tbuckley/cabot-search huggingface dataset:
Dynamics of Transposable Element Invasions with piRNA Clusters
Authors: Robert Kofler
Journal: Molecular Biology and Evolution (2019)

In mammals and invertebrates, the proliferation of an invading transposable element (TE) is thought to be stopped by an insertion into a piRNA cluster. Here, we explore the dynamics of TE invasions under this trap model using computer simulations. We found that piRNA clusters confer a substantial benefit, effectively preventing extinction of host populations from a proliferation of deleterious TEs. TE invasions consist of three distinct phases: first, the TE amplifies within the population, next TE proliferation is stopped by segregating cluster insertions, and finally the TE is inactivated by fixation of a cluster insertion. Suppression by segregating cluster insertions is unstable and bursts of TE activity may yet occur. The transposition rate and the population size mostly influence the length of the phases but not the amount of TEs accumulating during an invasion. Solely, the size of piRNA clusters was identified as a major factor influencing TE abundance. We found that a single nonrecombining cluster is more efficient in stopping invasions than clusters distributed over several chromosomes. Recombination among cluster sites makes it necessary that each diploid carries, on the average, four cluster insertions to stop an invasion. Surprisingly, negative selection in a model with piRNA clusters can lead to a novel equilibrium state, where TE copy numbers remain stable despite only some individuals in a population carrying a cluster insertion. In Drosophila melanogaster, the trap model accounts for the abundance of TEs produced in the germline but fails to predict the abundance of TEs produced in the soma.
SAT0213 PREGNANCY AND UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE: OUTCOME AND RISK OF FLARE IN 100 PREGNANCIES
Authors: Dina Zucchi, Chiara Tani, Elena Elefante, Linda Carli, Alice Parma, Francesca Anna Letizia Strigini, Marta Mosca
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Undifferentiated connective tissue disease (UCTD) is a group of systemic autoimmune conditions which do not fulfil the criteria for a definite connective tissue disease (CTD). The interaction between pregnancy and UCTD is still poorly studied and scarcely recognized. <h3>Objectives:</h3> The purpose of this study was to evaluate the risk of disease flares or differentiation into a well-defined CTD and also the risk of adverse outcome in pregnancy in patients with UCTD. <h3>Methods:</h3> A total of 100 pregnancies in 81 UCTD followed at a single center were included in this analysis. From the time the pregnancy was detected, each patient was evaluated every 4 – 6 weeks and the diagnosis was re-evaluated at each observation; the follow-up was considered completed after the last visit during puerperium. At each visit, patients were assessed by a rheumatologist and by a gynecologist. <h3>Results:</h3> Eleven pregnancies (11%) ended with abortion in the first trimester and the remaining 89 (89%) ended with a live birth. Twelve patients (12%) flared during pregnancy or puerperium and three (3%) had major flares and evolved to systemic lupus erythematosus (SLE) with renal involvement. Obstetric complications were observed in twenty-nine out of the 89 successful pregnancy (33%), including two cases (2%) of preeclampsia. We found a significant association between anti-dsDNA antibodies positivity at baseline and disease flare (p&lt;0.01), while disease activity at the beginning of pregnancy was associated with flare (p&lt;0.01) and also with cumulative obstetric complications (p&lt;0.05). <h3>Conclusion:</h3> The impact of pregnancy appears to be less serious in UCTD than in other CTDs, however disease flares and obstetric complications can represent a clinical challenge; disease clinical and serological activity seem important determinants of pregnancy outcomes. Thus, a pre-pregnancy counselling and planning as well as a close monitoring during pregnancy is warranted. <h3>Disclosure of Interests:</h3> Dina Zucchi: None declared, Chiara Tani: None declared, Elena Elefante: None declared, Linda Carli: None declared, Alice Parma: None declared, Francesca Anna Letizia Strigini: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB
AB1352-HPR INVESTIGATION OF EFFECT OF DISEASE AND RELATED FACTORS IN INDIVIDUALS WITH FIBROMYALGIA
Authors: Bilge Basakci Calik, Aylin Keskin, Elif Gur Kabul, Berna Cagla Caglayan, Ugur Karasu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Fibromiyalgia (FM), one of the most common rheumatologic disorders, is characterized by widespread pain in the body, sensitivity in the certain anatomical regions, fatigue, sleep disorders and reduced pain threshold, uncommon and extra-articular rheumatism disease (1). It has been reported that impairments in functional capacity and quality of life cause significant limitations in individuals with FM (2). <h3>Objectives</h3> The aim of this study was to examine the effect of disease and to investigate the factors associated with the disease in individuals with FM. <h3>Methods</h3> In our study, 334 voluntary individuals with FM (324 famele,10 male) who applied to Pamukkale University Department of Internal Medicine, Department of Rheumatology were diagnosed according to 2010 American College of Rheumatology criteria whom participated in the study with the mean age of 47,55±10.46 (years). Fibromyalgia Impact Questionnaire (FIQ) was used to determine the effect of disease, Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) for emotional status and Pittsburgh Sleep Quality Index (PSQI) for sleep quality, right after demographic information and disease related data were recorded. Multiple regression analysis were used to examine the factors related to disease activity. <h3>Results</h3> High body mass index (B=.121, p=0.023), high tender point score (B=.427, p=0.000), high depression score (B=.350, p=0.00), high anxiety score (B=.258, p=0.000) and poor sleep quality (B=.157, p=0.002) corresponded to the higher FIQ score. However, age (B=-.019, p=0.716), level of education (B=.009, p=0.858) and disease duration (B=.054, p=0.331) did not significantly affect FIQ. <h3>Conclusion</h3> As a result of our study the progress of body mass index in individuals with FM, increase in number of tender points, poor sleep quality, depression and anxiety were among the factors affecting the disease. Therefore, these factors must be considered in order to reduce the severity of the disease in individuals with FM. <h3>References</h3> [1] Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristic of fibromyalgia in the general population. Arthritis Rheum 1995;38:19-28. [2] Arnold LM, Crofford LJ, Mease PJ, et al. Patient perspectives on the impact of fibromyalgia. Patient Educ Couns 2008a;73:114-20. <h3>Disclosure of Interests</h3> None declared
Reply to Lorenzo Marconi, Karim Bensalah, and Axel Bex's Letter to the Editor re: Paul C.M.S. Verhagen, Egbert R. Boevé. The European Association of Urology Guideline on Renal Cell Carcinoma (RCC) is Not Concise in its Recommendation to Perform Partial Nephrectomy in T1b RCC. Eur Urol 2019;76:136–7
Authors: Paul C.M.S. Verhagen, Egbert R. Boevé
Journal: European Urology (2019)
Abstract 16625: Post-operative Cardiac Catheterization in Children Undergoing Congenital Heart Surgery: An Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database
Authors: Amelia S Wallace, Marshall L Jacobs, Christoph P Hornik, John M Costello, Gregory A Fleming, Jeffrey P Jacobs, Robert D Jaquiss, Bryan H Goldstein, Reid C Chamberlain, Kevin D Hill
Journal: Circulation (2017)

Introduction: Interventional cardiac catheterization (ICC) is often used to treat residual anatomic lesions after congenital heart surgery but with limited understanding of how frequently ICC is pe...
Allocation of liver grafts worldwide – Is there a best system?
Authors: Christoph Tschuor, Alberto Ferrarese, Christoph Kuemmerli, Philipp Dutkowski, Patrizia Burra, Pierre-Alain Clavien, Javier Lendoire, Oscar Imventarza, Michael Crawford, Wellington Andraus, Luiz Augusto Carneiro D'Albuquerque, Roberto Hernandez-Alejandro, M. Katherine Dokus, Koji Tomiyama, Shusen Zheng, Gabriel Jaime Echeverri, Pavel Taimr, Jiri Fronek, Marieke de Rosner-van Rosmalen, Serge Vogelaar, Mickael Lesurtel, Jean-Yves Mabrut, Sanjay Nagral, Farzad Kakaei, Seyed Ali Malek-Hosseini, Hiroto Egawa, Alan Contreras, Jaroslaw Czerwinski, Teresa Danek, Hugo Pinto-Marques, Sergey V. Gautier, Artem Monakhov, Espen Melum, Bo-Göran Ericzon, Koo Jeong Kang, Myoung Soo Kim, Patricia Sanchez-Velazquez, Christian Eugen Oberkofler, Beat Müllhaupt, Michael Linecker, Dilmurodjon Eshmuminov, Lukasz Filip Grochola, Zhoulon Song, Patryk Kambakamba, Chao-Long Chen, Mehmet Haberal, Sezai Yilmaz, Ian A.C. Rowe, Philipp Kron
Journal: Journal of Hepatology (2019)
Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation
Authors: Zhimin Gu, Yuxuan Liu, Feng Cai, McKenzie Patrick, Jakub Zmajkovic, Hui Cao, Yuannyu Zhang, Alpaslan Tasdogan, Mingyi Chen, Le Qi, Xin Liu, Kailong Li, Junhua Lyu, Kathryn E. Dickerson, Weina Chen, Min Ni, Matthew E. Merritt, Sean J. Morrison, Radek C. Skoda, Ralph J. DeBerardinis, Jian Xu
Journal: Cancer Discovery (2019)

Abstract Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRASG12D mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRASG12D to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. Significance: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics. See related commentary by Li and Melnick, p. 1158. This article is highlighted in the In This Issue feature, p. 1143
SAT0268 CLINICAL FEATURES OF INTERSTITIAL LUNG DISEASE ASSOCIATED WITH KOREAN IDIOPATHIC INFLAMMATORY MYOPATHIES ACCORDING TO THE AUTOANTIBODY PROFILE
Authors: Sang Wan Chung, Jinhyun Kim, In Seol Yoo, Seung-Jae Hong, Yeon-Ah Lee, Seong Wook Kang, Seungcheol Shim, In Ah Choi, Sung Hae Chang
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Myositis-specific and myositis-associated autoantibodies (MSA and MAA) have been used for more detailed classification and prediction of clinical course of idiopathic inflammatory myopathies (IIM). Interstitial lung disease (ILD) is known to be complicated with approximately 50% of IIM patients, having poor prognosis. <h3>Objectives:</h3> The aim of this study is to investigate clinical features of ILD in Korean adult patients with IIM according to the autoantibody profile including MSA and MAA. <h3>Methods:</h3> We conducted a multicenter cohort study including 108 adult patients (age≥18 years) who have been diagnosed as IIM by ENMC criteria MSA and MAA were screened with Immunoblot assay using Euroline strip (EUROIMMUN, Germany). Clinical information including the time of developing ILD and imaging findings of chest CT was reviewed using by medical record. <h3>Results:</h3> ILD was found in about half (52.8%, 57 of 108) of enrolled patients and closely associated with the presence of anti-ARS Abs, anti-MDA5 and anti-Ro52. Among 43 patients, Anti-ARS Abs were most common (46.5%) and included anti-Jo-1 (23.3%), -OJ (2.3%), -EJ (9.3%), -PL7 (14%), and -PL12 (7%) (Figure 1). To analyze the correlation of autoantibodies with pattern of ILD onset, we stratified the 43 patients into three groups: into ILD-preceding (7/43, 16.3%), simultaneous (31/43, 72.1%) and myopathy-preceding (6/43, 14%). In the ILD-preceding group, anti-ARS antibodies were frequent. ILD preceded myopathy by 19.5 months on average. The imaging pattern of ILD in the ILD-preceding group were Cryptogenic Organizing Pneumonia (COP) 6, Nonspecific Interstitial Pneumonia (NSIP) 1 and no <i>Usual interstitial pneumonia</i><b> (</b><i>UIP</i><b>).</b> A half of patient in ILD-preceding group had Raynaud`s phenomenon, and one patient had mechanic hand. On the other hand, in myopathy-preceding group, 30% of patients (2/6) were UIP and a half of patients had pulmonary function which required treatment (DLCO &lt;65%). <h3>Conclusion:</h3> In our study, ILDs were accompanied by over half of the cases of IIM and most of them had autoantibodies. There are characteristic clinical features by onset time of ILD, so paying attention to them will help early diagnosis and prognosis prediction of ILDs. <h3>Reference</h3> [1] Yoshifuji H. Clin Med Insights Circ Respir Pulm Med. 2016 Apr 3;9 (Suppl 1):141-6. <h3>Disclosure of Interests:</h3> None declared
More Evidence of an Inverse Association Between Cancer and Alzheimer Disease
Authors: Olivia I. Okereke, Mary-Ellen Meadows
Journal: JAMA Network Open (2019)

Monica Ospina-Romero, MD; Ekland Abdiwahab, MPH; Lindsay Kobayashi, PhD, MSc; Teresa Filshtein, PhD; Willa D. Brenowitz, PhD, MPH; Elizabeth R. Mayeda, PhD, MPH; M. Maria Glymour, ScD, MS
Abstract 11811: Importance of Pulmonary Arterial Capacitance in Pulmonary Hypertension With Left Heart Disease
Authors: Koichi Sugimoto, Kazuhiko Nakazato, Akiomi Yoshihisa, Takamasa Sato, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Hitoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi
Journal: Circulation (2016)

Background: Pulmonary hypertension due to left heart disease (LHD-PH) accounts for the largest proportion of pulmonary hypertension. However, prognostic factor of LHD-PH is poorly understood. Recently, pulmonary arterial capacitance (PAC) has attracted attention for being a factor of right ventricular afterload along with pulmonary vascular resistance. We investigated the clinical significance of PAC in LHD-PH. Methods: Two hundred fifty-two consecutive LHD-PH patients (145 men, mean age 63.4 ± 14.7 year) diagnosed by right heart catheterization were classified into four groups according to the level of PAC. PAC was estimated by the ratio between stroke volume and pulmonary arterial pulse pressure. The end point was a composite of cardiac mortality and rehospitalization due to worsening heart failure. The Cox proportional hazard regression model was used to determine what variables were associated with cardiac events. Results: Fifty-four patients encountered cardiac events during the follow-up period (median 943 days). The event free rate of the 1st quartile was significantly lower than that of the 3rd and 4th quartiles (66.7% vs 82.5% [3rd quartile], P = 0.008; and 92.1% [4th quartile], P &lt; 0.001). The Cox hazard analysis revealed that PAC was associated with cardiac events (HR 0.556, 95% CI 0.424 - 0.730, P &lt; 0.001). Cut-off value of 2.48 ml/mmHg of PAC from ROC curve analysis for prediction of cardiac events had 70.4% sensitivity and 58.1% specificity. Conclusion: PAC is the important prognostic factor in LHD-PH patients. PAC should be taken into account to manage patients with LHD-PH.
PB2068 THE CASTLEMAN DISEASE: HISTOLOGICAL VARIANTS, POEMS‐SYNDROME AND PRODUCTIVE PLASMA CELL VASCULITIS
Authors: A. Mihailov, S. Bessmeltsev, V. Rugal, N. Semenova, N. Khmelnitskaya
Journal: HemaSphere (2019)

Background: The Castleman disease (CD) is a rare, little‐studied disease characterized by lymphadenopathy with follicles hyperplasia and active neoangiogenesis. Occurs in the form of two histological variants: plasma cell and hyaline‐vascular. The total vasculitis in the vessels of internal organs, previously not noted by researchers, was revealed in the analysis of 2 sectional cases of CD. Aims: To study the state of microcirculatory vessels in patients with plasma cell and hyaline‐vascular type of CD in sections of biopsied lymph nodes. Methods Sections of biopsied lymph nodes were used. It was used hematoxylin‐eosin and reaction to antibodies to CD138 to identify plasma cells. In all patients with plasma cell variant cells were painted with antibodies to HSV‐8. Vessels estimated in perinodular tissue of capsule and fat. We examined 15 patients with CD. According to histology and CD138 content, the plasma cell variant was diagnosed in 8 patients, 7 men and 1 woman aged from 40 to 70 years. In 5 patients approved POEMS syndrome by the presence of M‐protein, disorders of neuro‐muscular conduction according to the electro‐neuromyography, and other symptoms. In 7 patients was diagnosed hyaline vascular type of CD, including 5 women and 2 men aged from 30 to 60 years. Results: In 1 patient with plasma cell variant of CD revealed HSV8 reaction with intranuclear staining antibodies. Vasculitis in the form of vascular walls thickening of the microcirculatory bloodstream with a decrease or obliteration of their lumen, wall fibrosis and plasma cell infiltration was found in all 15 patients. The most pronounced changes in the form of fibrosis, complete vascular obliteration and massive perivascular infiltration CD138+ cells by type of massive colonies of hundreds of cells were found in patients with the POEMS‐ syndrome. They also noted the location of single CD138 + cells inside the intima of the sclerosal vessels. Fibroplastic vascular changes in patients with POEMS‐syndrome were weirdly shaped in the form of “mood masks”. It coincided with massive osteosclerotic changes of the vertebrae on radiographs. Massive development of fibrosis corresponds to the POEMS pathogenesis. All patients with its presence later died. Summary/Conclusion: The Castleman disease, regardless of the histological variant, includes in its morphological pattern productive plasma cell vasculitis, most pronounced in the plasma‐cell variant with POEMS‐ syndrome.
The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes
Authors: Danika L. Hill, Wim Pierson, Daniel J. Bolland, Catherine Mkindi, Edward J. Carr, Jiong Wang, Sophie Houard, Steven W. Wingett, Regine Audran, Elizabeth F. Wallin, Said A. Jongo, Kassim Kamaka, Martin Zand, Francois Spertini, Claudia Daubenberger, Anne E. Corcoran, Michelle A. Linterman
Journal: The Journal of Experimental Medicine (2019)

The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE-formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.
Abstract 15001: Sustained Beneficial Effect of β-Blockers on Clinical Outcomes After Discontinuation in Patients With ST Elevation Myocardial Infarction
Authors: Jin-Sun Park, Kyoung-Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk, Joon-Han Shin
Journal: Circulation (2017)

Introduction: Our previous study demonstrated that beneficial effect of β-blockers on clinical outcomes in patients with ST elevation myocardial infarction (STEMI). In clinical practice, β-blocker ...
PB2359 THE ROLE OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN INCREASING THE EFFICIENCY OF TREATMENT IN PATIENTS WITH MULTIPLE MYELOMA
Authors: A. Garifullin, S. Voloshin, Z. Chubukina, A. Kuzyaeva, A. Sсhmidt, S. Bessmeltsev
Journal: HemaSphere (2019)

Background: Multiple myeloma remains an incurable disease despite the emergence of new drugs. The search of optimal therapeutic strategy to increase life expectancy and remission in patients with this disease is continues. This is facilitated to the achievement of the maximum possible response and eradication of residual tumor load. Existing recommendations for the treatment of multiple myeloma approve the use of autologous stem cell transplantation (autoSCT) to improve disease control. Aims: To determine the impact of autologous stem cell transplantation on efficiency of treatment and tumor load in patients with multiple myeloma. Methods: The study included 89 patients with MM (median age 58 years, male/female – 1.12:1). The induction therapy with Bortezomib‐based regimens (VD, CVD, VMP, PAD) was used in 62/89 (69.6%) patients, Immunomodulator‐based regimens (Thal + D, RD, VRD, PomD) – in 22/89 (24.8%), chemotherapy – in 4/89 (5.6%). High dose therapy (Mel200) and autoSCT is carried out in 64/89 (71.9%) patients. The efficiency of therapy was evaluated according to IMWG criteria. Tumor load was determined by multicolor flow cytometry (5‐colors): 79 patients – after 4‐6 courses of induction therapy, 39 patients – after autoSCT; 29 patients – tumor load was performed in dynamics (before and after autoSCT). Results: The sex, age, the variant induction antimyeloma therapy did not affect on response rate and tumor load. CR was achieved in 28/89 (31.4%) before AutoSCT and 50/89 (56.2%) after AutoSCT (p &gt; .05). However, high dose therapy (Mel200) and AutoSCT has increased the possibility of achieving complete response in dynamics: before AutoSCT in 5/29 (17.2%), after AutoSCT – in 13/29 (44.8%) (p&lt;.05). Tumor load after 4‐6 courses of induction therapy (n = 79) was 0.28 ± 0.34 for CR + sCR, 1.65 ± 2.66 for VGPR, 2.10 ± 2.53 for PR.Tumor load after HDT (Mel200) and AutoSCT (n = 39) was 0.06 ± 0.07 for CR + sCR, 0.15 ± 0.46 for VGPR, 0.17 ± 0.22 for PR. The effect of autoSCT on PFS in 39 patients. The median PFS was 97 months in the group “tumor load after autoSCT &lt;0.01%”, 70 months – in the group “tumor load without autoSCT &lt;0.01%”, 50 months – in the group “tumor load after autoSCT &gt;0.01%” and 25 months – in the group “tumor load without autoSCT &gt;0.01%” (p = .006). Examination of tumor load in the dynamics in 29 patients showed that autoSCT reduces the level of tumor load (before autoSCT = 2.27 ± 0.20, after autoSCT – 0.14 ± 0.01). Tumor load &lt;0.01% after autoSCT was detected more often than before autoSCT (14/29 and 5/29 patients, respectively) (p&lt;.05). Summary/Conclusion: AutoSCT increase the efficiency of therapy, reduce tumor load and increase the duration of progression free survival in patients with multiple myeloma. image