tbuckley/cabot-search huggingface dataset:
OP0187 Transgenic disruption of glucocorticoid-signaling in mature osteoblasts and osteocytes attenuates structural bone damage in a long-term murine k/bxn serum-induced arthritis model
Authors: E Wiebe, C Spies, J Tu, T Maleitzke, Y Zhang, M Seibel, H Zhou, F Buttgereit
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The role of endogenous glucocorticoids (GC) in bone metabolism in chronic inflammatory arthritis remains unclear. We have previously shown that disruption of GC-signaling in osteoblasts results in a marked attenuation of arthritis in the K/BxN serum-induced and CAIA mouse model with preservation of bone volume and structure<sup>1,2</sup>. <h3>Objectives</h3> In order to investigate the impact of endogenous GCs on bone erosion and turnover in chronic inflammatory arthritis, we now studied the effects of disrupted osteoblastic GC-signaling in a <i>long-term</i> murine arthritis model. <h3>Methods</h3> Intracellular GC-signaling in osteoblasts was disrupted by transgenic overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD type 2) under the control of a type 1 collagen promoter. Arthritis was induced in 5-week old male transgenic (tg) mice and their wild-type (WT) littermates. In order to maintain a chronically active arthritis, mice were boosted on day 14 and 28 by subcutaneous injection of K/BxN serum, controls (CTR) received PBS, respectively. Severity of arthritis was assessed daily by clinical scoring and ankle size measurements until the endpoint (day 42). Ankle joints were assessed by a histopathologic score and microfocal computed tomography (micro-CT). Systemic effects of inflammation on bone metabolism were quantified by histomorphometry and micro-CT of the tibia. <h3>Results</h3> Acute Arthritis developed in both tg and WT mice and remained active over the period of 42 days, with a reduced, yet non-significant, severity in tg compared to WT mice. Histological indices of inflammation, cartilage damage and especially bone erosion, additionally assessed by micro-CT, tended to be overall reduced in tg mice, yet not reaching a level of significance. Bone volume and bone turnover did not differ between tg and WT arthritic mice. <h3>Conclusions</h3> The modulating effect of disrupted GC-signaling in osteoblasts in serum-induced autoimmune-arthritis prevails in a chronic inflammatory setting, leading to less severe local inflammation and bone destruction. This supports the important role of endogenous GCs for an intact bone metabolism in inflammatory bone disease. <h3>References</h3> Tu J, Zhang Y, Kim S, Wiebe E, Spies CM, Buttgereit F, et al. Transgenic Disruption of Glucocorticoid Signaling in Osteoblasts Attenuates Joint Inflammation in Collagen Antibody-Induced Arthritis. Am J Pathol. 2016;186(5):1293–301. Buttgereit F, Zhou H, Kalak R, Gaber T, Spies CM, Huscher D, et al. Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum-induced arthritis in vivo. Arthritis Rheum. 2009;60(7):1998–2007. <h3>Disclosure of Interest</h3> None declared
Inhibition of Bone Marrow-Derived Mesenchymal Stem Cells Homing Towards Triple-Negative Breast Cancer Microenvironment Using an Anti-PDGFRβ Aptamer
Authors: Simona Camorani, Billy Samuel Hill, Raffaela Fontanella, Adelaide Greco, Matteo Gramanzini, Luigi Auletta, Sara Gargiulo, Sandra Albanese, Enrico Lucarelli, Laura Cerchia, Antonella Zannetti
Journal: Theranostics (2017)

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are shown to participate in tumor progression by establishing a favorable tumor microenvironment (TME) that promote metastasis through a cytokine networks. However, the mechanism of homing and recruitment of BM-MSCs into tumors and their potential role in malignant tissue progression is poorly understood and controversial. Here we show that BM-MSCs increase aggressiveness of triple-negative breast cancer (TNBC) cell lines evaluated as capability to migrate, invade and acquire stemness markers. Importantly, we demonstrate that the treatment of BM-MSCs with a nuclease-resistant RNA aptamer against platelet-derived growth factor receptor β (PDGFRβ) causes the inhibition of receptor-dependent signaling pathways thus drastically hampering BM-MSC recruitment towards TNBC cell lines and BM-MSCs trans-differentiation into carcinoma-associated fibroblast (CAF)-like cells. Moreover, in vivo molecular imaging analysis demonstrated the aptamer ability to prevent BM-MSCs homing to TNBC xenografts. Collectively, our results indicate the anti-PDGFRβ aptamer as a novel therapeutic tool to interfere with BM-MSCs attraction to TNBC providing the rationale to further explore the aptamer in more complex pre-clinical settings.
Developing and validating a multivariable predictive biomarker for treatment selection for oropharyngeal squamous cell carcinoma: The PREDICTR-OPC study.
Authors: Hisham Mohamed Mehanna, Syed Haider, Davy Carlos Rapozo, Sandra . von Zeidler, Kevin Harrington, Stuart Winter, Terence Jones, Miranda Pring, Catharine West, Pawel Golusinski, Philip Sloan, Selvam Thavaraj, Edward William Odell, Keith Hunter, Ketan A Shah, Gareth Thomas, Max Robinson
Journal: Journal of Clinical Oncology (2017)

6004 Background: To date there are no validated predictive tests to inform treatment selection for patients with oropharyngeal cancer (OPC). Currently treatment is decided on disease resectability, clinician preference and patient choice. Methods: Objective To develop a predictive test to select treatment for advanced OPC. Participants Training cohort: 543 cases from 10 cancer centres. External validation cohort: 442 cases from 3 centres. Design Multivariable logistic regression of 8 clinical parameters and 10 biomarkers to develop biomarker-only and composite clinical/biomarker predictive models; subsequently validated on a separate cohort. Biomarkers scored by ≥2 ‘blinded’ pathologists. Outcomes Primary: overall survival (OS). Results: 724 males, 261 females; Median follow-up =8.8 (6.86-10.47) years. More validation cases received surgery (53.5% vs 37.9%, p=0.001) and fewer received chemo/radiotherapy (42%vs67.5%; p=0.001) compared to training cohort. The biomarker-only model performed better than the clinical/biomarker one. The final OS model - comprising p16, high risk HPV DNA ISH, survivin and tumour infiltrating lymphocyte score (TILS)- was not only prognostic for OS, but importantly was predictive for surgery+/-adjuvant RT over CRT (3yr OS 63%, vs 42.5% respectively) in the High Risk group. Treatments were equally effective in the Low Risk group. The RFS model (p16, PLK1, survivin, TILS) was prognostic, but not predictive for treatment. Validation testing confirmed good calibration and concordance (C-index =0.73; 0.68-0.79). The OS model remained prognostic and predictive for surgical treatment in High Risk group (HR=0.51; 95%CI= 0.3-0.85, p=0.01). Conclusions: To our knowledge, this is the first-ever validated model for treatment selection in HNC. Clinicians can now recommend the treatment most likely to be effective on the basis of an easily-applied, relatively inexpensive panel of 4 biomarkers. [Table: see text]
Abstract 18166: Comparison of Surgical Aortic Valve Replacement and Transcatheter Aortic Valve Replacmeent: Analysis From Nationwide Inpatient Sample
Authors: Yashwant Agrawal, Sandeep Patri, Sourabh Aggarwal, Soji Patri, Chris Jacob, Frank Saltiel, Jagadeesh K Kalavakunta, Vishal Gupta
Journal: Circulation (2016)

Introduction:  Transcatheter aortic valve replacement (TAVR) is the newer modality recently approved by FDA for patients with severe aortic stenosis deemed inoperable or high risk for surgical aortic valve replacement (SAVR).   Hypothesis:  This study was done to compare demographics, length of stay (LOS), mean charges and in-hospital mortality of patients undergoing TAVR and SAVR procedures in the United States for years 2012 and 2013.   Methods:  We used Nationwide Inpatient Sample (NIS) data to extract data for patients who were hospitalized with a primary diagnosis of TAVR and SAVR as specified by International Classification of Disease code 35.05, 35.06 and 35.21, 35.22 respectively. NIS data is 20% representative of all hospital data in USA. Data was extracted for the year 2012-2013 and various parameters associated with TAVR and SAVR were analyzed.   Results:  A total of 117,610 and 18,925 hospitalizations associated with primary diagnosis of SAVR and TAVR procedures were identified respectively. Mean chargers were lower for SAVR compared to TAVR ($50,225 vs. $137,221). Most of patients were 65-84 years (61.2%) in the SAVR group while in the TAVR group majority were >85 years age (45.42%). Mean length of stay was 10.1 days and 8.0 days with in-hospital mortality of 3.07% and 4.76% for SAVR and TAVR groups respectively. More males (63.68%) were undergoing SAVR when compared males undergoing TAVR (47.71%). Both for SAVR and TAVR the main insurance was Medicare (>64%) and belonged to not low income by household (>70%). Both the procedures were performed mostly at private, not-for profit, urban, large bedsize teaching centers (>70%). Both procedures were performed with highest numbers in the south (>35%).   Conclusions:  This is perhaps the first study comparing the different demographics of patients undergoing SAVR and TAVR. As TAVR is performed patients deemed high risk for SAVR, it is expected to have higher in-hospital mortality for these patients with more number of older patients undergoing TAVR. However, the mean LOS was less for TAVR patients. It is important to understand the type high-risk patients undergoing TAVR which is a newer intervention and further strategies to reduce in-hospital mortality and costs for patients undergoing TAVR should be undertaken.
MicroRNA-647 Targets SRF-MYH9 Axis to Suppress Invasion and Metastasis of Gastric Cancer
Authors: Gengtai Ye, Kunzhai Huang, Jiang Yu, Liying Zhao, Xianjun Zhu, Qingbin Yang, Wende Li, Yuming Jiang, Baoxiong Zhuang, Hao Liu, Zhiyong Shen, Da Wang, Li Yan, Lei Zhang, Haipeng Zhou, Yanfeng Hu, Haijun Deng, Hao Liu, Guoxin Li, Xiaolong Qi
Journal: Theranostics (2017)

MicroRNAs (miRNAs) play important roles in regulating tumour development and progression.Here we show that miR-647 is repressed in gastric cancer (GC), and associated with GC metastasis.Moreover, we identify that miR-647 can suppress GC cell migration and invasion in vitro.Mechanistically, we confirm miR-647 directly binds to the 3' untranslated regions of SRF mRNA, and SRF binds to the CArG box located at the MYH9 promoter.CCG-1423, an inhibitor of RhoA/SRF-mediated gene transcription, inhibits the expression of MYH9, especially in SRF downregulated cells.Overexpression of miR-647 inhibits MGC 80-3 cells' metastasis in orthotropic GC models, but increasing SRF expression in these cells reverses this change.Importantly, we found the synergistic inhibition effect of CCG-1423 and agomir-647, an engineered miRNA mimic, on cancer metastasis in orthotropic GC models.Our study demonstrates that miR-647 functions as a tumor metastasis suppressor in GC by targeting SRF/MYH9 axis.
Preclinical studies of SB 11285, a novel STING agonist for immuno-oncology.
Authors: Sreerupa Valli Challa, Shenghua Zhou, Anjaneyulu Sheri, Seetharamaiyer Padmanabhan, Geeta Meher, Rayomand Gimi, Diane Schmidt, Dillon Cleary, Nezam Afdhal, Radhakrishnan Iyer
Journal: Journal of Clinical Oncology (2017)

e14616 Background: The activation of innate and adaptive immunity via Stimulator of Interferon Genes (STING) signaling is a potentially transformative immuno-therapeutic strategy in cancer. We report here in vivo efficacy and safety studies of SB 11285. Methods: Tumor Growth Inhibition (TGI) and Tumor Growth Delay (TGD) studies in syngeneic mouse models were initiated when mean tumor volume (MTV) reached 100mm 3 : A20 Lymphoma: (10 animals/Group); (A) Saline; (B) 100µg SB 11285, intratumoral (i.t.), days 3,4,6,8,10; (C) 100mg/kg Cyclophosphamide, intraperitoneal (i.p), days 1,2; and (D) combination of cyclophosphamide+SB 11285. CT26 Colon Carcinoma experimental design is shown in Table. Re-challenge study was initiated in tumor-free animals in A20 lymphoma model on day 73, and monitored for an additional 45 days. Presence of activated immune cells intumor tissues was evaluated by immuno-histochemistry. Cytokine response was evaluated in serum after a single i.p. injection of SB 11285 at 10mg/kg. Maximum Tolerated Dose (MTD) in mice was determined by daily i.p. injection of SB 11285 for 10 days. Results: A20 model: % TGI in the treatment groups were—A, 0; B, 86; C, 98, and D, 93; % TGD, day 70: A, 0; B, 64; C, 156; D, 288. In D, day 73, 90% of animals remained tumor-free. CT26 model: Table 1 shows MTV on day 19 and %TGD on day 43; Re-challenge study. All animals from the SB 11285-treated groups remained completely tumor-free on day 45 compared to control group (MTV,1666 mm 3 ); Immuno-histochemistry of SB 11285-treated groups, revealed the infiltration of CD8 + T and NK cells into tumor and surrounding tissues; Cytokine analysis did not show systemic inflammatory response; MTD of SB 11285 was 16 mg/kg/day. Conclusions: SB 11285, a novel STING agonist, showed very potent, and highly durable immune response-mediated anti-tumor activity. SB 11285 was well tolerated, safe, and is being advanced to IND-enabling studies. [Table: see text]
FRI0259 Lupus low disease activity state (LLDAS) in patients with lupus nephritis (LN)
Authors: DV Monova, S Monov, M Ivanova, E Peneva
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Lupus Low Disease Activity State (LLDAS) is a consensus-based definition of minimally acceptable disease activity in patients with Systemic lupus erythematosus (SLE). <h3>Objectives</h3> The aims of this study were to evaluate what proportion of patients with LN fulfils the definition of LLDAS and to evaluate the effect of LLDAS attainment on damage accrual over a period of 5 years. <h3>Methods</h3> This is a retrospective analysis of data prospectively collected in a longitudinal observational cohort of LN patients. The conceptual definition of LLDAS is a state, which if sustained, is associated with good long-term outcomes. The operational definition of LLDAS is fulfilled when all of the following criteria are met: (1) SLE Disease Activity Index (SLEDAI-2 K) ≤4, with no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new features of lupus disease activity compared to the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (PGA) (scale 0–3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7,5 mg daily; and (5) well-tolerated standard maintenance doses of immunosuppressive drugs and approved biologic agents, excluding investigational drugs. The definition of LLDAS was applied to each patient for each visit; organ damage was calculated with the SLICC/DI score (SDI) at study entry and at last observation. <h3>Results</h3> 294 patients were eligible for the study (89.79% females, mean age at first visit 31,4±11,9 years, mean disease duration at last visit 19,8±8,7 years). At last observation 219 patients (85,37%) were on treatment with glucocorticoids (GC) and/or immunomodulators. According with all the items of the definition, at last observation LLDAS was present in 146 patients (49,65%); among these, 37 patients (20,8%) maintained a stable LLDAS during the last 5 years of follow-up (LLDAS fulfilled for all visits). 68 patients (23,12%) accrued organ damage during the follow-up; in the cohort as a whole the mean increase in SDI was 0,4±0.67 resulting in a mean final SDI of 1,2±1,8. Patients who maintained LLDAS were younger (p&lt;0,05), had a lower disease activity score at study entry (p&lt;0,001) and were more likely GC-free at last observation (p&lt;0,001). Patients who maintained LLDAS accrued less organ damage but this difference did not reach statistical significance. <h3>Conclusions</h3> High percentage of patients fulfils the proposed definitions for LLDAS at last visit but only a minority maintained this state for all the follow-up period. A minimally acceptable disease activity state is associated with a successful GC tapering and, probably, better long-term outcomes. LLDAS was shown to be associated with protection from damage accrual. <h3>Disclosure of Interest</h3> None declared
SAT0402 Frequency and HLA phenotype of reactive arthritis, uveitis, and conjunctivitis in japanese patients with bladder cancer following intravesical BCG therapy: a 20-year, two-center retrospective study
Authors: H Nishikawa, Y Taniguchi, K Inoue, Y Yoshinaga, Y Terada
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Intravesical instillation of Bacillus Calmette-Guerin (iBCG) is used as an effective immunotherapy of bladder cancer. However it may have, as adverse event, a reactive arthritis (ReA) and the frequencies are known as about 0.5 to 1% in Western countries. <h3>Objectives</h3> To evaluate the frequencies and HLA phenotype of reactive arthritis (ReA), uveitis, conjunctivitis and other adverse events in Japanese patients with bladder cancer following iBCG therapy. <h3>Methods</h3> The clinical findings of Japanese patients who received iBCG (n=555 [250 and 305 in Kochi Medical School Hospital {KMSH} and Kurashiki Medical Center {KMC}, respectively]) for bladder cancer from March 1997 to February 2016 were retrospectively assessed, with specific attention to patients with ReA and conjunctivitis/uveitis. We also looked at human leukocyte antigen (HLA) phenotypes of patients with ReA. <h3>Results</h3> Patient age was 73±10 and 70±11 years and male/female ratio was 198/52 and 240/65 in KMSH and KMC, respectively. 91/555 (16.4%), 121/555 (21.8%), and 196/555 (35.3%) of all enrolled patients presented with fever, haematuria, and dysuria, respectively. Of the 555 cases, ReA, uveitis and conjunctivitis were revealed in 11/555 (2.0%), 4/555 (0.7%) and 33/555 (5.9%), respectively. The frequency and the protocol of iBCG therapy were stable over the 20 years. Notably, HLA-B27, -B35, -B39 and -B51 positivity was more frequent in ReA patients (9.1%, 36.3%, 36.3% and 63.6%, respectively) (p&lt;0.05) than in healthy subjects without ReA (0.3%, 8.3%, 4.0% and 9.1%, respectively). <h3>Conclusions</h3> The 2.0% ReA frequency in iBCG-treated Japanese patients exceeds that in Western countries. HLA phenotype, especially HLA-B51 and -B39 alleles in addition to -B27, may be a risk factor in iBCG-induced ReA in Japanese patients. <h3>Disclosure of Interest</h3> None declared
SP0107 Hot session: scleroderma treatment
Authors: CP Denton
Journal: Annals of the Rheumatic Diseases (2017)

This presentation will provide an up to date summary of current management of SSc that can be applied across the disease spectrum. Systemic sclerosis (SSc) remains a challenging multifaceted rheumatic disease with high mortality and morbidity. However, treatments are emerging for some aspects of the disease and long term survival has improved significantly over the past decades. This session will review the clinical challenge and current therapeutic landscape of SSc focusing on practical aspects of management such as identifying and treating significant organ based complications in the lung, heart, kidney and gastrointestinal tract. Current approaches to overall disease management will be summarized including the use of haemopoietic stem cell transplant in selected poor prognosis cases. Recently updated EULAR/EUSTAR treatment recommendations will be reviewed and other evidence based management guidelines will be considered within a practical patient-focused framework. <h3>Disclosure of Interest</h3> C. Denton Grant/research support from: Inventiva, CSL Behring, GSK, Bayer, Consultant for: GSK, Actelion, Inventiva, Roche
AB0978 Association of inflammatory arthritis with vogt-koyanagi-harada syndrome (VKHS)
Authors: D Ramos-Bello, G Barragán-Pickens Aguilera, AJ Pedro-Martínez, G Martínez-Flores, TA Luna-Zúñiga, AN Rangel-Botello, PLR Hernández-Briano, MG Rangel-Charqueño, E Santillán-Guerrero, C Abud-Mendoza
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> VKHS is a rare cause of granulomatous uveitis leading to significant visual loss in patients who develop it, usually accompanied with extraocular manifestations that include meningismus, vitiligo, poliosis, and hearing loss. In our country is responsible for 13% to 27% of all uveitis, affecting mainly young women. <h3>Objectives</h3> To describe the presence of inflammatory arthritis in patients with VKHS at a third level hospital. <h3>Methods</h3> A cross-sectional study of 4 patients with established VKHS that fulfilled the 2001 revised diagnostic criteria for Vogt-Koyanagi-Harada disease (1) was rolled out. Ultrasonography was performed to all patients by a trained rheumatologist in carpal, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints evaluating presence of power Doppler (PD) signal, bone erosions, and cartilage changes. <h3>Results</h3> We included 3 women and 1 man, mean age was 34.7±10.3 years, and they all had characteristics of complete VKHS. Mean disease duration (since first manifestation of ocular symptoms) was 5.2±3.5 months. One patient had synovitis on physical examination. Out of the 4 patients with PD signal, 4 had involvement of both wrist, MCP and PIP joints consistent with polyarthritis pattern, and bone erosions were detected in one patient (Table) <h3>Conclusions</h3> The presence of inflammatory arthritis in patients with VKHS has only been described in one case (2). Despite the exceptionality, we propose that polyarthritis and probably erosive arthritis can represent part of the spectrum of the disease, processes that share some features of the genetic susceptibility with rheumatoid arthritis as HLA-DR4, CTLA-4 and STAT4. <h3>References</h3> Read RW, et al. Revised diagnostic criteria for Vogt- Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131:647–652. Aydin T, et al. Association of Vogt Koyanagi Harada Syndrome and Seronegative Rheumatoid Arthritis. Ethiopian Journal of Health Sciences. 2016;26(2):193–196. <h3>Disclosure of Interest</h3> None declared