tbuckley/cabot-search huggingface dataset:
circRNA.33186 Contributes to the Pathogenesis of Osteoarthritis by Sponging miR-127-5p
Authors: Zhi-bin Zhou, Gao-xiang Huang, Qiang Fu, Bin Han, Jia-jia Lu, Ai-min Chen, Lei Zhu
Journal: Molecular Therapy (2019)

Osteoarthritis (OA), the most prevalent age-related joint disorder, is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. Accumulating evidences indicate that circular RNAs (circRNAs) play a critical role in various diseases, but the function of circRNAs in OA remains largely unknown. Here we showed that circRNA.33186 was significantly upregulated in IL-1β)-treated chondrocytes and in cartilage tissues of a destabilized medial meniscus (DMM)-induced OA mouse model. Knockdown of circRNA.33186 increased anabolic factor (type II collagen) expression and decreased catabolic factor (MMP-13) expression. Knockdown of circRNA.33186 also promoted proliferation and inhibited apoptosis in IL-1β-treated chondrocytes. Silencing of circRNA.33186 in vivo markedly alleviated DMM-induced OA. Mechanistic study showed that circRNA.33186 directly binds to and inhibits miR-127-5p, thereby increasing MMP-13 expression, and contributes to OA pathogenesis. Taken together, our findings demonstrated a fundamental role of circRNA.33186 in OA progression and provide a potential drug target in OA therapy. Osteoarthritis (OA), the most prevalent age-related joint disorder, is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. Accumulating evidences indicate that circular RNAs (circRNAs) play a critical role in various diseases, but the function of circRNAs in OA remains largely unknown. Here we showed that circRNA.33186 was significantly upregulated in IL-1β)-treated chondrocytes and in cartilage tissues of a destabilized medial meniscus (DMM)-induced OA mouse model. Knockdown of circRNA.33186 increased anabolic factor (type II collagen) expression and decreased catabolic factor (MMP-13) expression. Knockdown of circRNA.33186 also promoted proliferation and inhibited apoptosis in IL-1β-treated chondrocytes. Silencing of circRNA.33186 in vivo markedly alleviated DMM-induced OA. Mechanistic study showed that circRNA.33186 directly binds to and inhibits miR-127-5p, thereby increasing MMP-13 expression, and contributes to OA pathogenesis. Taken together, our findings demonstrated a fundamental role of circRNA.33186 in OA progression and provide a potential drug target in OA therapy.
Abstract 17286: Reconciling Systolic and Diastolic Measures of Left Ventricular Noncompaction Cardiomyopathy in Cardiac Magnetic Resonance
Authors: Richard B Stacey, Bharathi Upadhya, Michael M Milks, Christian Deutsch, Tiffany Lin, William G Hundley, Vinay Thohan
Journal: Circulation (2014)

Background: Previously, it was demonstrated that systolic measures identify higher levels of risk for events related to left ventricular noncompaction cardiomyopathy (LVNC) than diastolic measures. This analysis seeks to improve the ability of the diastolic measures to identify LVNC and predict associated events. Methods: Trabeculation/possible LVNC by cMRI was retrospectively observed among 122 consecutive cases. We assessed the extent of trabeculation, end-systolic noncompacted-to-compacted ratios (ESNCCR), end-diastolic noncompacted-to-compacted ratios (EDNCCR) along with myocardial thickening (MT) and ejection fraction (EF). Deaths, CHF readmissions, ventricular arrhythmias, and embolic events were pooled to increase statistical power and used to identify potential LVNC-associated events. Using logistic regression with an ESNCCR ≥ 2 to identify LVNC as the dependent variable and EDNCCR as the independent variable, analysis were performed with receiver operating curves with and without myocardial thickening as a covariate. Next, using pooled LVNC-associated events as the dependent variable, separate models were performed for ESNCCR ≥ 2 and EDNCCR ≥ 2.3, both adjusting for age, race, gender, body surface area, left ventricular ejection fraction, number of trabeculated segments, and myocardial thickening. Results: The area under the curve (AUC) for EDNCCR to identify potential LVNC was 0.84, but with adjustment for myocardial thickening, the AUC was 0.98, which was significantly increased (p-value = 0.005). Without adjusting for myocardial thickening, ESNCCR ≥ 2 was associated with LVNC-associated events, but EDNCCR ≥ 2.3 was not (p-value: 0.003 vs 0.2, respectively). With adjustment for myocardial thickening, both ESNCCR ≥ 2 and EDNCCR ≥ 2.3 were associated with LVNC-associated events (p-value: 0.03 vs 0.03, respectively). Conclusion: In using the diastolic measure to assess for possible left ventricular noncompaction cardiomyopathy, impaired function of the underlying compacted layer is important in identifying those with a higher risk of subsequent events. Further studies are needed to determine if individuals with increased trabeculations with preserved myocardial thickening are at increased risk of future events.
AB0081 Low lipocalin-2 in systemic lupus erythematosus pregnancies- a possible mechanism for loss of tolerance
Authors: T.T. Pedersen, M.H. Fenstad, B. Jakobsen, H.S. Koksvik, T.S. Moksnes, M. Wallenius, T.H. Flo, M. Haug
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Lipocalin-2 (LCN2) has become increasingly relevant as a potential clinical biomarker of rheumatic diseases.<sup>1</sup> The biological role of LCN2 in the adaptive immunity is less understood. It has been shown that LCN2 can induce immune tolerance by upregulation of human leukocyte antigen G (HLA-G) expression and by expansion of T-regulatory cells.<sup>2</sup> LCN2-deficient mice have been found to be more susceptible to induction of autoimmunity.<sup>3</sup> Systemic lupus erythematosus (SLE) is a disease associated with loss of tolerance. Pregnancy complications seen in SLE are also regarded as a consequence of immune dysregulation. LCN2 might therefore play a role as an immune modulator in SLE-pregnancies. <h3>Objectives</h3> The study objective was to obtain a better understanding of immune regulation in pregnant women with SLE. In this study, we analysed serum LCN2 and clinical parameters in women with RA, SLE and healthy controls during pregnancy and postpartum. <h3>Methods</h3> The Norwegian National Advisory Unit on Pregnancy and Rheumatic Diseases collects serum samples in a biobank from women with inflammatory rheumatic diseases. Samples were obtained before pregnancy, in each trimester and 6 weeks, 6 months and 12 months postpartum from pregnant women with SLE (n=28), RA (n=34) and healthy pregnant controls (n=19). A sandwich ELISA was used to measure LCN2 in the serum samples. The biobank database was linked to RevNatus, a Norwegian quality registry collecting comprehensive clinical data about these women. <h3>Results</h3> Our cohort of pregnant women with SLE and RA had low disease activity throughout pregnancy and 67%–95% used medication (table 1). LCN2 levels in serum samples from women with SLE were found significantly lower compared to samples from women with RA and healthy controls at all time-points (p&lt;0.05) (graph). <h3>Conclusions</h3> Pregnant women with SLE had lower levels of LCN2 compared to pregnant women with RA and healthy controls. Our cohort of women had well controlled disease, making it likely that our findings represent inherent biological differences rather than effects of disease activity. Low LCN2 levels can be a possible mechanism for loss of tolerance seen in SLE patients during pregnancy. <h3>References</h3> [1] Abella V. Biomarkers2015;20(8):565–71. [2] La Manna G. PLoS One2014Feb 27;9(2). [3] Pawar RD. Clin Immunol2014Sep;154(1):49–65. <h3>Acknowledgements</h3> This study is supported by grants from St. Olavs Hospital and Norsk Revmatikerforbund. <h3>Disclosure of Interest</h3> None declared
Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non–small Cell Lung Cancer Patients
Authors: Pauline L. de Goeje, Myrthe Poncin, Koen Bezemer, Margaretha E.H. Kaijen-Lambers, Harry J.M. Groen, Egbert F. Smit, Anne-Marie C. Dingemans, André Kunert, Rudi W. Hendriks, Joachim G.J.V. Aerts
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Chemotherapy has long been the standard treatment for advanced stage non–small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune-modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the response to checkpoint inhibitors in peripheral blood. Experimental Design: A total of 223 patients with stage IV NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle, proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and coinhibitory receptors on these subsets were determined. Results: Although proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RA+ effector subsets. The proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1 and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) compared with nonproliferating CD8 T cells. Immunologic responders (iR; &amp;gt;2 fold increased proliferation after treatment) did not show an improved progression-free (PFS) or overall survival (OS). Conclusions: Paclitaxel/carboplatin/bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing coinhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.
Targeted Genomic Profiling of Acral Melanoma
Authors: Iwei Yeh, Eric Jorgenson, Ling Shen, Mengshu Xu, Jeffrey P North, A Hunter Shain, David Reuss, Hong Wu, William A Robinson, Adam Olshen, Andreas von Deimling, Pui-Yan Kwok, Boris C Bastian, Maryam M Asgari
Journal: JNCI Journal of the National Cancer Institute (2019)

Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete.To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases.In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry.Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.
SP0094 New insights into antibody-based therapies and disease susceptibilities revealed by microscopy of human nk cells
Authors: D.M. Davis
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Natural Killer (NK) cells express the Fc receptor CD16 (FcγRIIIa), which can trigger antibody-dependant cellular cytotoxicity (ADCC) against opsonized cells. ADCC is clinically important as one of the mechanisms by which therapeutic antibodies work. The anti-CD20 mAb rituximab is, for example, widely used for targeting B cells in treatments of autoimmune disease and non-Hodgkin's lymphoma. Here, we set out to study individual NK cell-target cell interactions by microscopy to determine what happens as NK cells meet different target cells sequentially, some opsonised and some not. In addition, genetic diversity in human NK cell receptors has been linked with resistance and susceptibility to many diseases, but underlying mechanisms remain unclear. The effect of this genetic diversity on the cell surface organisation and signalling of receptors is a major unknown. Thus, we set out to study the organisation and signalling of inhibitory Killer Ig-like receptors (KIR) encoded by different genes and alleles using super-resolution microscopy. <h3>Results</h3> We found that repeated activation via CD16 decreased the amount of perforin secreted. However, perforin secretion was restored upon subsequent activation via a different NK cell activating receptor, NKG2D. Repeated stimulation via NKG2D also decreased perforin secretion but this was not rescued by stimulation via CD16. These different outcomes of sequential stimulation could be accounted for by shedding of CD16 being triggered by cellular activation. Shedding of CD16 shedding also increased NK cell motility and allowed for detachment of NK cells from target cells. In turn, this aided NK cell survival and boosted serial engagement of target cells. In addition, we report that inhibitory NK cell receptors encoded by different genes and alleles organise differently at the surface of primary human NK cells. In particular, expression level has major effects on receptor organisation. KIR that are expressed at a low level assemble in smaller clusters than KIR that are highly expressed. Unexpectedly, upon receptor triggering, low-expressed receptors in smaller clusters generate more phosphorylated Crk than highly expressed receptors. <h3>Conclusions</h3> (<sup><sup>1</sup></sup> Shedding of the Fc receptor CD16 has an unexpectedly complex impact on NK cell responses. Shedding this receptor renders NK cells less potent at CD16-mediated activation, as expected, but promotes the detachment from opsonized targets to aid sequential target cell surveillance. Thus, counter-intuitively, shedding of Fc receptor CD16 can positively impact immune responses. (<sup>2</sup> Genetic variation modulates the nanoscale organisation of inhibitory NK cell receptors, which in turn impacts receptor signalling. This may be important in how genetic variation impacts immune responses and disease susceptibilities. <h3>Disclosure of Interest</h3> None declared
Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis
Authors: Mark Barahman, Wei Zhang, Hillary Yaffe Harris, Anita Aiyer, Rafi Kabarriti, Milan Kinkhabwala, Namita Roy-Chowdhury, Amanda P. Beck, Thomas S. Scanlan, Jayanta Roy-Chowdhury, Patrik Asp, Chandan Guha
Journal: Journal of Hepatology (2019)
OP0128 The phenotype of axial psoriatic arthritis: is it dependent on hla-b27 status?
Authors: L. Coates, E. Alonso, X. Baraliakos, F. Blanco Garcia, J. Braun, V. Chandran, J.L. Fernandez-Sueiro, O. FitzGerald, P. Gallagher, D. Gladman, E. Gubar, T. Korotaeva, E. Loginova, E. Lubrano, J. Mulero, J. Pinto-Tasende, R. Queiro, J. Sanz Sanz, A. Szentpetery, P. Helliwell
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Up to 50% of patients with psoriatic arthritis (PsA) have associated spinal involvement similar to ankylosing spondylitis (AS). HLA-B27 positivity is lower in PsA compared to other SpA which may affect the disease phenotype. <h3>Objectives</h3> Our aim was to compare axial phenotype in PsA patients with and without HLA-B27 with AS patients. <h3>Methods</h3> A large international collaboration collected BASDAI, CRP, HLA-B27 status and sacroiliac joints (SIJ) and spine radiographs. These were read centrally by two blinded readers using consensus on the modified New York criteria, mSASSS and PASRI. AP spine radiographs were examined for symmetry (score difference ≥2 between sides) and morphology of syndesmophytes (typical marginal vs atypical chunky/non-marginal) were compared. <h3>Results</h3> Eight sites contributed 244 (25% HLA-B27+) PsA patients and 198 (75% HLA-B27+) AS patients. Mean BASDAI, mSASSS and PASRI were higher in AS. When categorised by diagnosis and HLA-B27 there were significant differences for age, sex, disease duration, mSASSS, PASRI and syndesmophyte symmetry. Regression analysis, with mSASSS and PASRI as dependent variables revealed significant associations with age, sex, duration of disease, and group (HLA-B27 and diagnosis). Binary multivariate logistic regression was used to investigate associations of age, sex, HLA-B27 status, diagnosis (PsA v AS) and concomitant diabetes with radiographic features. Sacroiliac symmetry showed no significant associations, whilst syndesmophyte symmetry was associated with increasing age and HLA-B27 positivity. Typical marginal syndesmophytes were associated with age, HLA-B27 status and disease duration: in the cervical spine significant associations with age, sex and HLA-B27 status; in the lumbar spine with age, HLA-B27 and diagnosis. Atypical chunky syndesmophytes were associated only with increasing age and male sex. <h3>Conclusions</h3> This analysis suggests less difference in radiographic phenotype between AS and axial PsA than previously thought. HLA-B27 negative PsA patients have less severe disease as measured by mSASSS and PASRI with less typical marginal syndesmophytes and symmetry, whilst HLA-B27 positive PsA appears similar to AS. <h3>Disclosure of Interest</h3> None declared
AB1188 Naredo and backhaus ultrasound scores in tunisian rheumatoid arthritis patients
Authors: S. ZROUR, H. Mouanaa, A. Arfa, H. Hachfi, M. Jguirim, I. bejia, T. Mongi, M. Youness, N. bergaoui
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ultrasound becomes increasingly important in the diagnosis and management of rheumatoid arthritis (RA). <h3>Objectives</h3> Our purposes are to evaluate Naredo (NS) and Backhaus (BS) ultrasound scores of synovitis, performed in daily practice in RA and to study their correlations with clinical assessment and SHARP radiological score modified by Vander Heijde (SS). <h3>Methods</h3> This is a cross-sectional study, conducted at the Rheumatology Department of Monastir Teaching Hospital, Tunisia, in 69 consecutive patients with RA. For each patient, clinical and biological evaluation (DAS 28 score), radiological assessment (SS) and ultrasound evaluation (by TOSHIBA machine) to determine NS and BS, were performed. <h3>Results</h3> The mean age of our patients was 52.01±10.1 years.<sup>27–78</sup> The women accounted for 89% of patients. The average of disease duration was 121±86 months [1- 333]. The mean tender joint count (TJC) was 5.9±5.6 [0–27]. The most frequently hands tender joints were the 5th MCP right, 3rd MCP right and the 1st MCP left and right. The mean swollen joint count (SJC) was 3 [0–22]. The most frequently swollen joints at both hands were the wrists and the 2nd MCP. The overall mean SS score was 105±59 [17–272], the overall mean score for joint erosion was 52±38 [0–166] and narrowing score was 53±26.<sup>3–136</sup> The mean NS was 17±15 [0–64] and BS was 21±10.<sup>2–44</sup> The mean duration of ultrasound assessment for calculating NS and BS was 21±7 min and 17±5 min, respectively. NS was significantly associated with SJC (p&lt;0.000) and DAS 28 (p&lt;0.01) but was not significantly associated with SS nor with its components. The BS was significantly associated with TJC (p&lt;0.000), SJC (p&lt;0.04) and DAS 28 (p&lt;0.02). It was not significantly associated with SS. The number of erosions found by the BS was significantly associated with the erosion score of both hands and overall erosion score found by the SS (p&lt;0.001). Ultrasound shows superiority in detecting erosions than standard radiographs: the number of erosions found by the BS was superior in 91% of cases to the number of erosions found by SS in the same joints. <h3>Conclusions</h3> NS and BS are significantly associated with RA disease activity. Ultrasound detects better osteoarticular erosions than radiological assessment. BS, which needs on average 17 min, can be used in daily practice. <h3>Reference</h3> 1 Contant, Elise, Paul Ornetti. "Ultrasound Scores: Interest in rheumatologic practice(example of rheumatoid arthritis and spondyloarthritis)". Journal of Rheumatism Monographs 2005 September;82(4):217-24. <h3>Disclosure of Interest</h3> None declared