tbuckley/cabot-search huggingface dataset:
SP0051 Metabolic Arthropathies (WIN with EULAR)
Authors: B. Manger
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> This lecture is intends to offer the delegates an update on recently published work about metabolic diseases, which present with musculoskeletal symptoms. It is part of the session track called “WIN with EULAR”, which focuses on new developments in different topic areas over the preceding twelve months. “Metabolic arthropathies” will cover crystal-induced arthritides, but also hereditary metabolic disorders with rheumatic manifestations (e.g. hemochromatosis, collagenopathies, lysosomal storage diseases) all depending on the availability of new trends in the literature. In addition, musculoskeletal involvement in other diseases (e.g. hepatic, renal) and paraneoplastic manifestations will be discussed. A conclusive summary on “What is the significance for our work” will sum up the new developments in the various areas. <h3>Disclosure of Interest</h3> B. Manger Consultant for: AstraZeneca, Novartis, SOBI, Berlin-Chemie, Savient, Genzyme, BioMarin
Abstract 1567: Use of humanized NOG mice within the pre-clinical development of new human specific therapies.
Authors: Caroline Mignard, Jean-Francois Mirjolet, Holger Kissel, Francis Bichat, Olivier Duchamp
Journal: Cancer Research (2013)

Abstract Immune cells within the tumor microenvironment are now well recognized as to be targets of interest for cancer treatment. However there are no available pre-clinical models that will accurately support the pre-clinical development of such therapeutic approaches. Humanized NOG (NOD/shi-scid/IL-2Rγnull) mice, bearing human immune cells with or without human target tumor cells, are relevant models to test various therapeutic strategies (e.g. antibody dependent cell cytotoxicity, Treg targeting antibodies, TLR agonists, vaccines, adoptive T cells transfer, …) in various pathologies (e.g. oncology, autoimmune disease, inflammation, transplantation, …). Humanization of NOG mice was already characterized and validated using freshly collected human PBMCs or hematopoietic stem cells (HSCs) in both newborn and adult NOG mice. The complete characterization of the reconstituted NOG mice was done in peripheral blood as well as central lymphoid organs such as bone marrow, spleen and thymus, using FACS analysis. Moreover, the human immune reconstitution and function in NOG mice was also evidenced with human cytokine and immunoglobulin quantification in mouse plasma samples. The injection of mature human PBMC in adult NOG mice leads to the consistent development of a xenogeneic graft-versus-host disease (GvHD), which mimics human GvHD (modification of CD4/CD8 ratio, expression of T cells activation markers and cytokine production). Growth characteristics of human tumors models on humanized mice will be presented either as subcutaneous or as disseminated intravenous model. Randomization parameters were selected regarding both tumor and immune cell sides. Required readouts to understand immune cell modulation (Cell phenotyping and functionality) and related antitumor efficacy will be described. Finally, such models, i.e. humanized NOG mice bearing or not human tumor cells in the context of evaluation of new therapies will be detailed in various pathologies. Citation Format: Caroline Mignard, Jean-Francois Mirjolet, Holger Kissel, Francis Bichat, Olivier Duchamp. Use of humanized NOG mice within the pre-clinical development of new human specific therapies. [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 1567. doi:10.1158/1538-7445.AM2013-1567
Point: Open Radical Prostatectomy Should Not Be Abandoned
Authors: William J. Ellis, Paul H. Lange
Journal: Journal of the National Comprehensive Cancer Network (2007)

Robotic-assisted laparoscopic radical prostatectomy is now one of the most common ways to treat prostate cancer. Although it is undoubtedly an outstanding procedure, in many contexts the advantages of the laparoscopic approach are overstated. The authors believe that open radical prostatectomy will continue to have an important role. For example, an extensive lymphadenectomy is more easily accomplished with the open technique and may be important in staging and possibly curing patients at high risk for prostate cancer. Also, tactile sensation is a valuable asset in assessing the extent of local tumor, and this cannot yet be replicated with a robotic approach. Furthermore, obese patients, those with a history of extensive prior surgical procedures, and men with extremely large prostates may experience advantages with the open technique. Finally, the open approach has a significant advantage in terms of hospital costs.
Abstract 1843: An unintended consequence of Nrf2-directed cytoprotection against a major human bladder carcinogen and a counteracting solution
Authors: Yi Ding, Joseph D. Paonessa, Kristen L. Randall, Dayana Argoti, Rex Munday, Paul Vouros, Yuesheng Zhang
Journal: Cancer Research (2011)

Abstract NF-E2 related factor 2 (Nrf2) plays a pivotal role in cytoprotection against carcinogens and oxidants. Activating Nrf2 has been widely suggested as a key chemopreventive strategy against cancer and other diseases. Here, we show that Nrf2 faces a serious dilemma in dealing with 4-aminobiphenyl (ABP), a major human bladder carcinogen from tobacco smoke and other sources. ABP is metabolized/activated primarily in the liver. While Nrf2 significantly protected mouse liver against ABP in vivo, bladder DNA damage was approximately 2.6 fold higher in Nrf2+/+ mice than in Nrf2-/- mice after ABP exposure, as measured by dG-C8-ABP, the predominant ABP-DNA adduct formed in bladder cells and tissues. Interestingly, Nrf2 significantly protected bladder cells against ABP in vitro. Subsequent experiments revealed that UDP-glucuronosyltransferase (UGT) might be the principal, if not the only mediator of the dichotomous effects of Nrf2. Nrf2 upregulated UGT, promoted glucuronide conjugation of ABP in the liver, and increased urinary excretion of the conjugate. While glucuronidation of ABP and its metabolites is generally a detoxification process, these conjugates, which are excreted in urine, are known to be unstable in acidic urine and deliver the parent compounds to bladder. Hence, higher liver UGT activity may protect liver against ABP but increases bladder exposure to ABP. We further show that 5,6-dihydrocyclopenta[c][1,2]-dithiole-3(4H)-thione (CPDT), a promising cancer chemopreventive dithiolethione, was able to significantly activate Nrf2 cytoprotective signaling and to inhibit dG-C8-ABP formation in the bladder in vivo, but did not modulate liver UGT expression. Thus, CPDT exemplifies a counteracting solution to the dilemma faced by Nrf2 with regard to ABP. In conclusion, our study shows that Nrf2 increases ABP genotoxicity in the bladder in vivo and that UGT may be the key mediator. Using CPDT, we also demonstrate how the adverse effect of Nrf2 may be mitigated. 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 1843. doi:10.1158/1538-7445.AM2011-1843
Women with endometriosis show higher risk for heart disease
Authors: Jacqui Wise
Journal: BMJ (2016)

Women who have endometriosis diagnosed at age 40 or younger are three times more likely to develop heart disease than those without the condition, says a large prospective study published in Circulation: Cardiovascular Quality and Outcomes .1

Researchers reviewed the records of 116 430 women enrolled in the Nurses’ Health Study II, and women with a history of heart …
Electrical Alternans and Vulnerability to Ventricular Arrhythmias
Authors: David S. Rosenbaum, Lance E. Jackson, Joseph M. Smith, Hasan Garan, Jeremy N. Ruskin, Richard J. Cohen
Journal: New England Journal of Medicine (1994)

Although electrical alternans (alternating amplitude from beat to beat on the electrocardiogram) has been associated with ventricular arrhythmias in many clinical settings, its physiologic importance and prognostic implications remain unknown.To test the hypothesis that electrical alternans is a marker of vulnerability to ventricular arrhythmias, we developed a technique to detect subtle alternation in the morphologic features of the electrocardiogram (which would not be detectable by visual inspection of the electrocardiogram). In a group of 83 patients referred for diagnostic electrophysiologic testing, we prospectively examined whether levels of alternans predicted vulnerability to arrhythmias as defined by the outcome of electrophysiologic testing and arrhythmia-free survival.Sustained ventricular arrhythmias were induced during electrophysiologic testing in 32 of the patients (39 percent). In this group, low-level electrical alternans (a beat-to-beat change in amplitude of < 15 microV) was detected over a broad range of physiologic heart rates (from 95 to 150 beats per minute) and primarily involved the ST segment and the T wave (i.e., the phase of repolarization). Alternans during repolarization was a significant and independent predictor of inducible arrhythmias on electrophysiologic testing (sensitivity, 81 percent; specificity, 84 percent; relative risk, 5.2). Of 66 patients followed for up to 20 months, 13 had arrhythmic events. Alternans affecting the T wave and inducibility of ventricular arrhythmias were significant and essentially equivalent predictors of survival without arrhythmia (P < 0.001). Actuarial survival without arrhythmia at 20 months was significantly lower among the patients with T-wave alternans (19 percent) than among the patients without T-wave alternans (94 percent).Electrical alternans affecting the ST segment and T wave is common among patients at increased risk for ventricular arrhythmias. Subtle electrical alternans on the electrocardiogram may serve as a noninvasive marker of vulnerability to ventricular arrhythmias.
OP0084 Patterns of circulating antibodies in the pre-clinical phase of rheumatoid arthritis suggest epitope spreading in the immune reaction against citrullinated peptides
Authors: C. Turesson, M. Hansson, U. Bergström, L.T. Jacobsson, L. Mathsson, L. Klareskog, P.-J. Jakobsson, R. Holmdahl, J. Rönnelid
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Previous studies indicate that anti-citrullinated peptide antibodies (ACPAs) may be detected in individuals who later develop rheumatoid arthritis (RA) years before onset, and that smoking is a predictor of RA. <h3>Objectives</h3> To investigate circulating autoantibodies and their relation to smoking before the onset of RA. <h3>Methods</h3> Incident cases of RA were identified among participants (n=30447) in a community based health survey, which was linked to local and national registers, followed by a structured review of the medical records. One control, matched for age, sex and year of inclusion in the health survey, was selected for each validated case. Using a multiplex assay system, developed in collaboration with Phadia AB (Uppsala, Sweden), sera were investigated for 10 different ACPA fine specificities and antibodies to 3 other autoantigens. For all investigated antibodies, previous studies had shown good correlations between results obtained using this system and standard ELISAs. Corrected net values for ACPA specificity were calculated by subtracting values for arginine control peptides from the corresponding citrulline peptides. Cut offs were set at the 98th percentile, based on investigation of sera from the matched controls. Analyses were stratified by time from inclusion in the health survey to RA diagnosis (1-3, 4-5, 6-8 and 9-13 years, respectively), and by history of current or ever smoking. <h3>Results</h3> Serum was available from 167 cases (79% women), who were diagnosed with RA a median of 5 years (IQR 3-8; range 1-13) after inclusion in the health survey. Eighty-four (50%) of the pre-RA cases were positive for ≥1 ACPA. The most frequently detected ACPAs were antibodies to citrullinated vimentin 60-75 (cit Vim 60-75) (27%) and antibodies to citrullinated alpha-enolase peptide 1 (CEP-1) (22%). Significantly greater numbers of positive ACPA specificities were detected among pre-RA cases sampled closer to RA diagnosis (p for trend 0.003). Most individual ACPA specificities, including those directed against cit Vim 60-75 and CEP-1, were more frequent among those with a shorter time to diagnosis. Current (p=0.005) and ever (p=0.02) smoking were associated with RA. There were no major differences in detected ACPAs before RA diagnosis between current smokers and current non-smokers, whereas ever smokers were more likely to be positive for most ACPAs and had higher numbers of positive ACPA specificities compared to never smokers (p=0.03). <h3>Conclusions</h3> The increase in ACPA specificities with a shorter time to diagnosis indicates that epitope spreading may precede disease onset. A history of smoking may contribute to the development of ACPAs before the clinical onset of RA. <h3>Disclosure of Interest</h3> None Declared
NEO212: A NOVEL TEMOZOLOMIDE-PERILLYL ALCOHOL CONJUGATE EXHIBITS SUPERIOR ACTIVITY AGAINST TEMOZOLOMIDE RESISTANT GLIOMAS AND INTRACRANIAL TRIPLE NEGATIVE BREAST CANCER METASTASIS
Authors: T. C. Chen, A. H. Schonthal, F. M. Hofman, W. Wang, H. Cho
Journal: Neuro-Oncology (2014)

BACKGROUND: Although the alkylating agent temozolomide (TMZ) has become the standard of care in the treatment of malignant gliomas, its overall efficacy is still limited by development of drug resistance, limited blood brain barrier (BBB) penetrance, and myelotoxicity. Recently, we have synthesized a TMZ analog where the monoterpene perillyl alcohol (POH) is covalently linked to TMZ via an amide bond. This new compound (NEO212) has been tested in two situations: TMZ resistant gliomas and breast cancer intracranial metastasis. METHODS: Glioma cell lines (U251TR, LN229TR2, T98G) determined to be TMZ resistant based on base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O6 methyl-guanine-DNA methyltransferase (MGMT) were evaluated in-vitro. In vivo experiments were performed using intracranial implant of luciferase labeled TMZ resistant cell lines. Triple negative breast cancer lines were tested, and implanted intracranially for in-vivo model. NEO212 was administered in both cases using subcutaneous injection using 10 day treatment, 7 day rest cycles. RESULTS: NEO212, at equimolar concentrations to TMZ, was more cytotoxic to TMZ resistant cells, and did not have significant toxicity on normal astrocytes and brain endothelial cells. NEO212 induced cell death appeared to be independent of the mechanism of DNA repair resistance. In vivo experiments using intracranial implant of luciferase labeled TMZ resistant cell lines demonstrated that NEO212 crossed the BBB, reduced intracranial growth, and increased animal survival significantly compared to TMZ, without significant toxicity (including bone marrow). NEO212 was also effective in TMZ resistant breast cancer lines. In an intracranial mouse tumor model with triple-negative breast cancer, NEO212 revealed considerably greater therapeutic efficacy than TMZ, where a single cycle of treatment (10 days) extended median survival benefit from 6 days (in the case of TMZ) to 28 days, with good tolerance. CONCLUSIONS: NEO212 appears to be a promising well tolerated new agent with similar mechanism of cytotoxicity to TMZ. Its increased potency is most likely multi-factorial: 1) increased DNA damage, involving a broader scope of DNA repair mechanisms. 2) linkage with POH, resulting in longer biological half-life and greater opportunity for placement of cytotoxic DNA lesions. 3) increased lipophilicity, allowing for better penetration of the BBB, and possibly cell membrane. Preliminary results demonstrate that it can safely be administered systemically; more detailed toxicity studies are currently underway. SECONDARY CATEGORY: Tumor Biology.
<i>Pneumocystis carinii</i>Pneumonia and Mucosal Candidiasis in Previously Healthy Homosexual Men
Authors: Michael S. Gottlieb, Robert Schroff, Howard M. Schanker, Joel D. Weisman, Peng Thim Fan, Robert A. Wolf, Andrew Saxon
Journal: New England Journal of Medicine (1981)

Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposi's sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3+ helper/inducer subset, an increased percentage of the Leu-2+ suppressor/cytotoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency. (N Engl J Med. 1981; 305:1425–31.)
AB0260 Comparison of rheumatoid arthritis (RA) patient parameters at anti-TNF treatment initiation demonstrates wide variability over time in a large real-life cohort treated with infliximab
Authors: A. Chow, C. Thorne, W. Bensen, D. Choquette, E. Rampakakis, J. Sampalis, S. Otawa, S. Khalil
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Anti-tumor necrosis factor alpha (anti-TNFα) agents revolutionized RA treatment by significantly reducing joint pain and inflammation, inhibiting disease progression, and improving patient function and quality of life(1). However, anti-TNFα agents are more expensive than traditional disease-modifying antirheumatic drugs (DMARDs) which may limit patient access. <h3>Methods</h3> Data were obtained from an ongoing, Canadian registry of patients initiating Infliximab as first biologic or after being treated with a biologic for less than six months. Patients who had at least one follow-up visit at 6 months were included in this analysis. Based on their enrolment year, patients were divided in three groups (2002-2005, 2005-2008, and 2008-2011). <h3>Results</h3> A total of 628 patients were included in this analysis, among whom 288 (45.9%), 217 (34.6%) and 123 (19.6%) were enrolled in 2002-05, 2005-08, and 2008-11, respectively. A trend towards earlier initiation of Infliximab was observed with the mean (SD) disease duration at baseline decreasing from 11.2 (10.3) years in 2002-05 to 9.2 (9.6) in 2005-08 and 9.6 (9.8) in 2008-2011 (P=0.072). In agreement, fewer patients were treated with ≥4 (25.7% vs. 12.1% vs. 3.3%, respectively) DMARDs prior to Infliximab initiation (P&lt;0.001). Patients in more recent years had significantly lower DAS28 (5.9 vs. 5.4 vs. 4.3; P&lt;0.001), swollen joint count (13.4 vs. 9.8 vs. 5.6; P&lt;0.001), tender joint count (15.4 vs. 12.0 vs. 6.3; P&lt;0.001), ESR (35.7 vs. 31.4 vs. 26.0 mm/h; P&lt;0.001), and CRP (22.7 vs. 18.7 vs. 13.3 mg/L; P=0.006) at baseline. Interestingly, a shift from public to private insurance coverage (37.8% vs. 44.0% vs. 55.7%; P=0.007) and an increase in the proportion of patients employed (29.6% vs. 38.2% vs. 44.2%; P=0.011) was observed in more recent years. Furthermore, unemployment due to disability also decreased over time (40.6% vs. 32.3% vs. 26.9%; P=0.080). However, employment rate was maintained stable even after 24 months of treatment with Infliximab, regardless of enrolment period. After 12 months of treatment, a significantly higher proportion of patients enrolled more recently achieved DAS28 (21.4% vs. 38.9% vs. 44.8%; P=0.001), SDAI (9.3% vs. 21.7% vs. 17.2%; P=0.024) and CDAI (9.3% vs. 19.5% vs. 17.8%; P=0.023) remission. <h3>Conclusions</h3> In this long-term, real-world Canadian registry, Infliximab was initiated earlier in the disease course in more recent years. This was associated with lower disease activity at baseline, as well as with increased remission rates, reduced unemployment due to disability and a shift from public to private payer coverage. <h3>References</h3> Singh JA et al. Cochrane Database Syst Rev 2009; 4: CD007848 <h3>Disclosure of Interest</h3> None Declared
RESPIRATORY MASK-FILTER PREVENTS CARDIOVASCULAR EFFECTS ASSOCIATED WITH DIESEL EXHAUST EXPOSURE: A RANDOMIZED, PROSPECTIVE, DOUBLE-BLIND, CONTROLLED, CROSSOVER STUDY IN HEART FAILURE (FILTER-HF TRIAL)
Authors: Jefferson L. Vieira, Guilherme V. Guimaraes, Paulo A. de Andre, Paulo H.N Saldiva, Edimar A. Bocchi
Journal: Journal of the American College of Cardiology (2015)
AB0766 Increased Prevalence of Metabolic Syndrome and Cardiovascular Disease Risk in Turkish Patients with Psoriatic Arthritis
Authors: V. Yazisiz, S.G. Ozkan, A. Behlul, H. Yazisiz, A. Gokbelen, F. Borlu
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Psoriatic arthritis (PsA) is a type of chronic inflammatory arthritis that will develop in 7-40 percent of patients with psoriasis. PsA is one of the spondyloarthropathies that can have differantiate clinical manifestations such as oligoarticular and polyarticular peripheral arthritis. Many studies indicate that PsA is associated with hypertension, obesity, hyperlipidemia, diabetes mellitus, metabolic syndrome (MetS) and cardiovascular diseases (CVD). <h3>Objectives</h3> Some authors claim that the prevalence of these comorbidities is higher in PsA compared with psoriasis without arthritis patients. We aimed to identify the prevalence of MetS and CVD risk in patients with PsA. <h3>Methods</h3> We performed a restrospective hospital based-case-control study on 102 adult patients with PsA (72 female, 30 male, mean age: 44±11,6) who fulfilled CASPAR criteria and 102 control patients with rheumatoid arthritis (RA) (76 female, 26 male, mean age: 47±11,6) who fulfilled EULAR-ACR criteria. MetS was diagnosed by NCEP ATP III and IDF criteria. The 10-year CVD and CHD risk score was calculated by Framingham risk score (http://www.framinghamheartstudy.org/risk). <h3>Results</h3> Prevalence of MetS was higher in PsA patients compared with RA patients according to the NCEP ATP III (p:0.019) and IDF criteria (p:0.05) But there was no significant difference between the two groups regarding to the 10-year CVD (p:0.333) and CHD (p:0.798) risk. There was no significant difference between clinical subtypes of PsA with regard to metabolic syndrome (p:0.229). Despite the prevalence of MetS was higher in female PsA patients (p:0.009), there was no difference between gender in control group (p:0.240). Significantly increased prevalence of hypertriglyceridemia was determined in PsA patients (p:0.019). Despite PsA patients had lower mean HDL levels (p:0.047), this difference was not significant according to the MetS diagnosis criteria. In control group, the prevalence of CVD risk and smoking habit was higher in male patients (p:0.003 via p&lt;0.001). <h3>Conclusions</h3> In this study, we have found increased MetS prevalence in PsA compared with RA patients. Two groups had similar risk of CVD and CHD. As compared with population based studies, MetS frequency was higher in PsA patients. Our results and the similar studies in the literature indicate that the frequency of MetS and CVD/CAD in PsA was significantly higher than RA. For this reason, prevention and control guidelines of RA for these comorbidities can be used in PsA patients, until the development of PsA guideline. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1440