tbuckley/cabot-search huggingface dataset:
COL4A2 in the tissue-specific extracellular matrix plays important role on osteogenic differentiation of periodontal ligament stem cells
Authors: Yi Wen, Hongxu Yang, Junjie Wu, Axian Wang, Xiaodong Chen, Sijun Hu, Yuxing Zhang, Ding Bai, Zuolin Jin
Journal: Theranostics (2019)

Periodontal ligament stem cells (PDLSCs) can repair alveolar bone defects in periodontitis in a microenvironment context-dependent manner. This study aimed to determine whether different extracellular matrices (ECMs) exert diverse effects on osteogenic differentiation of PDLSCs and accurately control alveolar bone defect repair. Methods: The characteristics of PDLSCs and bone marrow mesenchymal stem cells (BMSCs) with respect to surface markers and multi-differentiation ability were determined. Then, we prepared periodontal ligament cells (PDLCs)-derived and bone marrow cells (BMCs)-derived ECMs (P-ECM and B-ECM) and the related decellularized ECMs (dECMs). Transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), and protein mass spectrometry were used to distinguish the ECMs. The expression of Type IV collagen A2 (COL4A2) in the ECMs was inhibited by siRNA or activated by lentiviral transduction of relevant cells. The stemness, proliferation, and differentiation of PDLSCs were determined in vitro in different dECMs. For the in vivo analysis, different dECMs under the regulation of COL4A2 mixed with PDLSCs and Bio-Oss bone powder were subcutaneously implanted into immunocompromised mice or in defects in rat alveolar bone. The repair effects were identified by histological or immunohistochemical staining and micro-CT. Results: B-dECM exhibited more compact fibers than P-dECM, as revealed by TEM, SEM, and AFM. Protein mass spectrometry showed that COL4A2 was significantly increased in B-dECM compared with P-dECM. PDLSCs displayed stronger proliferation, stemness, and osteogenic differentiation ability when cultured on B-dECM than P-dECM. Interestingly, B-dECM enhanced the osteogenic differentiation of PDLSCs to a greater extent than P-dECM both in vitro and in vivo, whereas downregulation of COL4A2 in B-dECM showed the opposite results. Furthermore, the classical Wnt/β-catenin pathway was found to play an important role in the negative regulation of osteogenesis through COL4A2, confirmed by experiments with the Wnt inhibitor DKK-1 and the Wnt activator Wnt3a. Conclusion: These findings indicate that COL4A2 in the ECM promotes osteogenic differentiation of PDLSCs through negative regulation of the Wnt/β-catenin pathway, which can be used as a potential therapeutic strategy to repair bone defects.
FRI0340 LONG-TERM FOLLOW-UP OF PRIMARY RAYNAUD’S PHENOMENON COHORT OF 248 PATIENTS
Authors: Francisco Miguel Ortiz Sanjuan, Elvira Vicens Bernabeu, Cristina Alcañiz Escandell, Inés Cánovas Olmos, Inmaculada Chalmeta Verdejo, Marta De la Rubia Navarro, Jorge Juan Fragio-Gil, Roxana Gonzalez Mazario, Luis Gonzalez Puig, Elena Grau García, Jose Ivorra Cortés, Isabel Martínez Cordellat, Carmen Nájera Herranz, Rosa Negueroles Albuixech, Jose Eloy Oller Rodríguez, Cristobal Pávez Perales, Jose Andrés Román Ivorra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Raynaud's phenomenon (RP) is frequently associated with the presence of scleroderma or other connective tissue diseases (CTD). Identify the presence of secondary RP is important to perform an adequate therapeutic management and to achieve the early control of these patients. Nailfold capillaroscopy is safe, economic, easy to perform and has proven to be useful in identifying patients with secondary RP. <h3>Objectives</h3> To assess a long-term follow-up primary RP patient's cohort. <h3>Methods</h3> Retrospective observational study of a wide and unselected series of patients diagnosed as primary RP from a single university hospital from January 2012 to December 2018. Patients were classified as primary RP after the presence of CTD at the onset was excluded. <h3>Results</h3> We studied 248 patients (210 women/38 men), with a mean age of 46.3±15.2 years (range 15-88). After a mean follow-up period of 57.2±21.6 months, 9 (3.6%) patients were diagnosed of a CTD. The remaining 239 (96.4%) patients continued classified as primary RP. The main pathologies observed after follow-up were: Scleroderma/Systemic sclerosis (n=3), Systemic Lupus Erythematosus (n=3), Rheumatoid arthritis (n=1), Sjogren's syndrome (n=2). The main capillaroscopic patterns observed were: Normal (n=175), Unspecific (n=64), Scleroderma pattern (n=3) and suggestive of other rheumatic diseases pattern (n=6). All the patients who developed a CTD during follow-up showed changes at successive nailfold capillaroscopic examinations. 28 of 239 patients who remained primary RP showed minor changes at successive nailfold capillaroscopy. The main capillaroscopic changes detected on this group were: Presence of capillary tortuosity (n=6), presence of a decreased capillary density (2) and the presence of capillary bleeding (n=20). Antinuclear antibodies (ANA) were positive at he onset in 46 patients (16.9%) and after follow-up in 44 (17.7%) patients. <h3>Conclusion</h3> After a mean follow-up period next to 5 years, most of our primary RP patients remained free of CTD. A minority of our patients showed changes at nailfold capillaroscopy exam or positivity of ANA. <h3>Disclosure of Interests</h3> None declared
PB2003 ADDED RADIOTHERAPY IMPROVES PROGNOSIS IN HD PATIENTS TREATED WITH ABVD
Authors: O. Karanfilski, G. Amzai, S. Trpkovska Terzieva, M. Pavkovik, T. Sotirova, S. Genadieva Stavrik, S. Krstevska Balkanov, M. Cvetanoski, N. Ridova, B. Kocoski, A. Stojanovik
Journal: HemaSphere (2019)

Background: Results from many analyses and trials have shown that combined modality treatment contributes to better vital statistics for HD patients, compared to chemotherapy‐only treatment. In previous analyses, we have also argumented this point, validating it on our patient population. However, our previous analyses were performed mainly on HD patients initially treated with COPP‐like regimens. Aims: To analyze whether HD patients initially treated at our Clinic with the ABVD (and derived) regimen(s) still benefit from the addition of radiotherapy as a treatment component. Methods: Within the past two decades we used ABVD as initial treatment in a total of 272 HD patients. In more than 70% of these, chemotherapy only was the treatment mode administered. Almost 30% of these patients required addition of radiotherapy, as part of a recommended combined modality treatment option, or, in a minority of cases, as adjuvant treatment to sites of residual or bulky tumor mass. Results: ABVD as induction treatment achieves 5yOS in 91% of patients, and 10yOS for 85% of the patients. The survival curve maintains a plateau at 82.5% after the 150‐month mark. The 77 patients treated with the combined modality treatment/adjuvant chemotherapy maintain a 4% margin of superiority in the OS, across the first 10 years of follow‐up. Nevertheless, both survival curves almost merge after the 15th year, and maintain a continuous plateau thereafter. The benefit is more evident when PFS is analyzed. All clinical stages maintain a continuous difference between the plateaus of the curves, starting from the third year of follow‐up, varying from 2‐6% among different CS categories. Although a small category (8 patients), even the advanced stage patients treated with adjuvant radiotherapy benefit from this option, maintaining a 100% OS and PFS line. It should be clearly stated that in our analysis the differences do not reach a statistically significant level in terms of p‐values, probably due to the relatively small number of patients analyzed, the notable disproportion among the patients with completed vs. censored observations, as well as because of the numeric misbalance among the groups treated with the two treatment options. Summary/Conclusion: Having balanced all observations, we still recommend that radiotherapy is not omitted as a very beneficial mode of treatment across all stages of the disease (abiding firmly by the indications for evidence‐based utilization of this option), contributing to a (maybe) marginal, but still a continuous advantage in the vital statistics of HD patients. Not neglecting the everlasting concerns of the community with regard to the adverse late effects of radiotherapy, hopes should turn towards dose modifications and field adjustments, as well as technological improvements of radiotherapy, rather than abandoning this treatment modality.
PS969 HYPOMETHYLATING DRUGS SPECIFICALLY TARGET DNMT3A MUTATION ASSOCIATED CLONAL HEMATOPOIESIS AND ACUTE MYELOID LEUKEMIA
Authors: M. Scheller‐Wendorff, A.K. Ludwig, C. Rohde, S. Staeble, S. Kraemer, N. Bäumer, C. Arnold, J. Zaugg, D.B. Lipka, C. Müller‐Tidow
Journal: HemaSphere (2019)

Background: DNMT3A mutations commonly occur in myeloid malignancies and in clonal hematopoiesis. The codon arginine 882 (R882) is the major hotspot mutation in patients with de novo AML, in secondary AML as well as in individuals with clonal hematopoiesis in the absence of leukemic transformation. Although the majority of patients with DNMT3A‐R882H AML initially respond to conventional chemotherapy, many of them subsequently relapse, suggesting that DNMT3A‐R882H cells persist and drive relapse. No specific therapy exists to date for clonal hematopoiesis or DNMT3A‐R882H mutated AML. Recent studies have shown that DNMT inhibitors (DNMTi) could be particularly beneficial for patients with DNMT3A mutations. However, the extent of this association, the potential to cure patients and the mechanisms remain unresolved. Aims: Our aim is to identify in which context leukemic and pre‐leukemic stem cells with DNMT3A‐R882 mutation can be targeted by DNMT‐inhibitors as mono‐therapy and in combination. Methods: In order to understand the molecular and functional consequences of the DNMT3A‐R882H mutation in leukaemogenesis we generated a novel, inducible knock‐in mouse line of human DNMT3A‐R882H mutations (DNMT3A R882H ). DNMT3A R882H knock‐in mice that harbored a floxed stop cassette upstream of the Dnmt3a gene were crossed with mice carrying an interferon‐inducible Cre recombinase allele (Mx1‐Cre). Upon Cre induction the endogenous mouse Dnmt3a gene from exon 2 was efficiently replaced by human DNMT3A cDNA carrying the R882H mutation. Results: Analysis of aged DNMT3A R882H knock‐in mice at pre‐leukemic stage revealed accumulation of myeloid progenitor (GMP) and stem cells (HSC), which showed loss of dormancy, increased cell cycle and exhaustion in serial retransplantation in vivo . Using mouse model of leukemia by mouse‐intercross and retroviral infection, we have confirmed that DNMT3A R882H mutation accelerated leukaemogenesis in the presence of FLT3‐ITD, MLL‐AF9 and Myc‐Bcl2, whereas DNMT3A R882H mutation alone did not induce leukemia in mice up to eighteen months after Cre induction. In search of therapeutic strategies, we identified that DNMTi specifically target DNMT3A‐R882H mutant pre‐leukemic HSC and leukemic blasts. Loss of DNA methylation in DNMT3A‐R882H HSCs associated with enhanced immune signals including increased expression of endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN‐inducing cellular response. A single therapy cycle of low dose DNMTi (5‐Azacytidine) treatment accelerated loss of DNA methylation in DNMT3A‐R882H HSCs and exhaustion of DNMT3A‐R882H mutant hematopoiesis. 5‐Azacytidine in combination with chemotherapy induced long lasting remissions in DNMT3A‐R882H murine leukemias. Summary/Conclusion: These findings may open the path towards targeted therapy of DNMT3A mutated clonal hematopoiesis and AML.
Vardenafil Decreases Bladder Afferent Nerve Activity in Unanesthetized, Decerebrate, Spinal Cord–Injured Rats
Authors: Delphine Behr-Roussel, Stephanie Oger, Stéphanie Caisey, Peter Sandner, Jacques Bernabé, Laurent Alexandre, Francois Giuliano
Journal: European Urology (2010)
FRI0447 THE SURVIVAL OF BIOLOGICS IN PSORIATIC ARTHRITIS – THE FIRST DATA FROM MOSCOW UNIFIED REGISTER OF ARTHRITIS (MUAR)
Authors: Karine Lytkina, Evgeniya Shmidt, Galina Lukina, Ekaterina Koltsova, Evgeniy Zhilyaev
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Early started therapy of psoriatic arthritis with the goal to achieve minimal disease activity can slow the joint damage progression. Data concerning the persistence of psoriatic arthritis (PsA) patients on biologics in real clinical practice are insufficient. Objectives: to analyze the survival of biological treatment of PsA and detect possible predictors of persistence on biologics. <h3>Methods</h3> PsA patients from Moscow Unified Arthritis Registry (MUAR) treated with biologics were included in study. Unadjusted survival analysis was performed by the Kaplan-Mayer method. The search for independent risk predictors of the therapy discontinuation was carried out by the multivariate Cox regression. <h3>Results</h3> We analyzed 236 treatment episodes in 141 PsA patients enrolled in MUAR, 61 men (43%); mean age was 50.1 ± 11.5 years. We used the following biologics: etanercept (71 patients), infliximab (51), adalimumab (50), ustekinumab (35), golimumab (11), cerolizumab pegol (7). In unadjusted analysis mean treatment survival was longer with etanercept, adalimumab and infliximab. As significant independent predictors of withdrawal risk (potential confounders) low education, mutilating or polyarticular form of PsA, heel pain, shoulder joints swelling and absence of neck pain at the disease onset were detected. After the adjusting data for cofounders there was no significant difference in risk of withdrawal between different biologics. Neither the year of onset of the case of treatment nor the number of previous bDMARDs show a significant relation with the risk of drug withdrawal (Picture 1). This data show the difference between the patterns of treatment survival of rheumatoid arthritis and psoriatic arthritis <h3>Conclusion</h3> our analysis of PsA treatment persistence in real clinical practice detected several factors associated with withdrawal risk. These data can provide specialists with a tool for personalized treatment <h3>Disclosure of Interests</h3> None declared
THU0474 PREVALENCE OF TIREOIDIAN DISORDERS IN A POPULATION WITH FIBROMYALGIA
Authors: Marco Antonio G Pontes Filho, DOMICIANO DIOGO SOUZA, Rafael Pontes Andreussi, Leonardo Rodrigues Da Silva
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Fibromyalgia (FM) is a clinical syndrome characterized by diffuse pain associated with other symptoms such as fatigue, sleep disturbance and mood. It presents a series of differential diagnoses such as thyroid disorders, hypoparathyroidism, systemic inflammatory diseases and myopathies. Hypothyroidism is a disease with a prevalence of 4-6% of the population, having many symptoms in common with FM, such as fatigue, mood changes, constipation, and diffuse pain in some cases. <h3>Objectives</h3> The purpose is to evaluate the association between FM and thyroid disorders. <h3>Methods</h3> A retrospective monocentric case-control study in a tertiary hospital, with patients and controls having regular follow-up. The cases were composed of women over 40 years old, diagnosed with FM by the criteria ACR 1990 and ACR 2010, without autoimmune disease or other confounding diseases for pain. The control consisted of women over 40 years old, without autoimmune diseases. Laboratory tests included TSH and free T4 in all patients. Evaluation by ANA, anti-TPO and anti-thyroglobulin antibodies, only when appropriate. The sample was classified into euthyroid, clinical and subclinical hyperthyroid, clinical and subclinical hypothyroid. Statistical analysis included Fischer's T-tests and others where appropriate. The p value was significant when ≤ 0.05. <h3>Results</h3> The sample consisted of 142 patients (median age of 58 years) and controls with 136 patients (median age of 67 years). Patients with FM had a greater number of thyroid disorders (31.7%) than controls (14.7%) (p = 0,001). FM patients had a TSH higher than the controls (mean 9.06 <i>vs</i> 2.96; p = 0,0026), with a lower free T4 (mean 1.06 <i>vs</i> 1.31; p = 0,0001). ANA, anti-TPO and anti-thyroglobulin antibodies analysis showed no differences between both groups (p = 1; p = 0,08, p = 1; respectively), when performed. Because of the small difference in median age between the two groups, a sub analysis was performed separating patients between the ages of 40 to 60 years and over 60 years. The same results previously seen were found. <h3>Conclusion</h3> Patients with FM had a greater association with clinical hypothyroidism. However, we did not find any association with autoantibodies in our casuistic. <h3>References</h3> [1] Claw, DJ, JAMA, volume 311, página 1547, 2014. [2] Hollowell JG, J Clin Endocrinol Metab, 87:489, 2002. [3] Suk, JH, Experimental and Clinical Endocrinology and Diabetes, 120: 401, 2012. [4] J.Rodríguez-Espinosa, Reumatologia Clinica, 2:70, 2006. [5] J. Ahmad, Rheumatology International, 35:1415, 2015. <h3>Disclosure of Interests</h3> Marco Antonio G Pontes Filho Speakers bureau: Novartis and Janssen, DIOGO SOUZA DOMICIANO: None declared, Rafael Pontes Andreussi: None declared, Leonardo Rodrigues da Silva: None declared
Chronic myeloid leukemia
Authors: Oliver Hantschel
Journal: HemaSphere (2019)

Take home messages To review state-of-the-art treatment approaches in CML with treatment free remission as important goal. To improve knowledge on individual TKI toxicity profiles and side effect management. To discuss insights from NGS to optimize treatment of CML patients. Introduction Chronic myeloid leukemia (CML) became a paradigm for targeted cancer therapy due to the unprecedented clinical success of the tyrosine kinase inhibitor (TKI) imatinib. Most CML patients in the chronic phase of CML that are treated with imatinib achieve durable remissions and their survival is not different from that of the general population. Still, a fraction of patients is intolerant or resistant to imatinib. For these patients, 4 additional TKIs—dasatinib, nilotinib, bosutinib, and ponatinib—are approved as salvage therapies and subsequently dasatinib, nilotinib, and bosutinib were also approved for first-line therapy. The first paper of this educational session will provide an overview of the current treatment approaches in CML. As the 5 approved TKIs for CML strongly differ in their adverse events profile, the second paper will give an expert summary of transient reversible and potentially irreversible side effect of these TKIs. It will provide guidance how to identify the most efficacious treatment in early disease stages and how to manage side effects. The third paper of the session will review the insights that were obtained from next-generation sequencing (NGS) studies in CML and provide future perspectives of NGS for risk stratification of CML patients.
AB1073 A RETROSPECTIVE COHORT STUDY OF IGG-4 RELATED DISEASE IN IRISH PATIENTS
Authors: Aadil Al Ghafri, Aurelie Fabre, Eamonn S. Molloy
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Immunoglobulin (Ig) G4-related disease (IgG4RD) is a novel clinical entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. <h3>Objectives</h3> To describe the clinical presentations, laboratory features, imaging manifestations, histopathologic characteristics and treatments in a cohort of 38 patients with IgG4RD. <h3>Methods</h3> A retrospective study was performed at St. Vincent's University Hospital. Clinical, laboratory, imaging and histopathologic data was retrieved from electronic records. All data were assessed using SPSS 24.0. <h3>Results</h3> Median age was 59 years with M:F ratio= 2.2:1. 24 (63.2%) patients were between 25-65 years), 14 (36.8%) were &gt;65 years. 23 (60.5%) patients fulfilled the Comprehensive Diagnostic Criteria for IgG4RD as 'definite', whereas 5 (13.2%) patients fulfilled 'probable' diagnoses and 10 (26.3%) patients fall in 'possible' category. GI manifestations (followed by pancreatic) were the most frequent clinical presentation. 23 (60.5%) patients presented with single organ involvement; pancreas was the most frequently involved organ (17/38, (44.7%)). 55.3% had a serum IgG4 level above 135mg/dL. Lymphoplasmacytic infiltration was the commonest histopathologic pattern reported in 29 (76.3%) specimens. 25 (65.8%) patients had received steroid therapy and 19 (50.0%) had a good response. 11 (28.9%) patients received immunomodulatory agents including Rituximab (n=4), Azathioprine (n=7), and Mycophenolate mofetil (n=4). Overall, 28 (73.7%) patients had complete remission with treatment. <h3>Conclusion</h3> IgG4RD is a rare entity in Ireland and an inadequately understood condition overall. Further research is required to better understand the pathophysiology, clinical course and optimal treatment for IgG4RD. <h3>References</h3> [1] Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30. [2] Okazaki K, Kawa S, Kamisawa T, Naruse S, Tanaka S, NishimoriI, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006;41(7):626–31. [3] Hisanori Umehara et al, A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol (2012) 22:1–14 [4] Inoue D, Yoshida K, Yoneda N, et al. IgG4-related disease: dataset of 235 consecutive patients. Medicine (Baltimore). 2015;94(15):e680. <h3>Disclosure of Interests</h3> None declared