tbuckley/cabot-search huggingface dataset:
Identification of serum protein profiles of glioblastoma multiforme patients: Using image-guided microarray analysis of tumor samples to identify serum markers
Authors: Yi-Shan Yang, Samira Guccione, Yingyung Wang, Ron Homer, Steven Chang, Griff Harsh, Scott Atlas, Mark Bednarski
Journal: Cancer Research (2004)

1145   Resistance and tolerance to chemotherapy protocols remain a major concern in oncology. Therefore, novel strategies are required to predict response to treatment. Several biomarkers have been shown to be of prognostic value in colorectal cancer (CRC). However, their predictive value in assessing treatment response remains controversial. Controversy may be due to admixture of study population for age, race, gender, tumor location and stage. We evaluated archival tissue specimens for immunohistochemical expression of Bax, Bcl-2, Cox-2 and p53 in primary CRC of 56 patients who underwent surgery and received a complete regimen of 5-FU-based chemotherapy and a matched group (age, sex, ethnicity, tumor location and stage) of 56 patients who underwent surgery alone. These patients were treated at UAB-Hospital and had a minimum of 10 years follow-up. Specimens were probed with specific monoclonal antibodies for Bax, Bcl-2 and p53 and a polyclonal antibody for COX-2. The cut-off for each marker was calculated according to the median expression in normal tissues. Each marker was analyzed individually and response to treatment was measured by survival time. Kaplan-Meier survival analysis was performed to assess the differences between the positive and negative groups in relation to chemotherapy. Surprisingly, no difference was observed in survival, when the treated and untreated populations were compared. The most important finding was the impact of treatment in survival in Bax-negative patients; when untreated they had a median survival of 5 months compared to more than 10 years when treated (p=0.018). Bax positive patients did not benefit from treatment. When analyzed independently, Bcl-2 was not significant. However the ratio Bcl-2/Bax showed a trend towards significance suggesting that those patients with a low ratio will not benefit from treatment. The untreated group survived 58 months as compared to 22 months of survival for the treated patients (p=0.076). Patients with a high ratio value survived more than 5 years, independently of treatment. COX-2-negative patients survived for more than 10 years, irrespective of chemotherapy. However the COX-2 positive population behaved in a very different way according to the level of expression; low expressers had a survival of 5 months when not treated compared to 25 months when treated, whereas high expressers survived 10 years when not treated compared to 2 years when treated. No significance was observed with p53. These findings suggest that the phenotypic evaluation of primary CRC for expression of Bax and Bcl-2 and the ratio of Bcl-2/Bax value may help in identifying the aggressiveness of the lesions, thus, aid in the selection of patients for 5-FU treatment.
OP0331 A novel humanized effector-deficient fcyriia antibody inhibits immune complex mediated proinflammatory responses
Authors: B Chen, K Vousden, S Turman, H Sun, S Wang, L Vinall, B Kemp, S Kasturiangan, E Grant, MJ Hinrichs, S Eck, A DiGiandomenico, X Xiong, J Griffiths, R Herbst, D Close, R Kolbeck, G Sims
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Collectively, the cell surface Fc region of IgG receptors (FcγRs) engage soluble IgG and IgG containing immune complexes and trigger activation or inhibtory signals that play a critical role in the regulation of immune responses. The low affinity FcγRIIA (CD32A) is the most widely expressed activating FcγR in humans and appears to drive autoantibody and immune complex mediated autoimmune disorders. So far a therapeutic targeting this receptor has not been developed. <h3>Objectives</h3> To generate and characterize a novel humanized effector-deficient FcγRIIA antibody (MEDI9600) for clinical development. <h3>Methods</h3> The mode of action of MEDI9600 was assessed by confocal microscopy, whole blood internalization, and binding competition assays. Multiple cell based assays were used to measure autoantibody and immune complex mediated responses. The safety of MEDI9600 was assessed in <i>in vitro</i> by neutrophil migration, activation and opsonophagocytic killing assays. Safety and pharmacokinetics were examined <i>in vivo</i> in a single-dose PK/PD study in cynomolgus monkey. <h3>Results</h3> We generated a humanized effector-deficient FcγRIIA antibody (MEDI9600) that potently blocks both autoantibody and immuno complex-mediated proinflammatory responses from a variety of cell types. This includes the inhibition of Toll-like receptor stimulatory immune complexes that induce type I Interferons from pDC, and the inhibition of anti-neutrophil cytoplasmic antibody (ANCA) induced production of reactive oxygen species from neutrophils, which are associated with the pathogenesis of systemic lupus and ANCA vasculitis respectively. MEDI9600 specifically binds FcγRIIA and its suppressive activity is attributed to its capacity to block ligand engagement and to internalize the receptor from the cell surface. Moreover, <i>in vivo</i> studies indicate that MEDI9600 has a favorable pharmacokinetic and safety profile. <h3>Conclusions</h3> We have generated MEDI9600, a specific humanized antibody antagonist of FcγRIIA with null effector function that may provide a novel therapeutic approach in the treatment of immune complex mediated diseases. <h3>Disclosure of Interest</h3> None declared
AB0719 Baseline characteristic of newly diagnosed patients with axial spondyloarthritis: results from the single centre lithuanian cohort
Authors: J Sabaliauskiene, A Baranauskaite
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The prevalence rates for spondyloarthropathies has been investigated in an epidemiological study in Lithuania (1), but no studies are analysing the demographics, clinical characteristics of SpA in Lithuania. Changes in spondyloarthritis (SpA) concept and application of the new criteria for classification should improve spondyloarthritis diagnostic standards in routine clinical practice. <h3>Objectives</h3> To assess demographics and clinical manifestations of firstly diagnosed axial spondyloarthritis, to compare ankylosing spondylitis (AS) with non-radiographic axial spondyloarthritis (nr-axSpA) using standardized clinical assessment tools. <h3>Methods</h3> In September 2014 our centre began to collect a cohort of patients with newly diagnosed axial spondyloarthritis, according to ASAS criteria. Statistical analysis was performed with SPSS 20.0. A p&lt;0,05 was considered statistically significant. <h3>Results</h3> 97 patients (60 men, 37 women) have been included. All of them (100%) suffered from chronic back pain. Inflammatory back pain (according to ASAS criteria) was present in 77%. 34 (35,1%) patients already had definite radiographic changes in the sacroiliac joints (SIJ), therefore AS (based on modified New York criteria) was diagnosed. The mean age at first visit was similar: 34,3 (±10,0) in nr-axSpA and 36,1 (±11,0) in AS group. Duration of symptoms was significantly longer in AS group (mean 106,6 months in AS versus 44,8 months in nr-axSpA). The prevalence of HLA-B27 was similar: 74,6% vs 91.2% for nr-axSpA and AS, respectively. There were more males in AS group (76,5% vs 54,0%, p 0,03). The frequency of clinical features (peripheral arthritis, dactylitis) and extra-articular manifestations (enthesitis, uveitis, psoriasis, inflammatory bowel disease, preceding infection) was similar between the two subgroups (p&gt;0,05). Mobility was slightly more impaired in AS patients, but it did not reach a significant level. No differences in the level of global pain, patient9s global assessment were found. BASDAI did not show the significant difference between AS and nr-axSpA (mean 4,5±2,1 vs 3,9±2,0), as well CRP (mean CRP 17,33 mg/l vs 17,75 mg/l (p 0,2) and ESR. <h3>Conclusions</h3> Diagnosis of axial SpA in Lithuania remains delayed. The proportion of patients with AS among newly diagnosed axial SpA is high.There are more women in the nr-axSpA group. Both groups do not differ regarding clinical features, disease activity. <h3>References</h3> Adomaviciute D, Pileckyte M, Baranauskaite A, Morvan J, Dadoniene J, Guillemin F.Scand J Rheumatol. 2008 Mar-Apr;37(2):113–9 Prevalence survey of rheumatoid arthritis and spondyloarthropathy in Lithuania. <h3>Disclosure of Interest</h3> None declared
OP0335 Exploring associations between histologically assessed inflammation and pain and fatigue in knee osteoarthritis
Authors: MJ Minten, A Blom, GF Snijders, FH van den Hoogen, AA den Broeder, P van der Kraan, CH van den Ende
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Pain and fatigue are frequent symptoms of osteoarthritis (OA). However, the exact mechanism causing these symptoms remains unclear. Inflammation is important in OA pathophysiology. Associations between inflammatory aspects and clinical outcomes have been found. However, mainly (contrast-enhanced) MRI was used to assess synovial inflammation in these studies. Using this method, inflammation is assessed in an indirect way (e.g. infrapatellar fat pad signal enhancement, synovial fluid effusion and thickening of synovial tissue). Conversely, histological assessment of synovial inflammation is regarded as the gold standard. Using this method, specific aspects of inflammation can be distinguished and rated for severity. <h3>Objectives</h3> To evaluate the associations of inflammation-related histological parameters of the synovium with pain and fatigue in knee OA patients. <h3>Methods</h3> Fifty-nine patients fulfilling ACR criteria for knee OA were recruited from two prospective studies<sup>1,2</sup> and gave consent for synovial biopsy using a mini knee arthroscopy. Biopsies were taken from visually inflamed areas of the synovium. Tissue sections were histologically assessed for 1) number of synovial lining cells (absolute); 2) sub-synovial infiltration; 3) fibrin deposition; 4) vascularization; 5) fibrosis; and 6) perivascular edema (scores 0–3).<sup>3</sup> Average scores across sections were calculated for each parameter and for all parameters together. These data were combined with longitudinal clinical data from the prospective studies (WOMAC pain, SF36 vitality; 0=worst – 100=best). Associations between individual inflammatory features and clinical outcomes over time were assessed with mixed model analyses. <h3>Results</h3> Patient characteristics are shown in Table 1. Relatively mild levels of inflammation were found, in line with previous research (median 1.1 [95% CI 0.9–1.6]).<sup>3,4</sup> Longitudinal data was available for 56 patients. Age, gender, BMI and time since symptom onset were no confounders. No significant associations were found between any histological parameter and pain or fatigue over time (Table 2). <h3>Conclusions</h3> This is the first study to examine different parameters of histologically assessed synovial inflammation in knee OA patients and their associations with clinical outcomes over time. We were unable to identify individual inflammatory aspects which associate with pain or fatigue. Additional research is required to identify the underlying mechanism for pain and fatigue in OA. <h3>References</h3> Ann Rheum Dis 2011 70:1191–6. Scand J Rheum 2011 40:225–31. Clin Rheum 2010 29:1185–90. Arthritis Rheum 2005 52:3492–501. <h3>Disclosure of Interest</h3> None declared
OP0125 Mortality in patients with dermatomyositis/polymyositis in a chinese medical centre
Authors: X Yang
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To investigate the mortality and the causes of death in Chinese patients with dermatomyositis (DM) or polymyositis (PM). <h3>Methods</h3> We collected the clinical data of all DM/PM patients in Rheumatology department of Peking University First Hospital from January 2007 to May 2016.The primary causes of death were identified, the standardised mortality ratio (SMR) and years of life lost (YLL) were calculated based on the National Bureau of Statistics of China for the general population, the survival in the first decade was performed using Kaplan-Meier analysis, and the predictors of mortality were evaluated by multivariable cox regression. <h3>Results</h3> A total of 226 DM and 54 PM cases were included and the mean age of onset was 49.9±14.8 years for DM and 48.1±17.1 years for PM. The median follow-up duration was 40.6 (11.6–77.6) months. Among 267 patients who were successfully traced, 66 patients died. Infection (50.0%) was the leading cause of death followed by malignancy (19.7%), and interstitial lung disease (ILD) (9.1%). The overall age and sex adjusted SMR was 9.0 (95% CI 6.8–11.2) for DM, and 5.0 (95% CI 2.4–7.5) for PM. The overall age and sex adjusted SMR of DM/PM patients with ILD was 8.4 (95% CI 5.8–11.0), and the SMR of the patients with malignancy was 14.9 (95% CI 8.5–21.2). The YLL of women and men were 37.5 and 28.4 years respectively for DM, and 24.3 and 12.0 years respectively for PM (Table1). The 10-year survival of patients with ILD or malignancy was significantly worse than those without ILD or malignancy respectively (Figure 1 and 2). The independent predictors of mortality for DM were age of disease onset, respiratory muscle involvement and malignancy; and the independent predictor of mortality for PM was age at disease onset (Table2). <h3>Conclusions</h3> Mortality of DM/PM patients in China is substantial, especially in females, and those with ILD or malignancy. Infection was the leading cause of death. Patients with older age at onset, respiratory muscle involvement, ILD, and malignancy need to be paid more attention. <h3>Disclosure of Interest</h3> None declared
AB0873 Characteristics of adherence, persistence and therapeutic alliance in patients with gout
Authors: E Alvarez-Hernandez, LD Upegui-Arango, J Vazquez-Mellado, E Aranda-Arreola, R Burgos-Vargas, I Pelaez-Ballestas
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Adherence is the extent to which the patient takes their medications and follow the directions prescribed by their doctor. It has two components: compliance (the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage, and frequency) and persistence (the duration of time from initiation to discontinuation of therapy). The therapeutic alliance is the patient physician relationship that allows the patient to participate actively in their treatment. The reported adherence varies from 43 to 78% in patients with chronic diseases. In gout, the adherence varies from 10 to 46%. <h3>Objectives</h3> To evaluate the characteristics of adhesion in patients with gout. <h3>Methods</h3> Patients with gout from the GRESGO cohort were included. Sociodemographic, clinical, and treatment data were collected and the HAQ-DI, EuroQol-5d and a specific questionnaire of adherence and therapeutic alliance were applied. <h3>Results</h3> The study included 238 patients (97.1% male), whit a mean age of 47.7±12.7 years, educational level 9.2±4.2 years. The adherence index (prescribed doses/doses taken) was 86%. Only 28.6% never stopped treatment. 4.6% took the doses at the correct time. Most frequent causes of suspension were lack of supply (37%) and forgetfulness (30%). Only 5% buy all of their medications, 10% follow the lifestyle changes. 49.6% do not take the medication when they disagree with their doctor. <h3>Conclusions</h3> Despite having a good adherence index there are discrepancies with the qualitative answers, since more than 70% did not have good persistence and more than 90% did not comply with the schedule. <h3>Disclosure of Interest</h3> None declared
SP0117 Osteoporotic fractures in europe: are we doing enough
Authors: JA Kanis
Journal: Annals of the Rheumatic Diseases (2017)

The past 30 years has seen significant milestones in assessment and management of osteoporosis. These include the development of DXA and FRAX to identify individuals at high risk of fragility fracture and the development of interventions that have been shown to significantly decrease the risk of fracture in well-designed clinical trials. A major challenge has been how to apply these treatments. Measurements of bone mineral density (BMD) are used for diagnosis and for fracture risk prediction. Facilities for BMD testing are patchy and many European countries have inadequate resources to service the societal needs. In addition, BMD has poor sensitivity for the prediction of fracture so that the majority of fractures occur in individuals with T-scores &gt;-2.5 SD. The development of FRAX has improved the sensitivity of fracture risk prediction and is now adopted in many assessment guidelins. Despite these advances, there are a number of challenges to be faced. Of paramount importance is that few patients with a prior fracture and even less with osteoporosis alone actually receive treatment. In Europe, there is wide inter-country variation in the treatment of women at high risk for osteoporotic fractures. The treatment gap varies from 25% in Spain to 95% in Bulgaria. Large treatment gaps were identified in countries with populations at both high and low risk of fracture. In total in the EU, it is estimated that, out of the 18.4 million women that exceed the risk level in 2010, 10.6 million were untreated. These figures are conservative since an undetermined proportion of low-risk women will have received treatment. Moreover, the treatment gap is increasing in many countries. Thus the disease is under-recognised by the medical community. Urgent action is required to address the under-recognition of osteoporosis and fragility fracture. Simple measures include: The development of country-specific guidelines, Piloting screening strategies in the elderly, Identifying the determinants of imminent risk, The development of fracture liaison services. Whereas osteoporosis is recognized, worldwide, as a major Public Health issue, with one in two women and one in five men over the age of 50 years presenting a fragility fracture, a vast proportion of women at high risk remain untreated. Case-finding strategies prioritizing assessment of men and women with prior fracture are required to alleviate this problem. <h3>Disclosure of Interest</h3> None declared
FRI0078 ADENOSINMONOFOSFAT-AKTIVACTIVATING protein kinase (AMFK) – the biopower regulator of an autophagy in rheumatoid arthritis (PA)
Authors: VI Shihkin, GV Kudriavtseva, VV Shishkin, YA Malenkov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis is an autoimmune disease characterized by altered cellular homeostasis. A great role of an autophagy is expected in the pathogenesis of these changes. <h3>Objectives</h3> To assess the functional activity of AMFK as a strategic biopower regulator of an autophagy and specific indicator of red-ox potential of cells in the sinovial fluid (SF) of patients with rheumatoid arthritis (RA). <h3>Methods</h3> SF of knee joints of 7 RA patients with active synovitis and 5 donors were investigated. Activity of enzymes was measured in cytosol of SF cells after ultracentrifugation. Activity of AMFK was estimated with the Western blotting method. The consumption speed of oxygen by SF cells was recorded polarographycally using as the substrate glutamic acid (5 μ mol/ml in incubation fluid). Registration of the active forms of oxygen was carried out by EPR (electronic paramagnetic resonance). Levels of adenylic nucleotides were determined chromatographically. <h3>Results</h3> In RA SF we noted activation of AMFK (on average by 2,5 times) at the considerable increase of the AMP level and decrease in ADP and ATP. <h3>Conclusions</h3> These data demonstrate transition of cells of SF in RA to the energy saving mode of functioning that is followed by strengthening of oxidizing processes, deep dissociation of respiration with oxidizing phosphorylation and sharp increase of oxigen consumption speed by SF cells in vitro against the background of the progressing hypoxia of synovial cells and chondrocytes in vivo. Destabilization of mitochondrial and lysosomal membranes of SF cells appears against the background of shift of pH in RA in more acidic zone. It leads to the reinforced formation of the active forms of oxygen (short-lived toxiferous hydroxyl radicals), shift of red-ox potential of cells, activation of lysosomal hydrolyzing enzymes that forms biochemical mechanisms of development of an autophagy in RA. <h3>Disclosure of Interest</h3> None declared
Chromatin interactions reveal novel gene targets for drug repositioning in rheumatic diseases
Authors: Paul Martin, James Ding, Kate Duffus, Vasanthi Priyadarshini Gaddi, Amanda McGovern, Helen Ray-Jones, Annie Yarwood, Jane Worthington, Anne Barton, Gisela Orozco
Journal: Annals of the Rheumatic Diseases (2019)

Objectives There is a need to identify effective treatments for rheumatic diseases, and while genetic studies have been successful it is unclear which genes contribute to the disease. Using our existing Capture Hi-C data on three rheumatic diseases, we can identify potential causal genes which are targets for existing drugs and could be repositioned for use in rheumatic diseases. Methods High confidence candidate causal genes were identified using Capture Hi-C data from B cells and T cells. These genes were used to interrogate drug target information from DrugBank to identify existing treatments, which could be repositioned to treat these diseases. The approach was refined using Ingenuity Pathway Analysis to identify enriched pathways and therefore further treatments relevant to the disease. Results Overall, 454 high confidence genes were identified. Of these, 48 were drug targets (108 drugs) and 11 were existing therapies used in the treatment of rheumatic diseases. After pathway analysis refinement, 50 genes remained, 13 of which were drug targets (33 drugs). However considering targets across all enriched pathways, a further 367 drugs were identified for potential repositioning. Conclusion Capture Hi-C has the potential to identify therapies which could be repositioned to treat rheumatic diseases. This was particularly successful for rheumatoid arthritis, where six effective, biologic treatments were identified. This approach may therefore yield new ways to treat patients, enhancing their quality of life and reducing the economic impact on healthcare providers. As additional cell types and other epigenomic data sets are generated, this prospect will improve further.