tbuckley/cabot-search huggingface dataset:
AB0074 KRÜPPEL-LIKE FACTOR 10 IS A IMPORTANT MODULATORY FACTOR OF CHONDROCYTE HYPERTROPHY IN DEVELOPING SKELETON
Authors: J. Y. Ko, E. Lee, J. Kim, G. I. Im
Journal: Annals of the Rheumatic Diseases (2020)

Background: To investigate the functional role of KLF10 as a modulator of chondrocyte hypertrophy in developmental skeleton, the developmental characteristics in the long bone of KLF10 knockout mice and characteristics of MSCs from KLF10 KO mice were investigated regarding chondrogenesis and osteogenesis. Delayed long bone growth and delayed formation of primary ossification center were observed in an early embryonic stage in KLF10 KO mouse along with very low Ihh expression in epiphyseal plate. While the chondrogenic potential of mMSCs appeared normal or slight decrerased in KLF10 KO mice, osteogenesis and hypertrophy were extensively suppressed. KLF10 was found to be a mediator of chondrocyte hypertrophy in developing skeleton. Suppression of KLF10 may be considered as a new strategy for preventing hypertrophy in cartilage regeneration using MSCs. Objectives: Investigated the functional role of KLF10 to present new insights into the transcriptional network regulating skeletal development and provide a novel strategy for preventing aberrant hypertrophic differentiation in cartilage regeneration strategies using MSCs. Methods: Generation of KLF10 KO mice and genotyping / Skeletal preparations, embryo heights, and mineralized bone length measurements / Histological and Fluorescent Immunohistochemical Analysis / ALP staining and activity / Alizarin red staining / Von Kossa staining and calcium salts quantification / Isolation and Establishment of Mouse Clonal MSC Lines / Chondrogenic pellet culture and differentiation of mMSCs / DNA Quantification and GAG Contents Analysis / Rq-PCR Analysis / Statistics Results: The overall results showed that mMSCs from KLF10 KO mice have significantly decreased osteogenic potential with very low Ihh expression while an increase in chondrogenic potential was not significant. In addition to Ihh promotor demonstrated in our previous study, KLF10 can activate Runx2 expression through its proximal-promoter region. Thus, KLF10 may indirectly stimulate Ihh expression upstream of Runx2 or directly bind to Ihh promoter and activate Ihh expression. As shown in this and out previous study, KLF10 also enhances Wnt/β-catenin signalling in MSCs. KLF10 modulates β-catenin sub-cellular localization and enhances Wnt signalling in osteoblasts. Conclusion: In conclusion, primary ossification in KLF10 KO mice was critically delayed during early endochondral bone development. KLF10 KO inhibited hypertrophy via reduced Ihh expression in developing skeleton. TGF-β-induced hypertrophy was inhibited during chondrogenesis of KLF10 KO mMSCs. Our findings present new insights into the transcriptional-network system of skeletal development and provide a novel strategy for suppressing hypertrophy in cartilage tissue engineering. Figure. Acknowledgments: This research was supported by the National Research Foundation of Korea (NRF-2019R1H1A2039685 and 2019R1I1A1A01043778). Disclosure of Interests: None declared
SAT0025 NEUROMEDIN U SUPPRESSES COLLAGEN-INDUCED ARTHRITIS THROUGH ACTIVATION OF ILC2
Authors: Y. Zhang, Y. Qin, Z. Chen
Journal: Annals of the Rheumatic Diseases (2020)

Background: Reduction and dysregulation of ILC2 was linked to delayed resolution of arthritis. The neuropeptide Neuromedin U (NMU) has been reported to rapidly activate ILC2 and initiate a Th2 type immune response through NMUR1 expressed on the surface of ILC2. However, one previous study reported that NMU promoted autoantibody-mediated arthritis. Objectives: The aim of this work was to investigate the effect of NMU on collagen-induced arthritis (CIA) mice and the potential mechanisms. Methods: CIA was induced in C57BL/6 WT and C57BL/6 Nmu deficient mice on day 1. WT mice were treated i.p. daily by NMU-23 (20ug/mice) or by PBS for 10 days from day 1 to 5 and day 21 to 25. The clinical scores of CIA mice were assessed every two days from day 22 and determined on a scale of 0–4 for each paw. The proportion of ILC2 as well as Th1, Th2, Th17 and Treg in spleen, mesenteric lymph node (mLN) and joints of arthritic mice were analyzed by flow cytometry on day 42. Results: NMU-23 dramatically inhibited clinical onset and severity of arthritis in treated WT mice compared with control mice. Interestingly, NMU-deficient mice also developed significantly less severe arthritis compared with WT control (Fig 1). Flow cytometry analyses showed that the proportion of ILC2, which defined as Lin-CD45+CD127+KLRG1+ICOS+ST2+, was elevated in the joint but not in the spleen and mLN of arthritic mice treated with NMU-23. In contrast, the proportion of ILC2 was significantly lower in the spleen of NMU-deficient mice than WT control. The percentage of Th2 cells in the spleen and mLN tend to be higher in NMU-23 treated mice, but there is no statistical significance. Surprisingly, Th1 cells were increased in the mLN of NMU-23 treated and NMU-deficient mice compared with control whereas Th17 was comparable among groups. In addition, the proportion of Treg was decreased in the joint of NMU-23 treated and NMU-deficient mice compared with control mice. Conclusion: Our preliminary results show that repeated injection of NMU-23 during induction (early) and development (late) stage of CIA strongly suppressed clinical onset and severity of arthritis, which might be ascribed to activation of ILC2 in the joint. Further study is needed to explore other cellular and molecular mechanisms in the effect. References: [1] Cardoso V, Chesne J, Ribeiro H et al (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549 (7671):277-281. [2] Klose CSN, Mahlakoiv T, Moeller JB et al (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549 (7671):282-286. [3] Wallrapp A, Riesenfeld SJ, Burkett PR et al (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549 (7672):351-356. [4] Sindhuja M Rao, Jennifer L Auger, Philippe Gaillard et al (2012) The Neuropeptide Neuromedin U Promotes Autoantibody-Mediated Arthritis. Arthritis Res Ther, 14 (1), R29. Disclosure of Interests: None declared
The Probability of A1C Goal Attainment in Patients With Uncontrolled Type 2 Diabetes in a Large Integrated Delivery System: A Prediction Model
Authors: Kevin M. Pantalone, Anita D. Misra-Hebert, Todd M. Hobbs, Sheldon X. Kong, Xinge Ji, Rahul Ganguly, Alex Milinovich, Wayne Weng, Janine M. Bauman, Paul Petraro, Bartolome Burguera, Robert S. Zimmerman, Michael W. Kattan
Journal: Diabetes Care (2020)

OBJECTIVE To assess patient characteristics and treatment factors associated with uncontrolled type 2 diabetes (T2D) and the probability of hemoglobin A1c (A1C) goal attainment. RESEARCH DESIGN AND METHODS This was a retrospective cohort study using the electronic health record at Cleveland Clinic. Patients with uncontrolled T2D (A1C &amp;gt;9%) were identified on the index date of 31 December 2016 (n = 6,973) and grouped by attainment (n = 1,653 [23.7%]) or nonattainment (n = 5,320 [76.3%]) of A1C &amp;lt;8% by 31 December 2017, and subgroups were compared on a number of demographic and clinical variables. On the basis of these variables, a nomogram was created for predicting probability of A1C goal attainment. RESULTS For the entire population, median age at index date was 57.7 years (53.3% male), and the majority were white (67.2%). Median A1C was 10.2%. Obesity (50.6%), cardiovascular disease (46.9%), and psychiatric disease (61.1%) were the most common comorbidities. Metformin (62.7%) and sulfonylureas (38.7%) were the most common antidiabetes medications. Only 1,653 (23.7%) patients achieved an A1C &amp;lt;8%. Predictors of increased probability of A1C goal attainment were older age, white/non-Hispanic race/ethnicity, Medicare health insurance, lower baseline A1C, higher frequency of endocrinology/primary care visits, dipeptidyl peptidase 4 inhibitor use, thiazolidinedione use, metformin use, glucagon-like peptide 1 receptor agonist use, and fewer classes of antidiabetes drugs. Factors associated with lower probability included insulin use and longer time in the T2D database (both presumed as likely surrogates for duration of T2D). CONCLUSIONS A minority of patients with an A1C &amp;gt;9% achieved an A1C &amp;lt;8% at 1 year. While most identified predictive factors are nonmodifiable by the clinician, pursuit of frequent patient engagement and tailored drug regimens may help to improve A1C goal attainment.
Therapeutic potential of a TrkB agonistic antibody for Alzheimer's disease
Authors: Shudan Wang, Hongyang Yao, Yihua Xu, Rui Hao, Wen Zhang, Hang Liu, Ying Huang, Wei Guo, Bai Lu
Journal: Theranostics (2020)

Repeated failures of "Aβ-lowering" therapies call for new targets and therapeutic approaches for Alzheimer's disease (AD).We propose to treat AD by halting neuronal death and repairing synapses using a BDNF-based therapy.To overcome the poor druggability of BDNF, we have developed an agonistic antibody AS86 to mimic the function of BDNF, and evaluate its therapeutic potential for AD.Method: Biochemical, electrophysiological and behavioral techniques were used to investigate the effects of AS86 in vitro and in vivo.Results: AS86 specifically activated the BDNF receptor TrkB and its downstream signaling, without affecting its other receptor p75 NTR .It promoted neurite outgrowth, enhanced spine growth and prevented Aβ-induced cell death in cultured neurons, and facilitated Long-Term Potentiation (LTP) in hippocampal slices.A single-dose tail-vein injection of AS86 activated TrkB signaling in the brain, with a half-life of 6 days in the blood and brain.Bi-weekly peripheral administration of AS86 rescued the deficits in object-recognition memory in the APP/PS1 mouse model.AS86 also reversed spatial memory deficits in the 11-month, but not 14-month old AD mouse model. Conclusion:These results demonstrate the potential of AS86 in AD therapy, suggesting that neuronal and/or synaptic repair as an alternative therapeutic strategy for AD.
Covid-19: Lack of testing led to patients being discharged to care homes with virus, say auditors
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Covid-19: Lack of testing led to patients being discharged to care homes with virus, say auditors Gareth IacobucciMany patients in hospitals with covid-19 may have been discharged to care homes in March and April because of a lack of testing capacity at the time in England, auditors have reported.
AB0636 MODALITIES OF PRESCRIPTION OF ANTI-TNF ALPHA IN AXIAL SPONDYLOARTHRITIS: ON MONOTHERAPY OR COMBINED WITH CONVENTIONAL SYNTHETIC DMARDS
Authors: K. Ben Abdelghani, Y. Gzam, A. Fazaa, S. Miladi, K. Ouenniche, S. Kassab, L. Souabni, S. Chekili, A. Laatar
Journal: Annals of the Rheumatic Diseases (2020)

Background: The advent of biologics targeting tumor necrosis factor-alpha (anti-TNF alpha) has revolutionized the treatment of spondyloarthritis (SpA). Their association with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARD), although effective and used in clinical practice for the treatment of peripheral rheumatic diseases, is not clearly assessed in axial spondyloarthritis (ax-SpA). Objectives: The aim of this study was to assess the strategy of prescription of anti-TNF alpha in a population of ax-SpA and to compare patients treated with anti-TNF alpha on monotherapy with those who had combined therapy with cs-DMARDs. Methods: This is a retrospective descriptive study including 85 cases of ax-SpA diagnosed between January 2000 and October 2019 and treated with anti-TNF alpha. The clinical features, the erythrocyte sedimentation rate (ESR), the C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI) and Bath ankylosing spondylitis functional index (BASFI) were compared between groups of anti-TNF alpha on monotherapy or combined therapy with csDMARDs. Results: Of 85 ax-SpA, 67 were males (78,8%) and the mean age was 44,4 ± 10,9 years. The mean period of evolution was 12,3 ± 9,1 years and 52,2% of patients were HLA-B27 positive. The ax-SpA was a pure axial form in 74,1% of patients, associated with peripheral arthritis, enthesitis and dactylitis in 17,6%, 17,6% and 1,2% respectively. The ant-TNFs were administrated with a men delay of 78 ± 70,8 months. The anti-TNFs used were: Infliximab (41,1%), Etanercept (32,9%), Adalimumab (23,5%) and Golimumab (2,3%). Fifty-nine patients (69,4%) were treated with anti-TNF alpha on monotherapy and 26 patients (30,6%) had combined therapy. The csDMARDs prescribed were the Salazopyrine (22,4%) and the Methotrexate (7,1%). While comparing the groups of anti-TNFs combined therapy and monotherapy, we noticed that the arthritis were present in 30,7% of patients from the group of combined therapy versus 11,8% of patients from the group of monotherapy (p=0,03). The psoriasis also was more present in the group of combined therapy (11,5% vs 1,6%; p=0,04). There was no statically significant difference between the two groups in the following parameters: age, gender, HLA B27, enthesitis, dactylitis, uveitis, inflammatory bowel diseases, ESR, CRP, BASDAI and BASFI. Conclusion: Our results suggest that the concomitant use of csDMARDs with anti-TNFs is frequent in clinical practice in ax-SpA, but mainly justified by the presence of arthritis or psoriasis. References: [1]Engel-Nitz NM, et al. Rheumatol Ther. 2015;2(2):127–39. Disclosure of Interests: None declared
AB0415 SERUM RESISTIN LEVEL IN SYSTEMIC LUPUS ERYTHEMATOSUS: RELATION TO LUPUS NEPHRITIS AND DISEASE ACTIVITY
Authors: F. Ismail, S. Salah, M. Abdelhamed, M. Aboel Ela
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting different organs and systems.. Adipokines have recently been implicated as mediators of immune and inflammatory processes. Human resistin is a cytokine that induces low-grade inflammation by stimulating monocytes Objectives: The aim of this work is to assess the serum level of resistin in SLE patients and to detect its relation to lupus nephritis, and disease activity Methods: 40 patients with SLE with age ranged between 18-48 years and 20 healthy age, sex and BMI matched volunteer were enrolled in this study. According to the presence or absence of lupus nephritis (LN), patients were classified into two subgroups Full history, clinical examination and laboratory investigations were performed for all patients including serum resistin level Results: The level of serum resistin was higher in SLE patients than the controls (p=0.001). Also, serum resistin levels were higher in patients with lupus nephritis than those without nephritis (p= 0.02). Serum resistin level correlated positively with the levels of ESR (p&lt; 0.001 ), CRP (p= 0.005), Anti-dsDNA (p= 0.002 ) and serum urea (p= 0.002). Serum resistin levels correlated negatively with hemoglobin levels (p= 0.001 ) and levels of C3 (p&lt; 0.001 ) and C4 (p&lt; 0.001). There was a significant positive correlation between serum resistin level and the presence of albumin (p= 0.001), RBCs (p= 0.003), pus cells (p= 0.001 ) and casts (p&lt; 0.001 ) in urine and also with the levels of 24 hour urinary protein and protein/ creatinine ratio (p&lt;0.001). Serum resistin level was found to be strongly correlated with SLEDAI (p&lt; 0.001). No correlation was found between serum resistin levels and ISN/RPS classification of renal biopsy. Conclusion: Serum resisitin level can be used as a marker of inflammation, nephritis,disease activity in patients with SLE. Disclosure of Interests: : None declared
Epigenetic Switch–Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer
Authors: Geneviève Deblois, Seyed Ali Madani Tonekaboni, Giacomo Grillo, Constanza Martinez, Yunchi Ingrid Kao, Felicia Tai, Ilias Ettayebi, Anne-Marie Fortier, Paul Savage, Alexandra N. Fedor, Xiaojing Liu, Paul Guilhamon, Evelyne Lima-Fernandes, Alex Murison, Hellen Kuasne, Wail Ba-alawi, David W. Cescon, Cheryl H. Arrowsmith, Daniel D. De Carvalho, Benjamin Haibe-Kains, Jason W. Locasale, Morag Park, Mathieu Lupien
Journal: Cancer Discovery (2020)

Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TE) is compensated by large chromatin domains of H3K27me3 to warrant TE repression. This epigenetic state creates a vulnerability to epigenetic therapy against EZH2, the H3K27me3 methyltransferase, which alleviates TE repression in taxane-resistant TNBC, leading to double-stranded RNA production and growth inhibition through viral mimicry response. Collectively, our results illustrate how epigenetic states over TEs promote cancer progression under treatment and can inform about vulnerabilities to epigenetic therapy. SIGNIFICANCE: Drug-resistant cancer cells represent a major barrier to remission for patients with cancer. Here we show that drug-induced metabolic perturbation and epigenetic states enable evasion from the viral mimicry response induced by chemotherapy in TNBC. These epigenetic states define a vulnerability to epigenetic therapy using EZH2 inhibitors in taxane-resistant TNBC.See related commentary by Janin and Esteller, p. 1258.This article is highlighted in the In This Issue feature, p. 1241.
Christopher John Richard Newbegin
Authors: Andrew Grace
Journal: BMJ (2020)

Christopher John Richard Newbegin (“Chris”) was educated at Harrow County School for Boys and St Mary’s Hospital Medical School. He initially planned to become an orthopaedic surgeon, but his friendship with a fellow anatomy demonstrator who had experienced the delights of ENT as a career convinced him this was the path to follow. He worked as an ENT registrar at Charing Cross Hospital under Tony Cheeseman and then as a senior registrar on the Leeds/Bradford rotation. One of his registrars from this time describes him as “everything the fairy Godmother ordered.”

Chris was a great teacher, always on hand for friendly supportive advice. He gave up a lot of his own time in the evenings to do fellowship tutorials. He had a very …
FANTOM4 エッジエクスプレスDB:プロモーター、遺伝子、microRNA、発現ダイナミクスおよび調節的相互作用の統合データベース
Authors: Hume Da, Carninci P, Hayashizaki Y, Suzuki H, Daub Co, Forrest Arr, DE Hoon Mjl, Balwierz Pj, Severin J, Waterhouse Am, Kawaji H, Lassmann T, Van Nimwegen E
Journal: Genome biology (2009)
Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease
Authors: Pascal Haimerl, Ulrike Bernhardt, Sonja Schindela, Fiona D.R. Henkel, Antonie Lechner, Ulrich M. Zissler, Xavier Pastor, Dominique Thomas, Alexander Cecil, Yan Ge, Mark Haid, Cornelia Prehn, Janina Tokarz, Matthias Heinig, Jerzy Adamski, Carsten B. Schmidt-Weber, Adam M. Chaker, Julia Esser-von Bieren
Journal: Journal of Allergy and Clinical Immunology (2020)
Telerheumatology in COVID-19 era: a study from a psoriatic arthritis cohort
Authors: Luisa Costa, Marco Tasso, Nadia Scotti, Erika Mostacciuolo, Nicolò Girolimetto, Francesca Foglia, Antonio del Puente, Raffaele Scarpa, Francesco Caso
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the article by Gupta et al 1 who reported the management of treatments for rheumatic diseases during COVID-19 pandemic among practitioners in India. In this study, the authors showed that about half of the physicians would reduce the use of biological disease-modifying antirheumatic drugs (bDMARDs) or defer specific drugs such as rituximab.1 Choices were apparently made considering possible relationships between drug mechanism of action and effect on the viral infection.1 

During COVID-19 pandemic, telemedicine is emerging as a possible tool for reducing the risk of contagion and viral spread,2–4 and a useful strategy for the management of chronic diseases.5 6 

As of 29 April 2020, the outbreak of COVID-19 generated 201 505 confirmed cases in Italy, with 2405 confirmed cases in Naples Metropolitan area.

The objective of our study was to evaluate telemedicine when offered as part of routine care for the follow-up of patients …
Meta-analysis of diagnostic performance of serological tests for SARS-CoV-2 antibodies up to 25 April 2020 and public health implications
Authors: Saverio Caini, Federica Bellerba, Federica Corso, Angélica Díaz-Basabe, Gioacchino Natoli, John Paget, Federica Facciotti, Simone Pietro De Angelis, Sara Raimondi, Domenico Palli, Luca Mazzarella, Pier Giuseppe Pelicci, Paolo Vineis, Sara Gandini
Journal: Eurosurveillance (2020)

We reviewed the diagnostic accuracy of SARS-CoV-2 serological tests. Random-effects models yielded a summary sensitivity of 82% for IgM, and 85% for IgG and total antibodies. For specificity, the pooled estimate were 98% for IgM and 99% for IgG and total antibodies. In populations with ≤ 5% of seroconverted individuals, unless the assays have perfect (i.e. 100%) specificity, the positive predictive value would be ≤ 88%. Serological tests should be used for prevalence surveys only in hard-hit areas.
Activity of vincristine, L-asparaginase, and dexamethasone against acute lymphoblastic leukemia was enhanced by the Bcl-2 inhibitor ABT-737 in vitro and in vivo
Authors: Yun Hee Kang, Barbara Szymanska, Nancy Yen, Ulla Wilczynska-Kalak, C. Reynolds, Richard Lock, Min Kang
Journal: Cancer Research (2007)

510  Relapse remains a major problem in pediatric acute lymphoblastic leukemia (ALL). Adding a drug that can modulate drug resistance to combination chemotherapy used for therapy of ALL could enhance the durability and frequency of complete remissions. We evaluated ABT-737, a small-molecule Bcl-2 family protein inhibitor, in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in ALL cell lines (1 established at multiple-relapse) using the DIMSCAN cytotoxicity assay. Multi-log synergistic cytotoxicity (combination index   25% or toxicity-related events. Leukemia Growth Delay (LGD) was calculated as the median event-free survival of treated minus control groups. ABT-737 alone achieved LGDs of 26.6 days (ALL-7) and 2.6 days (ALL-19). VXL achieved LGDs of 71.6 days (ALL-7) and 36.5 days (ALL-19). VXL + ABT-737 achieved LGDs of 115.6 days (ALL-7) and 67.7 days (ALL-19). The LGDs for ABT-737 + VXL were 17.4 days (ALL-7) or 28.6 days (ALL-19) greater than the sum of individual LGDs for VXL and ABT-737. In conclusion, ABT-737 synergistically enhanced cytotoxicity of VXL in ALL cell lines and enhanced activity of VXL against ALL xenografts. Combining VXL with an inhibitor of the Bcl-2 family of proteins warrants clinical investigation in relapsed ALL.