tbuckley/cabot-search huggingface dataset:
Abstract 3546: Cucurbitacin B as a direct mTOR inhibitor synergizes with methotrexate for treatment of human osteosarcoma
Authors: Dhong Hyun Tony Lee, Nils Thoennissen, Catherine Goff, Gabriela Iwanski, Ngan Doan, Jonathan Said, H. Phillip Koeffler
Journal: Cancer Research (2011)

Abstract The mammalian target of rapamycin (mTOR) pathway is one of the most important oncogenic pathways in cancer, and the upregulation of the mTOR pathway is frequently observed in human osteosarcoma (OS). In this study, we demonstrated for the first time that cucurbitacin B, a plant-derived tetracyclic triterpenoid, is a direct mTOR inhibitor in OS using drug affinity responsive target stability (DARTS) analysis. Binding of cucurbitacin B to mTOR resulted in the inhibition of mTOR phosphorylation in MG-63 and SAOS-2 human OS cells in vitro, which was further confirmed by the inhibition of ribosomal S6 protein kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). This finding led us to hypothesize the possible use of cucurbitacin B as a single agent as well as in combination with methotrexate (MTX) for OS treatment. Cucurbitacin B in combination with MTX synergistically inhibited OS cell growth in vitro such that combination index (CI) &amp;lt; 0.9. Murine xenografts treated with either low-dose cucurbitacin B (LD-CuB, 0.5 mg/kg body weight) or low-dose MTX (LD-MTX, 150 mg/kg) alone failed to decrease tumor size. However, combined therapy at identical concentrations inhibited tumor growth by 62% vs LD-CuB and 81% vs LD-MTX (p&amp;lt;0.001). The effect persisted even at a two-thirds decrease (50 mg/kg) in the MTX dose. In conclusion, cucurbitacin B is a direct inhibitor of mTOR, and the combined use of cucurbitacin B with MTX showed promising antiproliferative activity against human OS. The use of this combination should be explored further in clinical studies. 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 3546. doi:10.1158/1538-7445.AM2011-3546
THU0429 Which diagnosis in case of positivity of anti-CCP in rheumatological daily practice? Evaluation of the performances of anti-CCP in 517 consecutive patients
Authors: L. Bialé, C. Goulvestre, N. Kavian, M. Dougados
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The performances of the anti-CCP have been evaluated in well defined cohorts of patients and controls but their relevance in rheumatological daily practice is less known in case of positivity of the results in patients not fulfilling the diagnostic criteria for rheumatoid arthritis (RA). <h3>Objectives</h3> To evaluate the performances (sensitivity (Se), specificity (Sp) but also positive and negative predictive values (PPV, NPV)) of anti-CCP test and to check the diagnosis of the underlying disease of patients with positive anti-CCP and not fulfilling the diagnosis of RA. <h3>Methods</h3> Study design: retrospective systematic evaluation of the diagnosis of patients who have been investigated for anti-CCP test (second generation) between December 2009 and December 2011. Data collected: anti-CCP results in the department of immuno-biology of Cochin Hospital and diagnosis of the evaluated patients (according to medical file record). <h3>Results</h3> Of the 634 evaluated samples, 74 were double (at least 2 evaluations in a same patient), no medical file was available for 28 samples and a diagnosis was not made in 15 patients, resulting in 517 evaluable patients. Anti-CCP was positive in 153 of the 222 RA patients, resulting in a sensitivity of 68,9%. Anti-CCP was negative in 282 of the 295 other patients, resulting in a specificity of 95,6%. PPV and NPV were respectively 92,2% and 80,3%. The 13 non-RA patients with positive anti-CCP were suffered from either undifferentiated monoarthritis (2 cases), Sjögren's syndrome (2 cases), osteoarthritis, systemic lupus erythematosus with Sjögren's syndrome (2 cases), juvenile idiopathic arthritis, mixed connective tissue disease, psoriatic arthritis (2 cases) or SAPHO. These 13 patients had a value of anti-CCP between one and three times the upper limit of normal (ULN) in 2 cases and over three times ULN in 11 cases. <h3>Conclusions</h3> These data confirm the high sensitivity of anti-CCP in rheumatological setting, more importantly confirm also its high specificity and suggests than despite the high performances of this test, false positive and false negative results can be observed in daily practice. Non-RA anti-CCP positive patients can have anti-CCP values over ten times ULN. <h3>Disclosure of Interest</h3> None Declared
CD1d-restricted peripheral T cell lymphoma in mice and humans
Authors: Emmanuel Bachy, Mirjam Urb, Shilpi Chandra, Rémy Robinot, Gabriel Bricard, Simon de Bernard, Alexandra Traverse-Glehen, Sophie Gazzo, Olivier Blond, Archana Khurana, Lucile Baseggio, Tayla Heavican, Martine Ffrench, Giuliano Crispatzu, Paul Mondière, Alexandra Schrader, Morgan Taillardet, Olivier Thaunat, Nadine Martin, Stéphane Dalle, Magali Le Garff-Tavernier, Gilles Salles, Joel Lachuer, Olivier Hermine, Vahid Asnafi, Mikael Roussel, Thierry Lamy, Marco Herling, Javeed Iqbal, Laurent Buffat, Patrice N. Marche, Philippe Gaulard, Mitchell Kronenberg, Thierry Defrance, Laurent Genestier
Journal: The Journal of Experimental Medicine (2016)

Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells. PTCLs showed phenotypic features of activated NKT cells, such as PD-1 up-regulation and loss of NK1.1 expression. Injections of heat-killed Streptococcus pneumonia, known to express glycolipid antigens activating NKT cells, increased the incidence of these PTCLs, whereas Escherichia coli injection did not. Gene expression profile analyses indicated a significant down-regulation of genes in the TCR signaling pathway in PTCL, a common feature of chronically activated T cells. Targeting TCR signaling pathway in lymphoma cells, either with cyclosporine A or anti-CD1d blocking antibody, prolonged mice survival. Importantly, we identified human CD1d-restricted lymphoma cells within Vδ1 TCR-expressing PTCL. These results define a new subtype of PTCL and pave the way for the development of blocking anti-CD1d antibody for therapeutic purposes in humans.
P230 OPTIMISATION OF A NEXT-GENERATION SEQUENCING PIPELINE FOR THE ANALYSIS OF THE HEPATITIS C VIRUS GENOME FROM HISTORICAL FORMALIN-FIXED PARAFFIN-EMBEDDED LIVER BIOPSIES
Authors: T. Klymenko, V.B. Sreenu, B. Nicolet, E. Deuchars, T. Abdelrahman, A. Lockhart, E.C. Thomson
Journal: Journal of Hepatology (2014)
Epidemic Erythema Infectiosum
Authors: Ernest A. Ager, Tom D. Y. Chin, Jack D. Poland
Journal: New England Journal of Medicine (1966)

ERYTHEMA infectiosum is an apparently benign exanthematous disease commonly occurring in somewhat localized epidemics during the winter and spring months. The viral etiology has been assumed but never proved and although the clinical features have been described in several papers, knowledge concerning transmission, length of incubation period and possible sequelae remains incomplete. The number of reports of series of cases and epidemics that have appeared in the literature suggests that the disease may be much more common than usual sources of morbidity data indicate. The disease was first described in 1889 by Tschamer,1 who thought it to represent a localized . . .
A Reversible Posterior Leukoencephalopathy Syndrome
Authors: Judy Hinchey, Claudia Chaves, Barbara Appignani, Joan Breen, Linda Pao, Annabel Wang, Michael S. Pessin, Catherine Lamy, Jean-Louis Mas, Louis R. Caplan
Journal: New England Journal of Medicine (1996)

In some patients who are hospitalized for acute illness, we have noted a reversible syndrome of headache, altered mental functioning, seizures, and loss of vision associated with findings indicating predominantly posterior leukoencephalopathy on imaging studies. To elucidate this syndrome, we searched the log books listing computed tomographic (CT) and magnetic resonance imaging (MRI) studies performed at the New England Medical Center in Boston and Hôpital Sainte Anne in Paris; we found 15 such patients who were evaluated from 1988 through 1994.
Endoscopic mucosal resection of a mid-esophageal carcinoid with EUS guidance
Authors: J. Babich, J. Klein, P. Khullar, D. Friedel
Journal: Endoscopy (2010)

A 58-year-old woman with a longstanding history of panhypopituitarism necessitating hydrocortisone and levothyroxine supplementation underwent upper endoscopy because of heartburn, and an esophageal submucosal lesion was detected. Surface biopsies were normal.
AB0680 Baseline Characteristic of Newly Diagnosed Patients with Axial Spondyloarthritis: First Results from the Russian Cohort:
Authors: A.G. Bochkova, E. Gubar, O. Rumyantceva, T. Dubinina, S. Schubin, E. Tukchova, A. Smirnov, S. Erdes, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Application of the new ASAS classification criteria for axial SpA has allowed defining a broader spectrum of SpA patients, ranging from non-radiographic axial SpA (nr-axSpA) to classic ankylosing spondylitis (AS) according to modified New York criteria. <h3>Objectives</h3> The present study describes the baseline characteristics of axial SpA patients presented for the first time in our department. <h3>Methods</h3> The Moscow Institute of Rheumatology in 2012 year began to collect new cohort of patients with axial and peripheral SpA, according to the ASAS criteria (duration of back pain less than 5 years): at present 80 patients have been included. <h3>Results</h3> Baseline characteristics of 73 newly diagnosed patients with axial SpA are reported (33 men, 40 women). Symptom duration varied from 3 month to 5 years (median: 19.9 month. Mean age was 28.3 years. All patients suffered from chronic back pain which started before 45 years; inflammatory back pain, defined by ASAS criteria was present in 80%. 90.4% of the patients were HLA-B27 positive and active inflammatory lesions on MRI were found in 85% patients: 72.6% - in sacro-iliac joints (SIJ), 11% - in lumbar spine, 28,7% - in the hip. Forty eight percent of the patients showed definite radiographic sacroiliitis according to modified New York criteria at first presentation. Symptom duration was comparable between the nr-axSpA and the AS groups. The female/male rate was reliably higher in nr-axSpA (24/13) versus AS (12/24), p=0.017. High CRP was reliably more frequently in AS patients. p=0.019. HLA-B27 positive and inflammatory parameters were equally present in both groups. Extra-articular manifestations were higher in the nr-axSpA group. <h3>Conclusions</h3> We found high frequency of AS in newly diagnosed patients with early9s axial SpA (48%) with comparable symptom duration. The nr-axSpA was observed more frequent in the women. The prevalence of extra-articular manifestations was low and they were only indicated in patients with nr-axSpA. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2384
Association between Lifetime Exposure to Inorganic Arsenic in Drinking Water and Coronary Heart Disease in Colorado Residents
Authors: Katherine A. James, Tim Byers, John E. Hokanson, Jaymie R. Meliker, Gary O. Zerbe, Julie A. Marshall
Journal: Environmental Health Perspectives (2014)

Background: Chronic diseases, including coronary heart disease (CHD), have been associated with ingestion of drinking water with high levels of inorganic arsenic (> 1,000 μg/L). However, associations have been inconclusive in populations with lower levels (< 100 μg/L) of inorganic arsenic exposure.Objectives: We conducted a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of CHD.Methods: This study included 555 participants with 96 CHD events diagnosed between 1984 and 1998 for which individual lifetime arsenic exposure estimates were determined using data from structured interviews and secondary data sources to determine lifetime residence, which was linked to a geospatial model of arsenic concentrations in drinking water. These lifetime arsenic exposure estimates were correlated with historically collected urinary arsenic concentrations. A Cox proportional-hazards model with time-dependent CHD risk factors was used to assess the association between time-weighted average (TWA) lifetime exposure to low-level inorganic arsenic in drinking water and incident CHD.Results: We estimated a positive association between low-level inorganic arsenic exposure and CHD risk [hazard ratio (HR): = 1.38, 95% CI: 1.09, 1.78] per 15 μg/L while adjusting for age, sex, first-degree family history of CHD, and serum low-density lipoprotein levels. The risk of CHD increased monotonically with increasing TWAs for inorganic arsenic exposure in water relative to < 20 μg/L (HR = 1.2, 95% CI: 0.6, 2.2 for 20–30 μg/L; HR = 2.2; 95% CI: 1.2, 4.0 for 30–45 μg/L; and HR = 3, 95% CI: 1.1, 9.1 for 45–88 μg/L).Conclusions: Lifetime exposure to low-level inorganic arsenic in drinking water was associated with increased risk for CHD in this population.Citation: James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA. 2015. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134; http://dx.doi.org/10.1289/ehp.1307839
Abstract SY03-01: Revealing new metabolic networks in cancer
Authors: Eyal Gottlieb
Journal: Cancer Research (2012)

Abstract The extent to which metabolism plays a role in tumorigenesis cannot be overstated and drugs that selectively target these processes are likely to at least delay, if not halt tumour progression. Our work utilizes analytical chemistry and system biology approaches to study metabolic transformation. We investigated cells deficient in the mitochondrial tumour suppressor fumarate hydratase (FH) and using extensive metabolomics data we applied a computer model, generated to study their unique metabolome. We identified several important metabolic pathways which are specific and crucial for the survival of cancer cells deficient in FH. These include the heme biosynthesis and degradation pathway as well as mechanisms of alleviating the tricarboxylic acid (TCA) cycle carbon stress. These technologies are not only important for understanding the basic biochemistry of cancer cells but they can inform us on future clinical management of cancer and may lead to new therapeutic approaches to target cancer-specific metabolic pathways. 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 SY03-01. doi:1538-7445.AM2012-SY03-01
Abstract 4789: Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics study of a thyroid hormone-regulated secretome in human hepatoma cells
Authors: Cheng Yi Chen, I-Hsiao Chung, Kwang-Huei Lin
Journal: Cancer Research (2012)

Abstract The thyroid hormone, 3, 3′, 5-triiodo-L-thyronine (T3), regulates cell growth, development, differentiation, and metabolism via interactions with thyroid hormone receptors (TR). However, the secreted proteins that are regulated by T3 are yet to be characterized. In this study, we used the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture (SILAC) coupled with nano-LC-MS/MS performed on a LTQ-Orbitrap instrument to identify and characterize the T3-regulated proteins secreted in human hepatocellular carcinoma cell lines overexpressing TRα1 (HepG2-TRα1). In total, 1742 and 1714 proteins were identified and quantified, respectively, in three independent experiments. Among these, 61 upregulated two-fold and 11 downregulated two-fold proteins were identified. Eight proteins displaying increased expression and one with decreased expression in conditioned media were validated using Western blotting. Real-time quantitative RT-PCR further disclosed induction of plasminogen activator inhibitor-1 (PAI-1), a T3 target, in a time-course and dose-dependent manner. Serial deletions of the PAI-1 promoter region and subsequent chromatin immunoprecipitation assays revealed that the thyroid hormone response element on the promoter is localized at positions –327/-312. PAI-1 overexpression enhanced tumor growth and migration in a manner similar to what was seen when T3 induced PAI-1 expression in J7-TRα1 cells, both in vitro and in vivo. An in vitro neutralizing assay further supported a crucial role of secreted PAI-1 in T3/TR-regulated cell migration. To our knowledge, these results demonstrate for the first time that proteins involved in the urokinase plasminogen activator system, including PAI-1, uPAR and BSSP4, are augmented in the extra- and intracellular space of T3-treated HepG2-TRα1 cells. The T3-regulated secretome generated in the current study may provide an opportunity to establish the mechanisms underlying T3-associated tumor progression and prognosis. 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 4789. doi:1538-7445.AM2012-4789
Abstract 3589: Characterization of 17-dihydroexemestane glucuronidation. A role for the UGT2B17 deletion in exemestane pharmacogenetics
Authors: Dongxiao Sun, Gang Chen, Ryan W. Dellinger, Arun K. Sharma, Philip Lazarus
Journal: Cancer Research (2010)

Abstract Exemestane is a 3rd-generation aromatase inhibitor (AI) used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to hydroexemestane-17-O-glucuronide is a major pathway for exemestane metabolism. In the present study, homogenates from a newly-developed HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine the activity of exemestane versus 17-dihydroexemestane in vitro. 17-dihydroexemestane exhibited an inhibition of estrone formation in HEK293-aro cell homogenates (IC50=2.3±0.83 μM) that was similar to that observed for exemestane (IC50=1.4±0.42 μM). UGT-overexpressing cell lines were screened for activity against 17-dihydroexemestane and UGTs 2B17&amp;gt;1A10&amp;gt;1A8&amp;gt;1A4 were the only UGTs that exhibited activity. Of the hepatic UGTs, UGT2B17 exhibited a 17-fold higher Vmax/KM than UGT1A4. In human liver microsome (HLM) specimens, the rate of hydroexemestane-17-O-glucuronide formation using 17-dihydroexemestane as substrate was shown to be significantly (p&amp;lt;0.001) decreased (14-fold) in HLMs from subjects with the UGT2B17 (0/0) deletion genotype as compared with HLMs from subjects wild type (+/+) for UGT2B17. A significant (r2=0.72) correlation was observed between HLM hydroexemestane-17-O-glucuronide formation and liver UGT2B17 expression in the same subjects, and the KM for UGT2B17(+/+) HLMs against 17-dihydroexemestane was 7.3 μM, ∼ 2-fold lower than that observed for UGT2B17 against 17-dihydroexemestane in vitro (14.5 μM). UGT2B17 (0/0) HLMs exhibited a 1.7-fold higher KM and a 36-fold lower Vmax/KM than UGT2B17 (+/+) HLMs. These data suggest that UGT2B17 is important in the metabolism of 17-dihydroexemestane, a major active metabolite of exemestane, and that the UGT2B17 deletion could have an important role in overall patient response to exemestane. 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 3589.
Sleep Disorders and Aging
Authors: Jane F. Desforges, Patricia N. Prinz, Michael V. Vitiello, Murray A. Raskind, Michael J. Thorpy
Journal: New England Journal of Medicine (1990)

DISTURBANCES in the pattern of sleep are common in older adults. These sleep–wake disturbances can be the result of physiologic changes that are apparently part of normal aging, a primary sleep disorder, a secondary sleep problem resulting from one of a variety of causes, or a combination of the three. Sleep disruption often leads older persons to report symptoms of disturbed sleep to their physicians in an attempt to alleviate the disturbance.1 2 3 4 5 With the rapid increase in the elderly population, the practicing physician should be aware of the changes in sleep–wake patterns that accompany normal aging, the various sleep disorders . . .
THU0448 Consistency and Usefulness of Data Items across European Rheumatoid Arthritis Clinical Cohorts and Registers
Authors: H. Radner, K. Hyrich, W.G. Dixon, J. Askling
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Heterogeneity in terms of data collection is thought to limit comparability and pooling of data in Rheumatoid Arthritis (RA) clinical cohorts and registers across Europe. Defining such standards should be informed by which data items are currently collected, how they are defined and collected, and their perceived utility. <h3>Objectives</h3> To identify overlaps, discrepancies, and perceived usefulness of the currently collected data in existing RA clinical cohorts and registries. <h3>Methods</h3> A survey was developed and sent to 29 European RA registers and clinical cohorts. The survey requested information on: IF specific data items are collected, HOW and with what Frequency they are collected, how often data are MISSING, and if these items are regarded as USEFUL for research purposes. <h3>Results</h3> 25 cohorts/registers with different inclusion criteria and definition of RA completed the survey, totaling 189,043 patients (range: 130 to 55,000). 6/25 cohorts (24%) were established before year 2000, 60% were multi-center collections. The figure displays frequency of collected data items. There were differences in HOW items were <i>defined</i> (Composite Scores (CoSc): 80%DAScrp/DAS4items, 40%SDAI/CDAI, 8%Ritchie Index; Joint Counts (JC): 71%28JC, 5%66JC; pain 25%general pain, 35%pain related to arthritis) and HOW they were <i>collected</i> (JC: 54% total JC, 46% individual joints; pain: 85% VAS, 20% numeric rating scale; Comorbidities: 57%patient self reported, 29%standardized questionnaire; 10%free text; 33%records). Items with higher proportions of <i>missing</i> information were EQ-5D, and fatigue. DMARD history and serology were collected mainly at baseline only, whereas items of disease activity and severity such as JC, CoSc, pain, and HAQ were collected at almost every follow up visit. CoSc (92%), disease duration (92%), biologic DMARDs (91%) and HAQ (91%) were most frequently used for research. Among all items collected, the responders ranked disease activity, treatment, and JC as the most essential, compared to extra-articular manifestations, smoking and imaging which had the lowest perceived utility. At the same time, smoking, imaging, co-morbidities and adverse event data were the top-ranked data items responders felt was missing from their data collection. <h3>Conclusions</h3> Even though common core items such as disease activity, treatment and comorbidities have been identified, the mode of data collection is heterogeneous. To facilitate future data sharing and combined analytical approaches, data collection across Europe needs to be better harmonized. <h3>Disclosure of Interest</h3> : H. Radner Grant/research support: IMI BT-Cure Project, K. Hyrich: None declared, W. Dixon: None declared, J. Askling Grant/research support: IMI BT-Cure Project <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3288