity can only be detected via mass spectrometry. It is important to note that the assays target intact/native proteins (in contrast to MRM-based peptide assays), and in such are capable of detecting any and all PTMs, without a priori knowledge of their existence. 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 4583.
Abstract 4108: SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival.
Authors: Shannon P. Fortin, Ian T. Mathews, Jonathan Rollo, Julianna T.D. Ross, Marc H. Symons, Jann N. Sarkaria, Nhan L. Tran
Journal: Cancer Research (2013)

Abstract Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and recur, invading brain tissue. Impaired response to treatment occurs rapidly conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance and spread in order to develop targeted therapies to combat this refractory setting. Our lab has previously published a role for the TWEAK-Fn14 ligand-receptor system in GB cell invasiveness and survival. Here we report that SGEF, a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and we hypothesize that SGEF plays an important role in promoting TWEAK-Fn14 mediated glioma invasion and survival. We show that upon TWEAK binding to Fn14, SGEF is recruited to the Fn14 cytoplasmic tail. The Fn14-SGEF interaction requires TRAF2 recruitment and leads to activation of Rac1. Importantly, SGEF mRNA expression is elevated in TMZ-resistant primary GB tumor grafts compared to those with known TMZ sensitivity. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-κB dependent manner and inhibition of SGEF expression via shRNA shutdown sensitizes glioma cells to TMZ-induced apoptosis and impairs colony formation following TMZ insult. Furthermore, gene expression analysis of SGEF depleted GB cells revealed impaired expression of a network of DNA repair and survival genes including ATM, ATR, BRCA2, and XIAP among others, as well as increased expression of the pro-apoptotic gene BAD. Understanding the role of SGEF in promoting chemotherapeutic resistance may direct the development of novel targeted therapeutics for TMZ refractory, invasive GB cells. Citation Format: Shannon P. Fortin, Ian T. Mathews, Jonathan Rollo, Julianna T.D. Ross, Marc H. Symons, Jann N. Sarkaria, Nhan L. Tran. SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival. [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 4108. doi:10.1158/1538-7445.AM2013-4108
THU0221 Pain Predicts Relatively Low Leg Muscle Mass in Knee Osteoarthritis: Table 1.
Authors: J.Y. Lee, J.H. Koh, Y.S. Suh, S.M. Jung, J.H. Lee, J. Lee, J.Y. Kang, J.-M. Kim, S.-K. Kwok, J.H. Ju, K.-S. Park, H.-Y. Kim, S.-H. Park
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Leg muscle mass is related to development and progression of knee OA, and some studies suggested low leg muscle mass quantified by cross-sectional images of CT or MRI was related to knee symptoms [1,2]. However, this direct method of quantification is hard to apply to clinical practices, and it can be affected by total body mass which can confound the relationship of leg muscle mass and knee symptoms. <h3>Objectives</h3> We sought to examine if the <i>ratio</i> of leg to whole body muscle or fat mass by DXA relates to knee symptoms in radiographic knee OA. <h3>Methods</h3> We performed a cross-sectional study using data from the Fifth Korean National Health and Nutrition Examination Survey. We included subjects with radiographic knee OA (Kellgren-Lawrence grade≥2) and obtained degree of symptoms, body composition of both legs and the whole body using DXA and calculated the ratios of leg to whole body for muscle and fat mass. Analysis of covariance and multivariable logistic regression models were used to examine the associations of leg to whole body mass with knee symptoms adjusting for possible confounders. <h3>Results</h3> 1664 subjects were eligible for analysis. The ratio of leg to whole body muscle mass (LTWBM) was significantly lower in the group with knee pain or stiffness (30.27±0.10 vs. 30.92±0.08, p&lt;0.0001) (Table 1). There was a significant inverse trend between degree of knee pain and LTWBM (p for trend&lt;0.01). LTWBM was 0.86 fold lower in subjects with severe pain (p=0.012, 95% CI 0.79 to 0.94) when adjusted for age and sex. Leg to whole body fat mass was higher in the group with knee pain or stiffness (28.65±0.22 vs. 27.95±0.17, p=0.009) (Table 1). <h3>Conclusions</h3> Symptomatic knee OA was associated with reduced leg muscle mass. Local sarcopenia indicated by low leg to whole body muscle mass could be an important and useful clinical marker for symptomatic knee OA. Strategies to increase leg muscle mass might counteract having symptomatic knee OA. <h3>References</h3> Sattler, M., et al., Side differences of thigh muscle cross-sectional areas and maximal isometric muscle force in bilateral knees with the same radiographic disease stage, but unilateral frequent pain - data from the osteoarthritis initiative. Osteoarthritis Cartilage, 2012. 20(6): p. 532-40. Wang, Y., et al., Increase in vastus medialis cross-sectional area is associated with reduced pain, cartilage loss, and joint replacement risk in knee osteoarthritis. Arthritis Rheum, 2012. 64(12): p. 3917-25. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2422
Abstract ADV05: From the golf course to education, outreach, and support for prostate cancer.
Authors: Egbert Brown
Journal: Cancer Research (2013)

Abstract Central Ohio Men Against Prostate Cancer (COMAPC) is a community-based, all volunteer, non-profit organization. Our mission is to increase prostate cancer awareness and routine screening through education, support, and advocacy across cultural and economic barriers. Our primary focus is to reduce disparities that exist in prostate cancer among minorities and the medically underserved. Prostate cancer is the second leading cause of cancer death in African American men. An estimated 35,110 cases of prostate cancer were expected to occur among African American men in 2011, accounting for 40% of all cancers diagnosed in African American men. It was estimated that 5,300 deaths from prostate cancer would occur in African American men in 2011. In addition, African American men have the highest mortality rate for prostate cancer of any racial or ethnic group in the United States with the death rate being 1 in 22 cases compared to 1 in 38 cases for white men. Our goal is to help Central Ohio men and their families become more informed about prostate cancer, better informed about treatment options for the disease and encourage men to seek early screening. COMAPC provides prostate cancer education, outreach and support for men, the friends and families of at-risk men and those diagnosed with prostate cancer. Our efforts help people connect with those resources so they become more aware of prostate cancer, better informed about treatment options, and support men to seek early screening for prostate cancer. Individual COMAPC board members actively participate in national service and advocacy initiatives such as the U. S. Army Research and Materials Command Prostate Cancer Research Program. American Association of Cancer Research Survivor&amp;lt;-&amp;gt;Advocate Program, US Too National Prostate Cancer Education and Support Team, National Association of African American Prostate Cancer Advocates, National Alliance of State Prostate Cancer Coalitions, American Cancer Society Cancer Action Network, We Work for Health-Ohio, and State and National Congressional Lobby Days. Citation Format: Egbert Brown. From the golf course to education, outreach, and support for prostate 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 ADV05. doi:10.1158/1538-7445.AM2013-ADV05
P157 DIFFERENTIAL TH17 PROFILE WITHIN THE PORTAL VEIN COMPARED TO SYSTEMIC CIRCULATION – A PROOF OF CONCEPT FOR DEFINING THE PORTAL VEIN AS A DISCRETE IMMUNOLOGICAL COMPARTMENT
Authors: T. Adar, S. Shteingart, Y. Edden, M. Mahamid, E. Broide, A. Bar-Gil Shitrit, E. Goldin
Journal: Journal of Hepatology (2014)
An Unusual Muscular Metastasis in a Patient Affected by Ileal Carcinoid Imaged With a 111In-Pentetreotide SPECT/CT Scan and Confirmed by Biopsy
Authors: Federico Caobelli, Francesco Bertagna, Maria Beatrice Panarotto, Barbara Paghera, Raffaele Giubbini
Journal: Clinical Nuclear Medicine (2011)

¹¹¹In-Pentetreotide SPECT/CT scan has been widely validated in diagnosis and follow-up of carcinoid and other neuroendocrine tumors. A 70-year-old man, who underwent an ileal resection for carcinoid 5 years ago, came to our observation during follow-up. We performed a In-DTPA-Pentetreotide (150 MBq) SPECT/CT scan. Images taken after 2 hours showed a focal, pathologic uptake on the left leg, confirmed at later acquisitions. Lateral projection showed that the uptake area was located in a leg muscle; the lesion was confirmed as an intramuscular metastasis by biopsy. Intramuscular metastasis of carcinoid tumors is an extremely rare manifestation, particularly if not adjacent to the primary tumor, because the muscle is a very uncommon location of hematogenous metastases.
Chemistry for Public Health Students.
Journal: JAMA (1920)

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