tbuckley/cabot-search huggingface dataset:
OP0206 ASSOCIATION BETWEEN FEMALE REPRODUCTIVE FACTORS AND GOUT: NATIONWIDE POPULATION-BASED COHORT STUDY OF 1 MILLION POSTMENOPAUSAL WOMEN
Authors: Y. Eun, I. Y. Kim, K. D. Han, K. Lee, S. Y. Kang, S. Lee, H. S. Cha, E. M. Koh, J. Lee, H. Kim
Journal: Annals of the Rheumatic Diseases (2021)

Background: Previous studies have shown that the incidence of gout differs according to gender, and its risk factors also differ according to gender. However, little research has been done on the association between reproductive factors and gout. Objectives: Our study attempted to determine whether there is an association between reproductive factors and the incidence of gout in a large nationwide population-based cohort of postmenopausal women. Methods: Postmenopausal women aged 40-69 who participated in national health screenings in 2009 were included in the study. Subjects who had been diagnosed with gout prior to medical examination were excluded from the study, and a total of 1,076,378 women were included in the study. Outcome was the occurrence of gout which was defined as a case of two outpatient visit or one hospitalization for gout using the ICD-10 code of gout (M10) in the claim database. The Cox proportional hazard model was used for the analysis, and stratified analysis according to the body mass index (BMI) and chronic kidney disease (CKD) was performed. Results: Mean follow-up duration was 8.1 years, and incident cases of gout were 64,052. Later menarche (adjusted HR 1.10, 95% CI 1.02-1.19 in &gt;16 years, compared with ≤12 years), earlier menopause (adjusted HR 1.12 in &lt;40 years, 1.06 in 40-45 years, 1.03 in 45-50 years, compared with 50-55 years), and shorter reproductive span (adjusted HR 1.10 in &lt;30 years, 1.06 in 30-35 years, compared with ≥40 years) were associated with a high risk of gout. No association between parity and gout incidence was observed. Use of oral contraceptives (OC; adjusted HR 1.03 in &lt;1 year, 1.05 ≥1 year, compared with non-user) and hormone replacement therapy (HRT; adjusted HR 1.16 in &lt;2 years, 1.16 in 2-5 years, 1.18 in ≥5 years, compared with non-user) were associated with an increased risk of gout. The association between reproductive factors and gout remained in the trend without statistical significance in the low BMI group, but not in the high BMI group. The effects of use OC and HRT on gout were not significant in the CKD group. Conclusion: Shorter exposure to endogenous estrogen was associated with a high risk of gout. Conversely, exposure to exogenous estrogen such as OC and HRT was associated with an increase in gout risk. This association was not significant in subjects with high BMI or CKD. Disclosure of Interests: None declared
AB0178 COMORBIDITIES IN RHEUMATOID ARTHRITIS: DO THEY INTERFERE WITH MYOCARDIAL FUNCTION?
Authors: R. Dhahri, W. Lahmar, Y. Ben Abderrazek, M. Slouma, B. Louzir, L. Metoui, I. Gharsallah, H. Mahfoudhi, C. Chourabi, W. Fehri
Journal: Annals of the Rheumatic Diseases (2021)

Background: Patients with rheumatoid arthritis are at increased risk for cardiovascular disease (CVD).The early myocardial dysfunction in RA patients may be detectable sooner using speckle-tracking echocariodgraphy to evaluate ventricular strain especially the global longitudinal strain (GLS), this has provided more comprehensive information on ventricular dysfunction in these patients. Objectives: In the present study, we evaluated comorbidities that interfered the most with the GLS in rheumatoid arthritis patients. Methods: The study population was comprised of a case group (36 patients with rheumatoid arthritis with no history of CVD and normal LVEF in the outpatient population of the Rheumatology department in the military hospital of Tunis) and a matched control group (individuals without a history of rheumatoid arthritis or cardiac abnormalities referred for clinical check-ups). In both groups, 2D and 3D echocardiographic examinations were performed by a single cardiologist to assess cardiac functional parameters. Results: Anemia (36%) was found to be the most common comorbidity followed by diabetes mellitus (25%), arterial hypertension (17%) and dyslipidemia (17%). Myocardial deformation study revealed that rheumatoid arthritis patients had a significantly worse global longitudinal strain than healthy controls (18.99±2.81% vs 20.42±1.33%; P =.015). Moreover, a third of the rheumatoid arthritis patients (and no healthy controls) exhibited subclinical left ventricular systolic dysfunction (GLS&lt;18%). Anemia (r=−0.368, P =.027), Age (r=−0.365, P =.029), Diabetes mellitus (r=−0.540, P =.001) and E/A (r=0.351, P =.036) were significantly correlated with GLS in our univariate study. Receiver operating characteristic curve analysis revealed hemoglobin as the best predictor for subclinical LVSD (AUC=0.752, 95% CI: 0.577-0.927, P =.02) when compared to Age and E/A. Conclusion: This prospective comparative study highlighted the diabetes mellitus and anemia burden on myocardial dysfunction in RA patients. Disclosure of Interests: None declared
AB0477 EFFECT OF ANTI-TNF THERAPY ON BONE MINERAL DENSITY IN ANKYLOSING SPONDYLORTHITIS
Authors: A. Ajerouassi, K. Nassar, S. Janani
Journal: Annals of the Rheumatic Diseases (2021)

Background: Osteoporosis is common in spondyloarthritis, due to reduced spinal mobility, and inflammation. Anti-inflammatory treatments have a beneficial effect on the bone, and there is a significant increase in bone density during treatment with anti-TNF alpha. Objectives: to study bone mineral density in patients with ankylosing spondyloarthritis (AS) treated with anti-TNF alpha. Methods: This is a retrospective descriptive study of patients with AS meeting the modified New York criteria. Bone mineral density, assessed by dual energy x-ray absorptiometry (DXA), of AS patients treated with anti-TNF alpha was compared to that of a control group of AS patients not treated with anti-TNF alpha. Inclusion criteria: - Male patients - Patients who do not have an abnormality disrupting phosphocalcic and bone metabolism - For Patients on anti-TNF alpha: the treatment must be received for more than 6 months Results: A total of 22 patients were included, including 11 patients on anti-TNF alpha and 11 patients not on anti-TNF. The mean age (standard deviation) was 28 (± 7.2) years and 41 (± 14.8) in the cases and controls respectively. The mean body mass index in the AS group on anti-TNF was 22.16 kg / m2 and in the control group was 19.64 kg / m2. In the AS group on anti-TNF alpha, the mean bone mineral density of the spine was 1.092 g / cm2 (mean T score = -0.63) and that of the femoral neck, the mean bone mineral density was 0.888g / cm2 (mean T score = -1.04). In the control group, the mean bone mineral density of the spine was 0.959 g / cm2 (mean T score = -1.91) and the mean bone mineral density of the femoral neck was 0.774 g / cm2 (mean T score = -1.99). Bone mineral density in the spine and cervix was higher in the group receiving anti-TNF alpha (p = 0.09, p = 0.173 respectively) Conclusion: Our study shows the increase, although not statistically significant, in bone mineral density in AS patients receiving anti-TNF alpha agents compared to controls. Our results agree with those of the literature which support the bone protective effect of anti-TNF alpha. The non-significant difference can be explained by the delay in the introduction of biotherapy at the advanced stage of the structural evolution of AS. The best solution is to start TNF inhibitors at the early inflammatory stage of AS. Disclosure of Interests: None declared.
Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure
Authors: Jin-Ling Huo, Lemin Jiao, Qi An, Xiuying Chen, Yuruo Qi, Bingfei Wei, Yichao Zheng, Xiaojing Shi, Erhe Gao, Hong-Min Liu, Dong Chen, Cong Wang, Wen Zhao
Journal: Circulation Research (2021)

[Figure: see text].
Efficacy and Safety of Decitabine As First-Line Therapy for Elderly Patients with Acute Myeloid Leukemia.a Real Life Multicentric Experience of the Northern Italy
Authors: Erika Borlenghi, Carla Filì, Claudia Basilico, Massimo Bernardi, Manuela Caizzi, Rosanna Ciancia, Eros Di Bona, Anna Ermacora, Davide Facchinelli, Nicola Fracchiolla, Monica Fumagalli, Michele Gottardi, Silvia Imbergamo, Daniela Lambertenghi, Alfredo Molteni, Marta Petullà, Marta Riva, Elisabetta Todisco, Giuseppe Rossi, Anna Candoni
Journal: Blood (2017)
FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm
Authors: Naval Daver, Sangeetha Venugopal, Farhad Ravandi
Journal: Blood Cancer Journal (2021)

Abstract Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 ( FLT3 ) gene. While the adverse prognostic impact of FLT3 -ITD mut in AML has been clearly proven, the prognostic significance of FLT3 -TKD mut remains speculative. Current guidelines recommend rapid molecular testing for FLT3 mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3 mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3 mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3 mut AML have improved outcomes in patients with FLT3 mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3 mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3 mut AML.
Lectures on the Action of Medicines, Being a Course of Lectures on Pharmacology and Therapeutics, delivered at St. Bartholomew's Hospital during the summer session of 1896.
Journal: JAMA (1897)

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Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model
Authors: Milena Simovic, Michiel Bolkestein, Mahmoud Moustafa, John K L Wong, Verena Körber, Sarah Benedetto, Umar Khalid, Hannah Sophia Schreiber, Manfred Jugold, Andrey Korshunov, Daniel Hübschmann, Norman Mack, Stephan Brons, Pei-Chi Wei, Michael O Breckwoldt, Sabine Heiland, Martin Bendszus, Jürgen Debus, Thomas Höfer, Marc Zapatka, Marcel Kool, Stefan M Pfister, Amir Abdollahi, Aurélie Ernst
Journal: Neuro-Oncology (2021)

Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy.We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological MRI, cellular (markers of neurogenesis and DNA damage-repair), and molecular characterization (whole-genome sequencing).In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days postirradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the postradiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, P < .0001). No major change in the clonal composition was detected in the relapsed model.The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Postradiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.
AB0257 IMPACT OF CONVENTIONAL ANTIRHEUMATIC TREATMENT ON CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: D. Gerasimova, E. Gerasimova, T. Popkova, A. Melkumyan
Journal: Annals of the Rheumatic Diseases (2021)

Background: Cardiovascular diseases (CVD) are the most common and socially significant comorbidities and the main cause of premature mortality in rheumatoid arthritis (RA). Appropriate RA therapy should not only suppress RA activity, but also reduce CVD risk. Objectives: To evaluate CVD risk and analyze its association with the use of conventional therapy in RA patients (pts). Methods: The study included 100 pts with RA (92 women and 8 men) aged 30 to 60 without established CVD. The median age was 49.5 [44.5;53] years, duration of RA was 144 [60;240] months, DAS28 was 4.4 [3.3;5.3] points. Eighty six RA pts (86%) treated with disease-modifying antirheumatic drugs (DMARDs) (methotrexate, n=55; leflunomide, n=12; hydroxychloroquine, n=8; sulfasalazine, n=11), including 33 pts (33%) in combination with glucocorticoids (GCs). Fourteen pts (14%) received monotherapy with GCs. Pts were divided into three treatment groups: DMARDs group, n=53; GCs group, n=14; DMARDs+GCs group, n=33. CVD risk was calculated with ASSIGN, QRISK3, and ERS-RA scales. Results: No differences were found between the groups when calculating CVD risk using ASSIGN (table 1). Estimated CVD risk by QRISK3 was lower in DMARDs group (4.9 [3.0; 7.7]) than in DMARDs+GCs group (7.1 [4.1; 13.6], p&lt;0.05). High CVD risk on the ERS-RA scale was determined less frequently (13%) and median CVD risk was lower in DMARDs group (4.2 [2.2; 5.4]) than in GCs group (57%; 8.9 [4.8; 11.7], p&lt;0.01) and DMARDs+GCs group (39%; 6.6 [3; 9.3], p&lt;0.05, respectively). In DMARDs group, significant differences in CVD risk by ERS-RA were found in pts treated with hydroxychloroquine (2 [1.4; 5.8]) and leflunomid (6.2 [2.8; 12.3], p&lt;0.05). Conclusion: RA pts treated with DMARDs have a reduced risk for CVD than pts treated with GCs or a combination of DMARDs and GCs. GCs significantly increase CVD risk. To clarify the impact of hydroxychloroquine and leflunomid on CVD risk, a study on a larger number of pts is required. Table 1. The impact of conventional antirheumatic therapy on CVD risk. Treatment ASSIGN QRISK3 ERS-RA High CVD risk, % median [25-75 percentiles] High CVD risk,% median [25-75 percentiles] High CVD risk,% median [25-75 percentiles] DMARDs, n=53 6 11 [6.5;14] 2 4.9 [3;7.7] v 13* v 4.2 [2.2;5.4] * v GCs, n=14 7 9.5 [7;13] 7 6.6 [4.4;15.8] 57* 8.9 [4.8;11.7] * DMARDs+GCs, n=33 15 10 [5;13.5] 9 7.1 [4.1;13.6] v 39 v 6.6 [3;9.3] v Note: * - p&lt;0.01 between pts receiving DMARDs and GCs; v - p&lt;0.05 between pts receiving DMARDs and DMARDs+GCs. Disclosure of Interests: None declared
Microbial polysaccharides: An emerging family of natural biomaterials for cancer therapy and diagnostics
Authors: None Prateeksha, Vivek K. Sharma, Xiaowen Liu, Diego A. Oyarzún, Ahmed M. Abdel-Azeem, Atanas G. Atanasov, Abd El-Latif Hesham, Saroj K. Barik, Vijai Kumar Gupta, Brahma N. Singh
Journal: Seminars in Cancer Biology (2021)
POS0411 TARGETING JAK-STAT SIGNALLING ALTERS THE PHENOTYPIC CHARACTERISTICS OF PsA SYNOVIAL FIBROBLASTS IN RESPONSE TO THE JAK/STAT ACTIVATOR ONCOSTATIN M
Authors: A. O’ Brien, M. Hanlon, V. Marzaioli, K. Flynn, S. Wade, D. Veale, U. Fearon
Journal: Annals of the Rheumatic Diseases (2021)

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. The JAK/STAT pathway has been linked to the pathogenesis of PsA. Recently, JAK/STAT inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Only a few of these inhibitors have been approved for use in PsA patients with others currently in clinical trials. Objectives: The aim of this study was to examine the effect of JAKi on primary PsA synovial fibroblasts (FLS) function. Methods: Primary PsA FLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of the pro-inflammatory JAK/STAT activator - Oncostatin M (OSM). The effect of JAKi on these cells was determined by Migration and Invasion Assays, ELISA and rtPCR. PsA FLS bioenergetics was assessed using an XF24 analyser, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and Oxidative phosphorylation (OCR). Results: OSM-induced Migration and Invasion was supressed by all JAKi with Peficitinib, Filgotinib and Baracitinib showing the greatest effect. Analysis by ELISA and rtPCR showed reduction in MCP-1 and IL-6 expression in response to JAKi, in contrast, an increase in IL-8 was observed. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsA FLS, where OSM significantly increased the ECAR:OCR ratio in favour of glycolysis where PsA FLS displayed a hypermetabolic phenotype. This effect was reversed in the presence of JAKi, which specifically targeted the glycolytic pathway with PsA FLS returning to a more quiescent phenotype. Conclusion: This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis, inhibition of which shows effective suppression of the pathogenic phenotype of PsA FLS that drives joint destruction. References: [1]Chen M, Dai SM. A novel treatment for psoriatic arthritis: Janus kinase inhibitors. Chin Med J (Engl ). 2020;133(8):959-967. Disclosure of Interests: Aisling O’ Brien: None declared, Megan Hanlon: None declared, Viviana Marzaioli: None declared, Keelin Flynn: None declared, Siobhan Wade: 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
Fludarabine inhibits type I interferon-induced expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2
Authors: Huiqing Xiu, Jiali Gong, Tiancha Huang, Yanmei Peng, Songjie Bai, Guirun Xiong, Shufang Zhang, Huaqiong Huang, Zhijian Cai, Gensheng Zhang
Journal: Cellular and Molecular Immunology (2021)

2][3] In addition, ACE2 is a human interferon-stimulated gene. 4In response to viral infection, host cells produce vast amounts of type I interferon (IFN) to defend against viral infection. 5Type I IFNs, such as IFN-α, can upregulate the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2). 6,7Thus, whether and how IFN-α could promote and whether blockade of the IFN-α-STAT pathway could inhibit the expression of ACE2 are largely unknown.Given the importance of ACE2 for SARS-CoV-2 invasion and the clinical practice of IFN treatment to combat viral infection, herein, we addressed these issues via a series of in vitro experiments.First, we assessed the expression of ACE2 in various human cell lines.Relatively high levels of ACE2 mRNA and protein expression were observed in HBE and HEK293 cells but low expression levels were observed in HeLa cells (Fig. S1a).Immunoblot analysis after IFN-α stimulation showed that the ACE2 protein level was increased in A549 and HBE cells (Fig. 1a) and in HCC-LM3, LoVo, and HEK293 cells (Fig. S1b); these findings were further confirmed by immunofluorescence staining (Figs. 1b,S1c).In addition, flow cytometric analysis showed an increase in membrane ACE2 protein expression at 12 h after IFN-α treatment in A549 and HBE cells (Fig. 1c).These data indicate that IFN-α can universally upregulate the protein expression of ACE2 in lung, kidney, liver, and intestinal cells.Next, we investigated the mechanisms by which IFN-α promotes ACE2 expression.IFN-α treatment significantly upregulated the expression of the Ace2 gene in A549 and HBE cells (Fig. 1d) and in HCC-LM3, HEK293, and LoVo cells (Fig. S1d).The increase in ACE2 protein expression in HBE cells 12 h after IFN-α treatment was abolished in the presence of the mRNA translation inhibitor cycloheximide (CHX) (Fig. 1e) but not in the presence of the proteasome inhibitor MG132 (Fig. S1e).These results suggest that the IFN-α-mediated increase in ACE2 protein expression occurs at the transcriptional level.As STAT1 is required for the transcriptional induction of IFN-α-responsive genes, 8 we determined whether STAT1 is involved in regulating the IFN-αmediated increase in Ace2 transcription.As expected, Stat1 gene
The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells
Authors: Reza Hosseini, Leila Asef-Kabiri, Hassan Yousefi, Hamzeh Sarvnaz, Majid Salehi, Mohammad Esmaeil Akbari, Nahid Eskandari
Journal: Molecular Cancer (2021)

Abstract Tumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide future treatment options, in particular DC-based vaccination strategy, and review advances in the design and discovery of exosome inhibitors. Understanding the exosomal content and the pathways by which TDEs are responsible for immune evasion may help to revise treatment rationales and devise novel therapeutic approaches to overcome the hurdles in cancer treatment.
Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation
Authors: Xinhua Song, Hongwei Xu, Pan Wang, Jingxiao Wang, Silvia Affo, Haichuan Wang, Meng Xu, Binyong Liang, Li Che, Wei Qiu, Robert F. Schwabe, Tammy T. Chang, Marion Vogl, Giovanni M. Pes, Silvia Ribback, Matthias Evert, Xin Chen, Diego F. Calvisi
Journal: Journal of Hepatology (2021)