tbuckley/cabot-search huggingface dataset:
AB0557 Effects of tocilizumab on bone homeostasis and DICKKOPF-1 in rheumatoid arthritis
Authors: M. Kitano, S. Kitano, C. Sato, M. Nogami, M. Morimoto, A. Nishioka, M. Sekiguchi, N. Azuma, N. Hashimoto, S. Tsunoda, K. Matsui, T. Iwasaki, H. Sano
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tocilizumab (TCZ) is a humanized monoclonal anti-IL-6 receptor antibody. TCZ has demonstrated efficacy in moderate to severe active rheumatoid arthritis (RA) with inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARD) or tumor necrosis factor (TNF) inhibitors. Moreover, it is reported that TCZ combined with MTX reduces systemic bone resorption in RA. Dickkopf (DKK)-1, an endogenous inhibitory factor in the canonical Wnt signaling pathway, plays an important role in osteoclastic bone resorption via regulation of receptor activator of NF-kappa B ligand (RANKL)-osteoprotegerin (OPG) balance in rheumatoid arthritis (RA). Recently, it was reported that circulating DKK-1 was correlated with bone erosion and inflammation in RA. <h3>Objectives</h3> To investigate the effects of TCZ on biochemical markers of bone, serum RANKL, OPG, and DKK-1 in patients with active RA. <h3>Methods</h3> Twenty-eight patients with active RA (20 females, 8 males; age 51.6±10.7 years; disease duration 13.0±13.6 years; DAS28-ESR 5.5±1.4) were started on treatment with TCZ 8mg/kg intravenously every 4 weeks. Eighteen patients had a history of TNF-antagonist therapy such as infliximab, etanercept, and, adalimumab. All patients had been treated with methotrexate, other DMARDs and prednisolone continued at the stable pretreatment doses during in this study. Circulating levels of osteocalcin, type I collagen cross-linked N-telopeptides (NTx), soluble RANKL (sRANKL), OPG, and DKK-1 were examined by ELISA at baseline and after12 weeks. <h3>Results</h3> At 12 weeks after the treatment of TCZ, a disease activity reduced significantly from the baseline (DAS28-ESR 5.5±1.4 vs 3.0±1.4; p&lt;0.01). Average of NTx, sRANKL, and DKK-1 levels at 12 weeks after the treatment of TCZ decreased significantly from the baseline (NTx: 19.20 nmol BCE/l vs 16.43 nmol BCE/l; p&lt;0.01, sRANKL: 0.819 pmol/l vs 0.689 pmol/l; p&lt;0.05, and DKK-1: 2536 pg/ml vs 2065 pg/ml; p&lt;0.01, respectively). Average of osteocalcin levels at 12 weeks increased significantly from the baseline (5.31 ng/ml vs 5.67 ng/ml; p&lt;0.05). Average of OPG levels did not change significantly. <h3>Conclusions</h3> These findings suggest that TCZ therapy improves systemic bone metabolism in patient with active RA through the increase of bone formation markers and the decrease of bone degradation markers. Moreover, TCZ might be improved osteoclastic bone destruction in RA via the regulation of DKK-1 and RANKL expression. <h3>Disclosure of Interest</h3> None Declared
AB1131 Gout Patient Education – is There Such A Reality in General Medical Practice?
Authors: M.S. Panchovska, N.G. Nikolov, E.I. Firkova-Bernard
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Gout is one of the most common rheumatic diseases in general medical practice. Management of patients with gout includes prevention and treatment of the disease during acute attacks, as well as in the symptom-free period. Treatment outcomes strongly depend on the relationship doctor-patient. <h3>Objectives</h3> The objective of the current study was to assess the level of competency of general practitioners (GPs) in the management and education of patients with gout to optimize disease control. <h3>Methods</h3> An anonymous survey among 31 GPs was conducted. The survey included six questions with a yes/no answer. Data was analyzed using alternative analysis. <h3>Results</h3> A positive answer was given to the following questions: 1) Is minimizing risk factors such as elevated BMI and chronic alcohol consumption a first-line treatment option? - 27/31 (87.06%); 2) Is diet an obligatory component in the prevention and treatment of gout attacks? - 24/31 (77.42%); 3) Does the patient with gout need information about the clinical manifestation of acute gout arthritis? - 15/31 (48.39%); 4) Does acute gout arthritis need urgent treatment? - 22/31 (70.97%); 5) Is it the doctor9s obligation to inform patients with gout about the side effects of the drug therapy? - 17/31 (54.84%); 6) Should patients be informed about the association between gout and the following factors: dyslipidemia, diabetes mellitus and arterial hypertension? - 14/31 (45.16%). <h3>Conclusions</h3> Data from the conducted study revealed that the predominant portion of the respondents recognized prevention and treatment of gout a main competency of the physician. Insufficient information and patient education are the basis of partially satisfactory results. <h3>References</h3> Rudichenko VM. Importance of the hyperuricaemia, gout and gender nosological features in the activity of general practitioner - family doctor. Lik Sprava. 2012 Jul-Sep;(5):44-57. Hamburger M, Baraf HS, Adamson TC 3rd, Basile J, Bass L, Cole B, Doghramji PP, Guadagnoli GA, Hamburger F, Harford R, Lieberman JA 3rd, Mandel DR, Mandelbrot DA, McClain BP, Mizuno E, Morton AH, Mount DB, Pope RS, Rosenthal KG, Setoodeh K, Skosey JL, Edwards NL; European League Against Rheumatism 2011 Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med. 2011 Nov;123(6 Suppl 1):3-36. doi: 10.3810/pgm.2011.11.2511. Chandratre P, Roddy E, Clarson L, Richardson J, Hider SL, Mallen CD.Health-related quality of life in gout: a systematic review. Rheumatology (Oxford). 2013 Nov;52(11):2031-40. doi: 10.1093/rheumatology/ket265. Epub 2013 Aug 11. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4114
1356 NAFLD IS SIGNIFICANTLY INCREASED IN PATIENTS AT HIGH RISK FOR CARDIOVASCULAR EVENTS AND IS CORRELATED WITH EARLY PREDICTORS OF ATHEROSCLEROSIS AND THE FRAMINGHAM SCORE
Authors: R. Pais, P. Giral, P. Lebray, D. Rosenbaum, D. Thabut, M. Rudler, T. Poynard, V. Ratziu
Journal: Journal of Hepatology (2013)
P398Aggregate prone desmin mutations reduced mitochondrial calcium uptake in primary myotubes upon electrical stimulation
Authors: N Smolina, J Bruton, G Sjoberg, A Kostareva, T Sejersen
Journal: Cardiovascular Research (2014)

Purpose: Calcium (Ca2+) plays key role in muscle cell physiology, e.g. takes part in the contraction and acts as co-factor in Krebs cycle. Mitochondria are capable to uptake calcium due to close proximity to SR Ca2+ releasing microdomains. Mitochondrial calcium balance is crucial for cell destiny, increased calcium leads to apoptosis, when decreased drives autophagy. On the other hand mitochondria within the muscle cells tightly connected to desmin. In desmin knock-out mice mitochondria were non-functional. Desmin mutations are associated with developing of myopathies, however machinery remains to be elucidated. We proposed that mitochondrial failure in desmin-compromised cells might result in disturbed calcium balance. We aimed to assess impact of non-aggregate prone (D399Y) and aggregate prone (L345P, A357P, L370P) desmin mutations on mitochondrial calcium. Materials and methods: Satellite cells were obtained from soleus muscle of young C57BL/6 males. Cells were transduced with lentiviral suspension, encoded desmin wild type or mutant and GFP as reporter gene. Cells were grown for one week, then differentiation was induced and continued two weeks more. Obtained myotubes were loaded with rhod-2 AM for 20 min, after that dye was washed out for 20 min. Electrical stimulation was applied for up to 30 s as follows: 1 Hz, rest, 10 Hz, rest, and 100 Hz, rest. Changes in rhod-2 fluorescence were detected using laser confocal microscopy. Intensity of fluorescent signal was measured in baseline (without stimulation (F0)) and during stimulation (F). Ratio F/F0 was calculated and represented peaks amplitudes of mitochondrial calcium transients. Results: After electrical stimulation the peak amplitude of mitochondrial calcium uptake was similar in non-transduced and DesWT cells being 2.61 ± 0.19 and 3.12 ± 0.29 respectively. However, in DesL345P myotubes and DesA357P myotybes, the mitochondrial calcium uptake was markedly decreased by 50% and 44% respectively in comparison with DesWT cells. Interestingly, mitochondrial calcium uptake in the DesD399Y myotubes was similar to that seen in DesWT cells and was equaled 3.45 ± 0.53. DesL370P cells didn't decrease peak amplitude as much as DesA357P and DesL345P and showed transitional peak, F/F0 was 2.85 ± 0.31. Conclusion: Therefore mitochondrial capacity to uptake calcium depended on conformational form of desmin protein and aggregate prone mutations markedly decreased calcium uptake in comparison with non-aggregate prone mutation. We assumed that desmin aggregates broke mitochondria localization within the calcium release microdomains.
Treatment of Acute Biliary Pancreatitis
Authors: John Baillie
Journal: New England Journal of Medicine (1997)

Almost 100 years ago, Opie postulated that a gallstone transiently obstructing the ampulla of Vater — the channel where the bile duct and pancreatic duct meet — could precipitate pancreatitis.1 At least half of all cases of pancreatitis are due to the passage of gallstones; we know this because stones are found in the bile ducts and stools of the affected patients.2 When alcohol consumption, trauma, certain metabolic abnormalities, tumors, and a host of rare causes, from ischemia to ascariasis, are ruled out, gallstones are the number-one suspect worldwide.3 There is little doubt about the diagnosis of biliary pancreatitis when . . .
Abstract 3601: Evaluation of a mathematical modeling framework to describe combination therapy with Gemcitabine
Authors: Mary E. Spilker, Shinji Yamazaki, Alessandra Blasina, Jill Hallin, Darian M. Bartkowski, Paolo Vicini
Journal: Cancer Research (2010)

Abstract The quantitative assessment of the effectiveness of chemotherapeutic combinations is of increasing interest. This is especially true given the complexities of different dosing schedules and animal model systems. This work evaluates a recently proposed mathematical modeling framework (Koch et al., J Pharmacokinet Pharmacodyn 36:179-197, 2009), and modifications thereof, for quantifying synergisms between drugs used in combination therapy based on preclinical data. In this study, we evaluated published NSCLC (H460a) tumor growth inhibition (TGI) data following treatment with Erlotinib and Gemcitabine (Higgins et al., Anticancer Drugs 15: 503-512, 2004), administered both alone and in combination. We simultaneously modeled the pharmacodynamic data from all therapeutic regimens. TGI data from both monotherapy and combination therapy were adequately described. The results suggest that Erlotinib and Gemcitabine at sub-maximal doses work in a synergistic manner to reduce tumor growth. This modeling framework may prove useful in the design and optimization of preclinical experiments involving drug combinations. 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 3601.
Case 17-1995
Authors: C.A. Hales, E.J. Mark
Journal: New England Journal of Medicine (1995)

Presentation of CaseAn 81-year-old woman was admitted to the hospital because of severe pulmonary edema after aortic-valve and mitral-valve replacements.The patient had been in good health until four years earlier, when severe dyspnea developed. A cardiac-catheterization study showed that the right atrial pressure was 4 mm Hg, the pulmonary arterial pressure was 28/17 mm Hg, and the pulmonary-capillary wedge pressure was 15 mm Hg. There was severe aortic stenosis, with a peak pressure gradient of 100 mm Hg. The cardiac output was 4.4 liters per minute. Left ventricular function was normal. A coronary angiographic examination revealed 80 percent . . .
AB0960 Autoantibodies to Heat-Shock Protein60 and Cardiovascular Disease in Patients with Mixed Connective Tissue Disease
Authors: E. Bodolay, Z. Prohaszka, D. Suszterics, J. Rynkiewicz, E. Zold, P. Szodoray
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Heat Shock Proteis (HSP) are intracellular proteins conserved in the course of evolution. Resulting from the antigenic homology of various species, HSP60 and antibodies produced against them can provoke inflammation. Several studies have confirmed that antibodies produced against HSP can facilitate the occurence of atherosclerosis in autoimmune diseases. <h3>Objectives</h3> The authors analysed the presence of anti-HSP antibodies and their correlation with cardiovascular diseases (CVD) in 30 MCTD patients. <h3>Methods</h3> The serum level of HSP60 antibodies was measured in the serum of thirty MCTD patients at the Division of Clinical Immunology. Fifteen out of the thirty patients had cardiovascular (CVD) disease. The antibodies were detected by ELISA assay. The lipid parameters, beside the paraoxonase activity, also identified the anti-U1RNP antibody, the antibody against endothelial cell (AECA), the anti-cardiolipin (anti-CL), the endothelin-1 (ET-1) levels and the intima-media (IMT) thickness. <h3>Results</h3> The level of anti-HSP60 antibodies was higher in the serum of patients with MCTD than in the control group (control and all MCTD: 104.0 (69.0-173.0) OD vs. 173.0 (125.0-265.0) OD, p&lt;0.016). The CVD positive patients had a higher anti-HSP60 level than the CVD negative ones (MCTD CVD positive and CVD negative: 259.0 (176.0-316.0) OD, vs. 137.0 (84.0-157.0) OD, p=0.0013). The MCTD patients9 HDL cholesterol level (p=0.024) and their paraoxonase acitivity were lower than those of the control group. The anti-U1RNP (p&lt;0.0022) serum level and the IMT were also higher in the control group (p=0.002). The CVD positive patients9 serum concentration of anti-HSP60 (p&lt;0.0013), anti-CL IgG (p=0.0005) the ET-1 (p&lt;0.05), and IMT (p&lt;0.001) were significantly higher than that of the CVD negative control group. A close correlation was found between the anti-HSP60 antibody and the AECA (r=0.36, p=0.01) and between the serum levels of anti-HSP60 and ET-1 (r=0.62, p&lt;0.001) <h3>Conclusions</h3> The presence of anti-HSP60 antibody showed a strong correlation in MCTD with CVD disease, endothelial injury, IMT value and can be considered an atherosclerotic risk factor in MCTD patiens. <h3>References</h3> Prohaszka Z, Furst G: Immunological aspects of heat-shock proteins-the optimum stress of life. Mol Immunol 2004; 41: 29-44 Bodolay E, Seres I, Szodoray P, Csipo I, Jakab Zs, Vegh J, Szilagyi A, Szegedi Gy, Paragh G: The evaluation of paraoxonase (PON) activity in patients with mixed connective tissue disease. J Rheumatol 2008. 35 (2): 237-43 Zhu J, Quyyumi AA, Rott D: Antibodies the human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for and autoimmune component of atherogenesis. Circulation 2001; 103: 1071-75 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2894
Another Breast Cancer Entity Confirmed: Genomics of Invasive Lobular Breast Cancer
Authors: Michael L. Gatza, Lisa A. Carey
Journal: Journal of Clinical Oncology (2016)

The most frequent signi ficantly altered gene identified in this study was CDH1 in which loss-of-function mutations occurred in 65% of cases and loss of heterozygosity or deletion was identified in 94% of patients. These findings are consistent with other studies and underscore the role of E-cadherin loss in contributing to the characteristic discohesive morphology associated with ILC. 3
Long-Term Outcomes after Radiosurgery for Acoustic Neuromas
Authors: Douglas Kondziolka, L. Dade Lunsford, Mark R. McLaughlin, John C. Flickinger
Journal: New England Journal of Medicine (1998)

Stereotactic radiosurgery is the principal alternative to microsurgical resection for acoustic neuromas (vestibular schwannomas). The goals of radiosurgery are the long-term prevention of tumor growth, maintenance of neurologic function, and prevention of new neurologic deficits. Although acceptable short-term outcomes have been reported, long-term outcomes have not been well documented.
Abstract LB-475: 3′UTR polymorphisms affect expression and activity of IGF1R, a therapeutic target in pediatric neuroblastoma
Authors: Elena Sotillo-Piñeiro, Liu Xu, Le Nguyen, Travis Laver, Edward Attiyeh, Kristina Cole, Sharon Diskin, John Maris, Andrei Thomas-Tikhonenko
Journal: Cancer Research (2012)

Abstract For patients with high-risk neuroblastoma (NB) survival remains below 40%, and survivors suffer from life-long treatment-related disabilities. This necessitates the development of oncogene-specific targeted therapies. We and others observed that small-molecule inhibitors of IGF1R exhibit anti-proliferative effects against NB cells in vitro and in vivo. Yet given the apparent lack of somatic mutations in the IGF1R gene, it remains to be determined what subset of NB patients would benefit from this approach. We hypothesized that IGF1R expression could be affected by alterations in the 3′UTR that prevent binding by microRNAs. Indeed, as evidenced by cancer gene sequencing data on 188 primary high-risk NBs, IGF1R was the gene by far most frequently affected by 3′UTR alterations. We initially focused on the genetic variant rs3833015, a small 2-nt deletion found in ∼50% of NB patients and overlapping with the putative miR-140 binding site. The positive effects of this 3′UTR variant on IGF1R expression were established using luciferase sensor assays, immunoblotting on commonly available NB cell lines, and transcriptome profiling of 28 primary neuroblastomas using Gene Set Enrichment Analysis. Additional 3′UTR variants that affect IGF1R expression and map in the proximity of miR-binding sites were identified using Expression Quantitative Trait Loci (eQTL) analysis. Our experimental data lead us to postulate that rs3833015 and other IGF1R 3′UTR variants help sustain IGF1 signaling, resulting in the “addiction” to this survival pathway and increased sensitivity to small-molecule IGF1R inhibitors. 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 LB-475. doi:1538-7445.AM2012-LB-475
A8.36 Activated human B cells induce an inflammatory phenotype in synovial fibroblasts
Authors: Theresa Tretter, Hannah Stoerch, Lars Tykocinski, Babak Moradi, Hanns-Martin Lorenz
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Synovial fibroblasts (SF) are key players in pathogenesis and progression of rheumatoid arthritis (RA). A cross-talk between immune cells and SF is suggested to contribute to chronification of the disease. RA-SF can be found in close proximity to B cells in vivo, with activated proliferating B cells often organised in germinal center- like pseudofollicles. While various reports deal with the influence of SF on B cells, our intention was to clarify the potential influence of B cells on SF <h3>Materials and Methods</h3> Highly purified CD19<sup>+</sup> B-cells were separated from PBMC by magnetic cell sorting. B-cells were polyclonaly stimulated by BCR-cross-linking with anti-IgM/IgG Antibody or SAC (Staphylococcus aureus Cowan I antigen) and cocultured with SF, that were isolated from synovial biopsies of patients with osteoarthritis (OA-SF). After 48-72h cytokine production was determined by ELISA of cell culture supernatants and phenotypical changes in both cell populations were determined by flow cytometry <h3>Results</h3> SF and B cells cultured alone produced low amounts of IL-6 and IL-8. However, in B-SF cocultures the concentrations of both cytokines increased up to 100-fold suggesting that the observed values not just reflect additive but rather synergistic effects. Intracellular staining with fluorochrome-labelled anti-cytokine Abs revealed that the increased cytokine concentrations originated from SF. In contrast, B cell specific production of TNF-alpha and IL-1-beta decreased in cocultures with SF by more than 50%, suggesting an inhibitory feedback mechanism by activated SF towards the B cells. Of note, after removal of B cells SF-specific cytokine production remained constantly increased for several days. Separation of B cells from SFs by semipermeable cell culture inserts (transwell) did not abolish observed effects, suggesting that soluble factors were the main mediators. Addition of neutralizing Abs against TNF-alpha and IL-1-beta to the cocultures significantly reduced SF activation. All effects proved to be stable with little variation between individual donors, different B cell: SF ratios, cell culture media or B cell stimuli used. In addition to IL-6 and IL-8, the production of Matrix-Metalloproteinase-3 (MMP-3) increased in coculture with B cells as well, suggesting that OA-SF developed potentially tissue destructive properties. <h3>Conclusions</h3> Activated B cells interact with SF in a reciprocal crosstalk resulting in conversion of OA-SF into SF with an inflammatory phenotype. This process is mediated by B cell derived TNF-alpha, IL-1 beta and other yet to be identified soluble factors.
STATIN USE AND ANEURYSM RISK IN PATIENTS WITH BICUSPID AORTIC VALVE DISEASE
Authors: Alexander Perry Taylor, Patrick McCarthy, Adin-Cristian Andrei, Zhi (Carrie) Li, Edwin McGee, S. Chris Malaisrie, Colleen Clennon, Jyothy Puthumana
Journal: Journal of the American College of Cardiology (2014)