tbuckley/cabot-search huggingface dataset:
Phosphorylation of IRS4 by CK1γ2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway
Authors: Xinchun Li, Li Zhong, Zhuo Wang, Huiming Chen, Dan Liao, Ruhua Zhang, Hongyu Zhang, Tiebang Kang
Journal: Theranostics (2018)

IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level.Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4.The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment.In vitro kinase assay was used to determine the phosphorylation of IRS4 by casein kinase 1γ2 (CK1γ2).Colony formation assay and xenograft-bearing mice were employed to assess the cancer cell growth in vitro and in vivo, respectively.Immunohistochemistry was performed to examine protein levels of both IRS4 and CK1γ2 in osteosarcoma specimens and their relationship was evaluated by χ 2 test.Two-tailed Student's t-test or the Mann-Whitney U test were used to compare the differences between subgroups.Results: IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).Using osteosarcoma cell lines, the ectopic nonphosphorylated mutant of IRS4 by CK1γ2 triggered higher level of p-Akt and displayed faster cell proliferation and cancer growth in vitro and in nude mice.In addition, a negative correlation in protein levels between CK1γ2 and IRS4 was observed in osteosarcoma cell lines and tissue samples.Conclusions: IRS4, as a new substrate of CHIP, is negatively regulated by CK1γ2 at the posttranslational level, and specific CK1γ2 agonists may be a potentially effective strategy for treating patients with osteosarcoma.
A novel role for neutrophils in IgE-mediated allergy: Evidence for antigen presentation in late-phase reactions
Authors: Dominika Polak, Christine Hafner, Peter Briza, Claudia Kitzmüller, Adelheid Elbe-Bürger, Nazanin Samadi, Maria Gschwandtner, Wolfgang Pfützner, Gerhard J. Zlabinger, Beatrice Jahn-Schmid, Barbara Bohle
Journal: Journal of Allergy and Clinical Immunology (2018)
SAT0689 Thymectomy in patients with myasthenia gravis and the risk of autoimmune rheumatic diseases: a nationwide cohort study
Authors: C.C. Chang, J.-H. Chen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Previous studies have shown myasthenia gravis (MG) and autoimmune rheumatic diseases (ARDs) share common pathogenetic mechanisms. <h3>Objectives</h3> Therefore, the present study investigated the possible relationship between MG and ARDs. <h3>Methods</h3> We analysed Taiwanese medical data from the Registry of Catastrophic Illness and identified patients with MG. From the entire general population data of the National Health Insurance Research Database, we randomly selected a comparison cohort that was frequency-matched by age (in 5 year increments), sex, and index date. We analysed the risk of ARDs by using a Cox proportional hazards regression model stratified by sex, age, and treatment. <h3>Results</h3> We enrolled 6478 patients with MG (58.03% women; mean age, 50.55 years) and 25 912 age- and sex-matched controls in the present study. The risk of total ARDs was 6.25 times higher in the MG cohort than in the non-MG cohort after adjustment for age and sex. Furthermore, the MG cohort was associated with a significantly higher risk of primary SS (pSS), SLE, and other ARD types (adjusted hazard ratios [HRs]: 15.84 [95% CI: 8.39–23.91]; 11.32 [95% CI: 5.04–25.429]; and 4.07 [95% CI: 1.31–12.62], respectively). MG cohort who received thymectomy had an increased risk of RA, pSS, and SLE (adjusted HRs: 4.41; 15.06; and 23.68, respectively). <h3>Conclusions</h3> The present nationwide cohort study revealed an association between MG and incident ARDs. MG cohort who received thymectomy had an increased risk of RA, pSS, and SLE. Future studies are needed to elucidate the underlying pathogenesis and to translate them into clinical therapeutic options. <h3>References</h3> [1] Voight BF, Cotsapas C. Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity.Curr Opin Immunol2012;24:552–557. [2] Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet2013;14:661–673. [3] Fang F, Sveinsson O, Thormar G, et al. The autoimmune spectrum of myasthenia gravis: a Swedish population-based study. J Intern Med2015;277(5):594–604. [4] Christensen PB, Jensen TS, Tsiropoulos I, et al. Autoimmune diseases in myasthenia gravis. A population-based studyActa Neurol Scand1995;91(3):192–195. <h3>Disclosure of Interest</h3> None declared
AB0678 Peripheral ulcerative keratitis associated to autoimmune systemic diseases: visual prognosis and occurrence while systemic disease in remission
Authors: L. Pelegrin, J. Hernández-Rodríguez, J. Torras, G. Espinosa, A. Adán, M.T. Sainz
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> <b>Background:</b> Peripheral ulcerative keratitis (PUK) is a corneal crescent-shaped inflammatory damage with/without concomitant scleritis. PUK can occur isolated or as part of an underlying systemic disease (SD). <h3>Objectives</h3> <b>Objective:</b> To characterise a cohort of PUK patients with a long-term follow-up and to evaluate clinical (ocular and systemic) parameters as predictors of ocular prognosis, in terms of relapses and visual outcomes. <h3>Methods</h3> <b>Methods:</b> Retrospective review (1996–2017) of patients with PUK from a multidisciplinary Uveitis Unit (Ophthalmology/Autoimmune Diseases). Data recorded included ophthalmological features, clinical assessment and laboratory markers at disease onset, and therapeutic interventions, ocular relapses and visual outcomes during follow-up. <h3>Results</h3> <b>Results:</b> Among 18 PUK patients evaluated, 3 were idiopathic, 3 infectious and 12 (67%) associated with systemic diseases (SD-PUK): 8 rheumatoid arthritis (RA), 2 ANCA-vasculitis, 1 SLE and 1 Takayasu's arteritis. Among SD-PUK patients, sex ratio favoured women (rate 9:3) with a median age of 72 (range 33–85) years. Unilateral/bilateral involvement occurred in 7/5 patients and associated scleritis in 50% (11 eyes). All patients presented with eye pain/redness and visual impairment. Four (33%) patients (5 eyes) suffered ocular perforation and required surgery. All patients received topical glucocorticoids (GC), 75% systemic GC, 33% additional immunosuppressant, and 42% biologic therapy. Mean follow-up were 7.3 (range 0.5–12) years. The annual relapse rate was 0.3. Final visual acuity worsened in 42% (8 eyes). In 10 (83%) patients PUK onset occurred previous to SD diagnosis or with SD in remission, and only 3 (25%) were receiving treatment for SD. No prognostic factors were found to correlate with PUK relapses and final visual acuity/ocular perforation. <h3>Conclusions</h3> <b>Conclusions:</b> RA and ANCA-vasculitis are the SD more frequently associated with PUK. Visual outcomes are poor in less than 50% of patients despite of topical and systemic GC/biologic therapy. SD-PUK may emerge previous to the SD diagnosis or with the associate SD in remission. <h3>Disclosure of Interest</h3> None declared
FRI0384 Primary sjÖgren’s syndrome stratified based on the severity of patient-reported fatigue
Authors: S. Gandolfo, E. Doriguzzi Breatta, C. Fabro, S. Zandonella Callegher, L. Quartuccio, S. De Vita
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> fatigue is one of the most common symptoms reported by patients affected by primary Sjögren's syndrome (pSS), and a major contributor to impaired quality of life. <h3>Objectives</h3> to analyse the clinical, serological and histological features of pSS patients stratified according to the severity of their self-reported fatigue. <h3>Methods</h3> among pSS patients undergoing clinical evaluation in our Sjögren's Clinic in a six-months period (January-June 2017), 86 consecutive unselected patients, fulfilling the latest ACR/EULAR pSS classification criteria, accepted to report their degree of fatigue on a 10 cm VAS (range 0–100) and to complete the ESSPRI questionnaire. Four subgroups of fatigue severity were defined, as previously published<sup>1</sup>: no fatigue (VAS=0); low fatigue (VAS=1–24); moderate fatigue (VAS=25–74); high fatigue (VAS=75–100). For each subgroup demographic, serological, histological features and ESSDAI score were collected, as well as the prevalence of pSS-related lymphoma, fibromyalgia (FM), autoimmune thyroiditis, and anaemia. <h3>Results</h3> fatigue was reported by the 87.2% (n=75) of pSS patients, distributed in subgroups as following: 25.3% (n=19) with low fatigue, 58.7% (n=44) with moderate fatigue and 16% (n=12) with high fatigue. Lymphoma was significantly (p=0.0133) more frequent in the pSS subgroup with high fatigue (33.4%, by considering active lymphoma cases; 50%, by considering also the cases with lymphoma in remission). FM patients were a minority (4.7% ; n=4), and never complained of high fatigue, all of them reporting moderate fatigue. A significant correlation was finally found between fatigue severity and ESSPRI (p&lt;0.0001), but not with ESSDAI (p=0.31). No significant age or sex difference was observed between subgroups. Also autoimmune thyroiditis, anaemia, anti-SSA and/or anti-SSB positivity, rheumatoid factor positivity, and cryoglobulinemia showed no significant difference between subgroups. <h3>Conclusions</h3> when fatigue is better stratified in pSS, it appears that it is usually moderate or severe, rather than mild. Furthermore, it is unrelated to FM. Overall, fatigue appears as a consequence of pSS itself. Of note, severe fatigue was related in this study with the most important complication influencing patient survival in pSS, i.e., lymphoma. Further studies are needed to disclose the pathogenetic events leading to fatigue in pSS, and investigation of lymphoma in pSS might be also helpful to this end. <h3>Reference</h3> [1] Ng WF, et al. Transcriptional Signature of Fatigue Derived from Patients with Primary Sjögren's Syndrome. PLoS One2015Dec 22;10(12):e0143970. <h3>Disclosure of Interest</h3> None declared
AB0424 Il-6 receptor blockade induced a different immune response in rheumatoid arthritis patients with and without remission
Authors: C. Diaz-Torne, P. Estrada, M.A. Ortiz, P. Moya, C. Moragues, D. de la Fuente, V. Torrente, J. Ramirez, D. Reina, M. Moreno, E. Casado, N. Busquets, M. Pujol, M.V. Hernandez, P. Santo, S. Ros, E. Garcia-Casares, H. Corominas, S. Vidal, J. de Agustin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Tocilizumab (TCZ) is a humanised antibody that blocks IL-6 receptor. Despite its effectiveness in rheumatoid arthritis (RA), there are patients that do not respond to the IL-6R blockade. The immune characteristics that would explain this lack of response are not known. <h3>Objectives</h3> Our aim was to determine the tocilizumab-induced changes in CD4 +T cells of patients that achieve, or not, remission at 12 m. <h3>Methods</h3> Prospective, multicenter study in 47 RA patients treated with TCZ during one year following standard clinical practice. Demographic, disease and treatment characteristics were collected at each visit. Ultrasound (US) grey scale and power doppler were assessed for joints and tendons using a semiquantitative scale from 0–3 points. Phenotyping of T lymphocytes was determined by flow cytometry and the plasma cytokine concentration was quantified by ELISA. <h3>Results</h3> Forty seven patients were treated with a mean age of 54±11 y and 85% were women. Years of disease were 13±8. We segregated patients according to the DAS28-remission. 44% achieved remission at month 12. We observed that absolute counts of neutrophils and CD4 +T lymphocytes decreased significantly in the remission group but not in the other one. Both memory and naïve CD4 +T cells decreased in the remission group. The analysis of T cells classified according to chemokine receptors showed that memory (29.1±4.0 vs 22.7±2.7 × 10<sup>4</sup> cells/mL; p=0.06) and naïve (22.6±4.1 vs 17.2±2.8; p=0.04) CD4 +with CXCR3 +and with CCR4 +were the subsets that decreased significantly in the remission group but not in the non-remission group. Since the expression of chemokine receptors defines the different Th subpopulations, we analysed them in the two groups of patients. Th1 tended to decreased in the remission group (3.5±0.7 vs 2.5±0.4; p=0.06) and Th9 decreased significantly in both groups (R: 5.0±0.8 vs 2.5±0.3; p=0.006 and Non R 5.5±0.8 vs 3.1±0.4; p=0.001). In regard to the cytokines produced by CD4 +T lymphocytes, IL-17 (2.1±1.1 vs 1.2±0.5 ng/ml; p=0.04) and VEGF (0.5±0.2 vs 0.3±0.1 ng/ml; p=0.05) but not IL-6 and IL-22 changed significantly in the remission group. Interestingly, IL-17 and VEGF correlated with US findings before the initiation of the treatment (grey scale R=0.378, p=0.01 and R=0.322, p=0.03; power Doppler R=0.415, p=0.004 and R=0.320, p=0.03 respectively). <h3>Conclusions</h3> Tocilizumab induced changes in specific subsets of CD4 +T cells and their inflammatory associated cytokines in the remission group. <h3>Disclosure of Interest</h3> None declared
SAT0587 Major salivary glands ultrasonography in differential diagnosis of igg4-related disease and primary sjogren’s syndrome
Authors: E. Sokol, E. Rodionova, V. Vasilyev, S. Palshina, M. Burtseva
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> IgG4-related disease (IgG4-RD) is a group of fibro-inflammatory immunomediated conditions with IgG4 overexpression in the serum and affected tissues in the majority of patients. Major salivary and lacrimal glands are the most frequently affected sites in IgG-RD. Moderate sicca symptoms can be present as well thus requiring differential diagnosis with primary Sjogren's syndrome (pSS). Major salivary glands ultrasonography (sUS) has been reported as an effective diagnostic tool in pSS. <h3>Objectives</h3> To evaluate the difference in sUS score in pSS and IgG4-RD patients <h3>Methods</h3> 15 patients with IgG4-related sialoadenitis consecutively admitted to our clinic and 28 with pSS underwent sUS. Parenchymal echogenicity, homogeneity, hypoechogenic and hyperechogenic areas and clearness of salivary gland border were scored according to the Hocevar scoring system (cut-off – 15 points). Statistical analyses were performed using MEDCALC program. Median values of the sUS score and Mann-Whitney U-test were used to evaluate differences in total ultrasound score between patients in two groups. <h3>Results</h3> All patents with IgG4-related sialadenitis and pSS had some sUS abnormalities. The most frequent feature in IgG4-RD were: the presence of hypoechotic lesions in major salivary glands (53% of patients) or diffuse salivary gland parenchyma hypoechogenity (27% of patients) and multiple intraglandular lymph nodes (66,7% of patients). Median value of sUS score in IgG4-RD group was 12 points and in pSS group – 22 points. The difference was significant (Mann-Whitney U-test 60.5, p&lt;0.05). <h3>Conclusions</h3> Although different US-changes are frequently seen in IgG4-RD patients, sUS Hocevar score seems to be a rather reliable tool to differentiate IgG 4-related sialoadenitis and pSS. <h3>Disclosure of Interest</h3> None declared
Precision Prevention and Early Detection of Cancer: Fundamental Principles
Authors: Timothy R. Rebbeck, Karen Burns-White, Andrew T. Chan, Karen Emmons, Matthew Freedman, David J. Hunter, Peter Kraft, Francine Laden, Lorelei Mucci, Giovanni Parmigiani, Deborah Schrag, Sapna Syngal, Rulla M. Tamimi, Kasisomayajula Viswanath, Matthew B. Yurgelun, Judy E. Garber
Journal: Cancer Discovery (2018)

Prevention and early detection is critical for reducing the population cancer burden. Two approaches have been used: Population approaches change social norms (e.g., smoking bans) or impose incentives (e.g., cigarette taxes); high-risk strategies intervene upon individuals with elevated cancer risk (e.g., smoking cessation). Knowledge about carcinogenesis mechanisms, extreme exposures, and inherited susceptibility provides opportunities to develop precision prevention and early-detection (PPED) strategies. PPED aims to understand the basis of risk, identify groups that optimally benefit from interventions, characterize heterogeneity in intervention responses, optimize intervention timing, and minimize toxicities. We propose a framework around which PPED strategies can be developed. Currently available cancer prevention and early-detection approaches have the potential to reduce a large proportion of the cancer burden in the population. However, even if fully implemented, existing methods cannot fully eliminate the cancer burden. New PPED approaches that exploit the growing knowledge of molecular and biological cancer mechanisms should be developed and implemented. Cancer Discov; 8(7); 803-11. ©2018 AACR.
THU0401 Global longitudinal strain as early predictor of systolic dysfunction in systemic sclerosis
Authors: C. Fischetti, F. Guerra, A. Ferrarini, L. Zuliani, G. Stronati, P. Fraticelli, M.G. Danieli, A. Capucci, A. Gabrielli
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology, characterised by microvascular abnormalities, immune abnormalities and progressive cutaneous and internal organs fibrosis. Subclinical heart disease in SSc patients is common but difficult to detect through conventional imaging. <h3>Objectives</h3> We sought to evaluate speckle-tracking derived global longitudinal strain (GLS) as an early marker of subclinical systolic dysfunction in patients with SSc. <h3>Methods</h3> We enrolled 52 patients with SSc and 52 age and gender matched controls. Patients with structural heart disease, heart failure, atrial fibrillation or pulmonary hypertension were excluded. An echocardiographic exam was performed for all patients, and standard and specke-tracking derived variables for the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV) were acquired. SSc variant, antibodies pattern, cardiovascular risk factors and involvement of other organ systems were recorded. <h3>Results</h3> Common parameters of left and right systolic function did not differ between SSc patients and controls and were on average well above the cut-off for normality (all p=NS). LV and RV GLS were significantly impaired in patients with SSc when compared to healthy controls (−19.2% vs. −21.1%; p=0.009 and −18.2% vs. −22.3%; p=0.012 respectively). In patients with SSc, GLS impairment was greater in basal segments when compared to midventricular and apical ones and homogeneous between the endo-, meso-, or epicardial layers of the RV, while LV showed an eccentric pattern with the epicardial layers mostly impaired. Using −20% as a cut-off for GLS, SSc patients had a 2.5-fold increased risk of subclinical LV systolic impairment (OR 2.5; 95% CI 1.1–5.5; p=0.027) and a 3.3-fold increased risk of subclinical RV systolic impairment when compared to age and gender matched controls (OR 3.3; 95% CI 1.4–7.7; p=0.004). <h3>Conclusions</h3> While traditional parameters are ineffective in detecting subclinical systolic impairment, a reduced GLS is common in patients with SSc and is significant for both LV and RV. While GLS impairment recognises a basal-apical gradient, transmural heart involvement seems different between RV and LV, suggesting a different mechanism of disease between the two ventricles. <h3>Disclosure of Interest</h3> None declared
Novel endoscopic approach to resection of large symptomatic duplication cysts
Authors: Lionel D’Souza, Arvind Trindade, Brian Markowitz, David Carr-Locke, Petros Benias
Journal: Endoscopy (2018)

We present the case of a 51-year-old man with dysphagia to solids and occasional retrosternal chest pain. Computed tomography of the chest revealed an esophageal mass, which on endoscopy was just distal to the gastroesophageal junction. An esophagram found a delay in the passage of contrast as a result. An endoscopic ultrasound (EUS) demonstrated an anechoic/hypoechoic third layer cyst, with internal debris and a redundancy of layers, consistent with a large duplication cyst. Although definitive management is surgical excision, simple endoscopic fenestration has been described [1] [2]; however, there remains a concern about recurrence in the long term. We offered the patient a novel endoscopic approach aimed at complete excision of the luminal cyst wall, reducing any long-term recurrence ([Video 1]).
Ruxolitinib for the Treatment of Essential Thrombocythemia
Authors: Arief Gunawan, Patrick Harrington, Natalia Garcia‐Curto, Donal McLornan, Deepti Radia, Claire Harrison
Journal: HemaSphere (2018)

Deregulated Janus Kinase 2 (JAK2) activation is central to the pathogenesis of most myeloproliferative neoplasms (MPNs), of which essential thrombocythemia (ET) is the most common entity. Patients with ET are risk-stratified according to their risk of thrombo-hemorrhagic complications. High-risk patients are offered treatments to reduce their platelet count using cytoreductive therapy. The disease course is often long and therapy intolerance is not infrequent. Ruxolitinib, a Janus Kinase (JAK) 1/JAK2 inhibitor, has demonstrated efficacy in patients with both myelofibrosis (MF) and polycythemia vera and is well tolerated. Side effects include predictable cytopenias and an augmented risk of infections. Ruxolitinib has been investigated in a small group of ET patients who were refractory/intolerant to hydroxycarbamide (HC) and demonstrated improvements in both symptoms and splenomegaly. Of note, a proportion of treated patients (13.2%) also had a significant reduction in platelet counts. However, these results require further validation in comparison with conventional therapy. Recently, a randomized-controlled phase 2 study (MAJIC-ET) assessed the role of Ruxolitinib in patients refractory or intolerant to HC. This study revealed that Ruxolitinib demonstrated some clinical efficacy but was only superior in terms of symptom control. In clinical practice, some individuals with ET do exhaust all potential treatment options and there may well be a role for Ruxolitinib in such patients or those with a significant symptom burden. However, in the wider context the goal of therapy with the use of JAK inhibitor therapy in ET needs to be defined carefully and we explore this within this timely review article.