tbuckley/cabot-search huggingface dataset:
TET2 and DNMT3A mutations and exceptional response to 4′-thio-2′-deoxycytidine in human solid tumor models
Authors: Sherry X. Yang, Melinda Hollingshead, Larry Rubinstein, Dat Nguyen, Angelo B. A. Larenjeira, Robert J. Kinders, Michael Difilippantonio, James H. Doroshow
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Challenges remain on the selection of patients who potentially respond to a class of drugs that target epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods Seventeen cancer cell lines and multiple xenograft models bearing representative human solid tumors were subjected to 4′-thio-2′-deoxycytidine (T-dCyd) or control treatment. Gene mutations in cell lines were examined by whole exome and/or Sanger sequencing. Specific gene expression was measured in cells and xenograft tumor samples by Western blotting and immunohistochemistry. TET2/DNMT3A mutation status in 47,571 human tumor samples was analyzed at cBioPortal for Cancer Genomics. Results Cell survival was significantly inhibited by T-dCyd in breast BT549, lung NCI-H23, melanoma SKMEL5 and renal ACHN cancer lines harboring deleterious TET2 and nonsynonymous DNMT3A mutations compared to 13 lines without such mutation pattern ( P = 0.007). The treatment upregulated p21 and induced cell cycle arrest in NCI-H23 cells, and dramatically inhibited their xenograft tumor growth versus wildtype models. T-dCyd administrations led to a significant p21 increase and near eradication of tumor cells in the double-mutant xenografts by histological evaluation. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers and frequently in angioimmunoblastic and peripheral T cell lymphomas and several types of leukemia. Conclusions Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.
AB0069 ANTIBODIES AGAINST PHOSPHORYLCHOLINE AS PROTECTION MARKERS IN AUTOIMMUNITY, ATHEROSCLEROSIS, CARDIOVASCULAR DISEASE AND CHRONIC INFLAMMATION – IMPLICATIONS FOR TREATMENT
Authors: J. Frostegård
Journal: Annals of the Rheumatic Diseases (2021)

Background: Autoimmunity, atherosclerosis and cardiovascular disease (CVD) are chronic inflammatory conditions and represent a major part of global burden of morbidity and also mortality. The immune system plays an important role in these conditions. Further, the risk of CVD and atherosclerosis is raised in several autoimmune conditions, where SLE is an important example. Its major cause, atherosclerosis (where activated immune competent cells producing cytokines are abundant), for example, active and passive immunization can influence the degree of atherosclerosis in animal experiments, but no treatment developed to specifically ameliorate inflammation is presently available. The cause of the chronic inflammation and immune activation in atherosclerosis has not been fully defined, and there are different, non-mutually exclusive and potentially synergistic possibilities including oxidized LDL (oxLDL) heat shock proteins (HSP) and infections. We focused on the lipid moiety in OxLDL, especially phosphorylcholine (PC) which is a small hapten, immunogenic when exposed and reported that OxLDL´s immunological effects is to some extent caused by PC. Antibodies against PC (anti-PC) are abundant, about 5-10% of circulating IgM is IgM anti-PC. This is thus a theranostic concept, combining novel risk markers with possible underlying mechanisms and potentially immunization to raise anti-PC. Objectives: We reported that anti-PC, especially IgM (and Ig1) anti-PC is negatively associated with atherosclerosis progress, CVD (including both MI and stroke) in different populations, and also with autoimmune diseases, especially systemic rheumatic diseases as SLE. Potential mechanisms include anti-inflammatory effects, inhibition of uptake of OxLDL in the vascular wall, promotion of T regulatory cells, inhibition of cell death, and increased clearance of dead cells. Methods: We have used a combination of experimental and translational/clinical studies. Results: Based on our findings, we have proposed a novel hypothesis which is a development of the hygiene/old friends-hypothesis, namely that low exposure to microorganisms as nematodes, parasites and some bacteria which from an evolutionary point of view has been with humanity for millions of years, leads to low levels of the antibodies described and a lack of ability to prevent autoimmune conditions. Indeed, individuals from Kitava, New Guinea leading a traditional life as hunter-gatherers and horticulturalists appear not to have CVD or rheumatic disease, but strikingly high anti-PC levels. Conclusion: anti-PC could be a novel factor protecting against rheumatic disease. Disclosure of Interests: Johan Frostegård Shareholder of: I am named as inventor on patents related to antibodies against phosphorylcholine, Grant/research support from: From Amgen, related to PCSK9 and inflammation, unrelated to this topic
POS0227 SHOULD ALL PATIENTS TRIAL SUBCUTANEOUS METHOTREXATE PRIOR TO COMMENCING BIOLOGIC THERAPY – A REAL WORLD STUDY
Authors: A. Mirza, M. K. Nisar
Journal: Annals of the Rheumatic Diseases (2021)

Background: Methotrexate (MTX) is the bed rock of inflammatory arthritis management. However intolerance is a major limiting factor for drug optimisation and retention. There is data to suggest that subcutaneous (SC) MTX is tolerated better and is now being recommended in several guidelines including ACR’s. It is less clear though whether this strategy is effective in those where oral preparation is inefficacious and its potential to avoid escalation to biologic therapy. Objectives: Our aim was to analyse the reasons for switching to SC formulation in a real world setting, clinical outcomes achieved and proportion requiring biologic prescription. Methods: We undertook a retrospective survey of all patients prescribed SC MTX in a large university teaching hospital between 1983 and Apr 2019. We had access to full patient records including details on co-morbidities, drugs and disease management. We analysed demographics, reasons for SC MTX initiation, clinical outcomes and impact on biologic prescription. Results: 352 patients were identified during the study period. The mean age of the cohort was 54 yrs (3-87). 192 (70%) were women. 260 (74%) were Caucasian, 64 (18%) Asian, 21 (6%) Afro-Caribbean and remaining of other ethnicity. Two most common diagnoses were RA [n=243 (69%)] and pSpA [n=66 (18%)]. Average disease duration was 74 months (11-324) with mean of three comorbidities (0-11). 284 (80%) had switched from oral to SC MTX. 137 (49%) stopped oral MTX due to side effects. Mean duration of oral MTX prior to switching was 26 months (0.25-167). Follow up period for SC MTX ranged from two to 132 months (mean 29) until the data cut-off date of Apr 2019. 103 (29%) patients progressed to biologic therapy. Amongst RA patients, DAS28 improved from mean 4.16 (0.63-8.06) to 2.83 (0.14-7.32) following the switch. pSpA cohort’s mean TJC and SJC improved from mean seven (0-42) and two (0-26) to two (0-25) and one (0-6) respectively. Conclusion: Our study confirms that SC MTX is an effective solution irrespective of whether oral MTX is inefficacious or intolerable. This applies to people with both RA and pSpA. In accordance with prior published data, our findings support the utility of SC MTX for those intolerant of enteral option. Additionally, it shows that even in instances where oral MTX was ineffective, a switch to SC formulation achieved low disease activity despite multi-morbidity, long disease course and protracted oral MTX exposure. This intervention also prevented over two-thirds of patients progressing to biologic therapy with significant financial savings. SC MTX therefore remains a durable strategy with excellent disease outcomes and confers substantial economic benefits to healthcare. Disclosure of Interests: None declared
Association between mucosal barrier disruption by <i>Pseudomonas aeruginosa</i> exoproteins and asthma in patients with chronic rhinosinusitis
Authors: Jannatul Ferdoush Tuli, Mahnaz Ramezanpour, Clare Cooksley, Alkis James Psaltis, Peter‐John Wormald, Sarah Vreugde
Journal: Allergy (2021)

Abstract Background Chronic rhinosinusitis (CRS) is a common chronic respiratory condition, frequently associated with asthma and affecting the majority of cystic fibrosis (CF) patients. Pseudomonas aeruginosa infections and biofilms have been implicated in recalcitrant CRS. One of the mechanisms of action for bacteria in CRS and CF is mucosal barrier disruption by secreted products that contribute to the inflammation. However, the role of biofilm and planktonic forms of P . aeruginosa in this process is not known. The aim is to determine the effect of P . aeruginosa exoproteins isolated from CF and non‐CF CRS patients on the mucosal barrier. Methods Exoproteins from 40 P . aeruginosa isolates were collected in planktonic and biofilm forms and applied to air‐liquid interface (ALI) cultures of primary human nasal epithelial cells (HNECs). Mucosal barrier integrity was evaluated by transepithelial electrical resistance (TEER), passage of FITC‐dextrans and immunofluorescence of tight junction proteins. Cytotoxicity assays were performed to measure cell viability, and IL‐6 ELISA was carried out to evaluate pro‐inflammatory effects. Results Planktonic exoproteins from 20/40 (50%) clinical isolates had a significant detrimental effect on the barrier and significantly increased IL‐6 production. Barrier disruption was characterized by a reduced TEER, increased permeability of FITC‐dextrans and discontinuous immunolocalization of tight junction proteins and was significantly more prevalent in isolates harvested from patients with comorbid asthma ( P &lt; .05). Conclusion Exoproteins from planktonic P . aeruginosa clinical isolates from asthmatic CRS patients have detrimental effects on the mucosal barrier and induce IL‐6 production potentially contributing to the mucosal inflammation in CRS patients.
Notice of Retraction. Yousaf A et al. Association Between Alopecia Areata and Natural Hair Color Among White Individuals. <i>JAMA Dermatol</i>. Published Online March 10, 2021.
Authors: Ahmed Yousaf, Justin Lee, Wei Fang, Michael S. Kolodney
Journal: JAMA Dermatology (2021)

overlying epidermis, with loss of rete ridges.These phases of regression are not independent of each other and may coexist to varying degrees in a single tumor.While lymphocytes may be a feature of intermediate and late regression, only lymphocytes in direct association with tumor cells are classified as tumor-infiltrating lymphocytes.In some studies, the authors required the complete absence of in situ or invasive melanoma cells in the area of regression. 4 However, in our view, this restrictive definition of regression may lead to partially regressed melanomas being inappropriately classified as having absent regression.This viewpoint is supported by many clinical examples of melanoma in which there is clear clinical evidence of partial tumor loss on clinical and dermoscopic examination and histological evidence of regressive fibrosis with overlying melanoma in situ and, in some cases, residual dermal invasive melanoma.Pathological assessment is inevitably subjective and requires logical and reasoned judgment based on all available evidence.The interobserver reproducibility of pathologists' assessment of regression is likely imperfect, 5 and we agree with Mochel and Elder that efforts to standardize the definition and reporting of regression are needed.In our study, 1 750 pathologists reported the melanomas in the Dutch cohort of 17 271 patients and 17 pathologists reported the Australian cohort of 4980 patients without centralized review of the cases.The Dutch data were population-based, and a range of definitions may have been used by the reporting pathologists.The Australian data were from a single large institution where a more uniform interpretation of regression was likely to have been used by the institutional pathologists.Despite these limitations, the fact that there were remarkably similar results in the 2 large independent patient cohorts suggests that the results are applicable to everyday clinical practice.Harnessing the body's immune system to eliminate melanoma has already revolutionized treatment of patients with metastatic disease.Further studies to better understand the complex interaction between the immune system and primary melanomas, including cases with and without regression, will likely yield new insights that may provide opportunities to further improve outcomes for patients with melanoma.
AB0916-PARE KNOWLEDGE OF DISEASE, DIAGNOSIS, ADHERENCE AND IMPACT OF RESEARCH IN PATIENTS WITH INFLAMMATORY ARTHRITIS
Authors: M. Canavan, V. Marzaioli, A. Donnelly, S. Wade, A. Fraser, T. O’sullivan, S. Harney, A. Ireland, D. Veale, U. Fearon
Journal: Annals of the Rheumatic Diseases (2021)

Background: The diagnosis and treatment of inflammatory arthritis has been transformed largely by the development of drugs that target specific molecules of the immune system. However, these changes have increased the complexity of the mechanisms of disease, its treatment and patients understanding. Patient education is needed in this area to facilitate decision making and to facilitate strong patient-partnerships in research. Objectives: The aim of this study was to examine the level of understanding of inflammatory arthritis patients and the need for strong patient-partnership in research. Methods: An online anonymous survey addressed questions about diagnosis, routine tests, medications and how they work, medication adherence, disease flare, heredity, pregnancy, and patient involvement in research. Results: There were 1,873 respondents, 1416 of which had inflammatory arthritis (IA)-RA (65.8%) and PsA (34.2%). They were predominantly female (RA 86%, PsA 85 %), aged 55±13 and 50±12. Less than 35% of patients had an understanding of diagnostic tests, what was measured and the implication for disease, with 75.5% also concerned about heredity. There was a high level of understanding of how specific medications treat inflammatory arthritis (72.9%). Adherence was also very high (&gt;87%), with the main reasons for stopping medication without the advice of their clinician, ‘feeling better’ and ‘side effects’ however a significant proportion of patients (69.9%) reported a disease-flare following cessation of medication. Patients of childbearing age (69%) were also concerned that inflammatory arthritis reduced their chances of getting pregnant, with only 8% believing arthritis medications were safe to take during pregnancy. Finally, only 9% of patients had ever been asked to participate in a research study. Conclusion: This study demonstrates a need for the development of stronger patient-partnerships with clinicians and researchers in relation to patient education and engagement with research, to create a platform where patients can have meaningful input and involvement in future research studies. Acknowledgements: We wish to thank all the patients who contributed to this study Disclosure of Interests: Mary Canavan: None declared, Viviana Marzaioli: None declared, Alex Donnelly: None declared, Siobhan Wade: None declared, Alexander Fraser: None declared, Tim O’Sullivan: None declared, Sinead Harney: None declared, Arthritis Ireland: None declared, Douglas Veale Speakers bureau: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Consultant of: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Grant/research support from: Janssen, Abbvie, Pfizer, UCB, Ursula Fearon Speakers bureau: Abbvie, Grant/research support from: Janssen, Abbvie, Pfizer, UCB
Durable endothelium-mimicking coating for surface bioengineering cardiovascular stents
Authors: Qing Ma, Xiuying Shi, Xing Tan, Rui Wang, Kaiqin Xiong, Manfred F. Maitz, Yuanyuan Cui, Zhangmei Hu, Qiufen Tu, Nan Huang, Li Shen, Zhilu Yang
Journal: Bioactive Materials (2021)

Mimicking the nitric oxide (NO)-release and glycocalyx functions of native vascular endothelium on cardiovascular stent surfaces has been demonstrated to reduce in-stent restenosis (ISR) effectively. However, the practical performance of such an endothelium-mimicking surfaces is strictly limited by the durability of both NO release and bioactivity of the glycocalyx component. Herein, we present a mussel-inspired amine-bearing adhesive coating able to firmly tether the NO-generating species (e.g., Cu-DOTA coordination complex) and glycocalyx-like component (e.g., heparin) to create a durable endothelium-mimicking surface. The stent surface was firstly coated with polydopamine (pDA), followed by a surface chemical cross-link with polyamine (pAM) to form a durable pAMDA coating. Using a stepwise grafting strategy, Cu-DOTA and heparin were covalently grafted on the pAMDA-coated stent based on carbodiimide chemistry. Owing to both the high chemical stability of the pAMDA coating and covalent immobilization manner of the molecules, this proposed strategy could provide 62.4% bioactivity retention ratio of heparin, meanwhile persistently generate NO at physiological level from 5.9 ± 0.3 to 4.8 ± 0.4 × 10-10 mol cm-2 min-1 in 1 month. As a result, the functionalized vascular stent showed long-term endothelium-mimicking physiological effects on inhibition of thrombosis, inflammation, and intimal hyperplasia, enhanced re-endothelialization, and hence efficiently reduced ISR.
AB0730 HIP INVOLVEMENT IN JUVENILE IDIOPATHIC ARTHRITIS
Authors: S. Bouden, N. Ben Chekaya, A. Ben Tekaya, O. Saidane, R. Tekaya, I. Mahmoud, L. Abdelmoula
Journal: Annals of the Rheumatic Diseases (2021)

Background: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases that have in common an onset before the age of 16 years, more than 6-month duration, and the presence of arthritis for at least 6 weeks with no identifiable cause. Hips are the commonly affected joints in severe destructive JIA. Hip disease develops in 20% to 50% of children with JIA. Objectives: We aimed to analyze the epidemiological, clinical, and radiological aspects of hip involvement in Tunisian JIA. Methods: A retrospective study including 35 patients was conducted between 2010 and 2019. The patients enrolled met the ILAR criteria for the diagnosis of JIA. Clinical, biological and radiological parameters relating to the hip involvement were collected. Results: Thirty-five patients were enrolled. The mean age of the disease onset was 9 years [3-15]. The mean age of the patients at the time of the study was 37.8 years [17-69]. The mean duration of the disease was 27 years [2- 56]. These patients were assigned to discrete JIA categories: rheumatoid factor positive polyarthritis (43.5%), rheumatoid factor negative polyarthritis (21.7%), enthesitis-related arthritis (17.4%), oligoarthritis (13%) and psoriatic arthritis (4.4%). A biological inflammatory syndrome was noted in 52% of patients. Hip involvement was noted in 43.5% of patients. Coxitis occurred on average 15 years after the JIA onset [[4-37]. Thirty four percent of the patients had bilateral hip involvement. The mean Lequesne index was 14. Joint space narrowing and erosions were noted in respectively 68% and 34% of cases. The majority of patients (82.6%) received medical treatment combining nonsteroidal anti-inflammatory drugs (NSAID) and rehabilitation. In the other cases, a total hip replacement was necessary. Coxitis was significantly correlated with rheumatoid factor positive polyarthritis subtype (p=0.02) and with the presence of biological inflammatory syndrome (p=0.03). Conclusion: Hip involvement is a major and highly prevalent issue in our JIA patients. Disclosure of Interests: None declared
AB0072 SERUM AMYLOID A PROTEIN (SAA) IN ANKYLOSING SPONDYLITIS AND THE RELATIONSHIP WITH SYSTEMIC INFLAMMATION
Authors: K. Sakharova, M. Cherkasova, S. Erdes
Journal: Annals of the Rheumatic Diseases (2021)

Background: Serum amyloid A protein (SAA) likely has a critical role in control and possibly propagation of the primordial acute phase response and is the precursor of AA amyloid fibrils. Prolonged elevations in SAA are the major inciting factor for AA amyloidosis developing in chronic inflammatory diseases. In Russia 2-4% of patients with ankylosing spondylitis (AS) have secondary (AA) amyloidosis. Objectives: To study the level of SAA in AS its relationship with indicators of disease activity. Methods: 124 patients with AS (according to mNYC 1984) 70 men, 54 women, of whom HLA B 27 positive 91.1% mean age 38.1 (± 12.9), age at the onset of the disease 23.5 (± 9.9) consecutively admitted to the clinic of the Research Institute rheumatology from February to November 2020. In addition to the standard examination (the median CRP 6.7 mg/l [1.4; 24.9], ESR 13 mm/h [7; 27], SAA was studied in all patients by the nephelometric method. Results: The median SAA in 124 patients was 12.5 mg/l [4;71.6]. Among them, 31% had normal SAA level (&lt;5 mg/l), and 69 % - more than 5 mg/l. In 21 (17.5 %) cases, the level of SAA was increased at normal CRP levels, and only in 2 cases an increase in the level of CRP at normal SAA levels; 50 patients (40.3 %) with normal ESR had elevated SAA levels, and 7 (5.6%) - ESR exceeded the upper limits of the norm with normal SAA levels. Comparison of the average values of the levels of SAA, CRP, ESR in men and women did not reveal significant differences between them. The SAA level was weakly correlated with ESR (r = 0.2; p=0.002) and BASDAI (r=0.3; p=0.002), moderately with ASDAS-CRP (r=0.5; r&lt;0.0001), but showed a strong association with CRP (r = 0.80; p&lt;0.00001). Patients with elevated SAA levels (&gt;5 mg/l) had a shorter disease duration (10 and 12 year; p&lt;0.0004), higher ASDAS-CRP (2.9 and 2.4; p&lt;0.003), blood CRP level (14.6 and 1.3; p&lt;0.00001), and significantly more peripheral arthritis (60% and 39%; p&lt;0.05) than patients with normal indicators. Conclusion: The level of SAA correlates well with indicators of AS activity, especially with the level of CRP, and can be used as an alternative indicator of disease activity. Disclosure of Interests: None declared
Metformin effects on brain development following cranial irradiation in a mouse model
Authors: Nili Yuen, Kamila U Szulc-Lerch, Yu-Qing Li, Cindi M Morshead, Donald J Mabbott, C Shun Wong, Brian J Nieman
Journal: Neuro-Oncology (2021)

Cranial radiation therapy (CRT) is a mainstay of treatment for malignant pediatric brain tumors and high-risk leukemia. Although CRT improves survival, it has been shown to disrupt normal brain development and result in cognitive impairments in cancer survivors. Animal studies suggest that there is potential to promote brain recovery after injury using metformin. Our aim was to evaluate whether metformin can restore brain volume outcomes in a mouse model of CRT.