tbuckley/cabot-search huggingface dataset:
PF657 USE OF A NGS MYELOID PANEL TO FIND CLONALITY IN TRIPLE NEGATIVE ESSENTIAL THROMBOCYTHEMIA. IDENTIFICATION OF NEW MUTATIONS IN DRIVER GENES
Authors: G. Carreno‐Tarragona, N. López, X. Gutiérrez López de Ocariz, I. Rapado, J. Martínez‐López, R. Ayala
Journal: HemaSphere (2019)

Background: Essential Thrombocythemia is a clonal haematopoietic stem cell disorder characterized by hypercellularity of the bone marrow with effective haematopoietic maturation and increased numbers of platelets in the peripheral blood. Although more than 90% of the cases present typical mutations in JAK2, MPL and CALR, the remaining cases can become a diagnostic challenge as it requires the presence of a clonal marker or the absence of evidence for reactive thrombocytosis. Aims: To evaluate the use of a Myeloid Panel for the identification of clonal markers in TN ET cases and try to identify new mutations and prognostic determinants in these patients. Methods: A cohort of 32 ET negative for JAK2 V617F mutation (RT‐PCR), CALR canonic mutations (GENESCAN) and MPL W515K and W515L mutations (RT‐PCR) was selected. Average age at diagnosis was 49,08 (range 14–88). Male:Female ratio was 11:21. Average Haemoglobin, leukocytes and platelets at diagnosis were 14.14 g/dl 8,93 x10 9 /L and 820x10 9 /L, respectively. We performed targeted gene sequencing by NGS (Ion Torrent S5XL System–Thermofisher Scientific) using a panel of 33 (before March 2018) or 43 genes (after March 2018) implicated in leukemia prognosis. Results: With a median follow‐up of 5 years (range 0,02–25,43) 2 patients suffered transformation to acute myeloid leukemia, 1 progression to myelofibrosis and 1 presented with suffered a thrombotic event after diagnosis. We found clonality markers in 19 (59%) out of 32 patients. These presented an average of 1,84 (range 1–3) and 1,68 (range 1–3) mutations and mutated genes, respectively. 6 patients (31,57%) presented mutations in driver genes (JAK2, MPL and CALR). Three of them, family, presented with JAK2 R683G, a mutation previously described in acute lymphoblastic leukemia but not in myeloproliferative neoplasms. Other patient had JAK2 L393 V mutation, of undetermined significance and reported in population databases. Another presented the previously described MPL S505C and W515R mutations. Finally, we identified a new deletion in CALR exon 9 (c.1153_1155delAAG, p.K385del). 17 (89,47%) mutated patients presented mutations in non driver genes. Among those the most frequently mutated ones were TET2 (29%), ETV6 (17,6%), SF3B1 and KMT2A (both 11,7%). We found one mutation in VHL, DNMT3A, WT1, TP53, EPAS, CBL, IDH1, TPHO, KIT, ASXL1, EPOR and KRAS. Summary/Conclusion: Triple Negative TE suppose a diagnostic challenge. Here we show that targeted gene sequencing by a myeloid panel is able to identify clonality in up to 59% of the cases. Also, we have described new mutations in driver genes, gaining knowledge on TE molecular basis. Finally, larger cohorts of TN ETs are needed to clearly define the determinants and prognostic factors of this disease.
THU0139 IS ADDING ANTI-CARP OR ANTI-PADI4 BENEFICIAL FOR DIAGNOSIS OF RHEUMATOID ARTHRITIS?
Authors: Bogdan Kolarz, Magdalena Dryglewska, Marek Ciesla, Maria Majdan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Post-translatory modification (PTM), such as protein citrullination or homocitrullination (carbamylation) are key issues for the development of RA. There are known more than 300 PTMs. Some of them such as homocitrullination, are of chemical origin, but most of them (over 200) are of enzymatic origin. ACPA, anti-PADI4, anti-CarP and indirectly RF are originated as a result of such post-translational modifications [1]. From the above-mentioned RA markers only synthesis of anti-CarP is a result of chemical protein modification. The synthesis of anti-PADI4 may facilitate the production of citrullinated proteins and contribute to the formation of ACPA. All of the above markers appear before RA onset [2]. <h3>Objectives</h3> The aim of our study is to discover the potential utility of using additional markers (anti-CarP and anti-PADI4) in RA diagnosis. <h3>Methods</h3> 121 RA patients, 82.4% female, aged 52.2±12.3 years (mean±SD) and 30 healthy controls (HC), 76.7% female, aged 53.2±8.1 years, were enrolled in the study. ACPA, RF, anti-CarP and anti-PADI4 antibodies were determined in serum by enzyme-linked immunosorbent immunoassay (ELISA). <h3>Results</h3> The markers positivity rate was 85.95%, 67%, 55.37% and 46.28% in ACPA, RF, anti-PADI4 and anti-CarP respectively. Among ACPA negative patients we found 44.44% and 16.67% anti-CarP and anti-PADI4 positive results respectively. The data concerning ACPA are gathered in Table 1. In HC group we found 0%, 0%, 7.14% and 7.14% positivity in ACPA, RF, anti-PADI4 and anti-CarP respectively. We found 91.7% positivity for ACPA(+) or anti-CarP (+) vs 88.4% for ACPA(+) or RF(+). <h3>Conclusion</h3> The measurement of anti-CarP antibodies may be useful in RA diagnosis. The positivity for ACPA/anti-CarP is even higher than ACPA/RF. This might be caused by the similarity of the origins of ACPA and RF (enzymatic citrullination), while anti-CarP origin is different (chemical carbamylation). It is known that anti-CarP appears years before RA onset and might be used as a potential biomarker for pre-RA diagnosis. We didn't confirmed the usefulness of anti-PADI4 as RA biomarker. <h3>References</h3> [1] Tan, E.M. and J.S. Smolen, Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. The Journal of Experimental Medicine, 2016. 213(10):1937-1950. [2] Shi J, van de Stadt LA, Levarht E, et al. Anti Carbamylated Protein Antibodies (anti-CarP) are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 2012;21:37830. <h3>Disclosure of Interests</h3> Bogdan Kolarz: None declared, Magdalena Dryglewska: None declared, Marek Ciesla: None declared, Maria Majdan Speakers bureau: MSD, UCB, Abbvie, Roche
A review on anti-bacterials to combat resistance: From ancient era of plants and metals to present and future perspectives of green nano technological combinations
Authors: Lakshmi Kalyani Ruddaraju, Sri Venkata Narayana Pammi, Girija sankar Guntuku, Veerabhadra Swamy Padavala, Venkata Ramana Murthy Kolapalli
Journal: Asian Journal of Pharmaceutical Sciences (2019)

In the primitive era, humans benefited partially from plants and metals to treat microbial infections. Later these infections were cured with antibiotics but further suffered from resistance issues. In searching of an alternative, researchers developed an adjuvant therapy but were hampered by spreading resistance. Subsequently, nanoparticles (NPs) were proposed to cease the multi-drug resistant bacteria but were hindered due to toxicity issues. Recently, a novel adjuvant therapy employed metals and botanicals into innovative nanotechnology as nano-antibiotics. The combination of green synthesized metallic NPs with antibiotics seems to be a viable platform to combat against MDR bacteria by alleviating resistance and toxicity. This review focuses on the primitive to present era dealings with bacterial resistance mechanisms, newer innovations of nanotechnology and their multiple mechanisms to combat resistance. In addition, special focus is paid on greener NPs as antibiotic carriers, and their future prospects of controlled release and toxicity study.
Regulated Delayed <i>Shigella flexneri</i> 2a O-antigen Synthesis in Live Recombinant <i>Salmonella enterica</i> Serovar Typhimurium Induces Comparable Levels of Protective Immune Responses with Constitutive Antigen Synthesis System
Authors: Huali Su, Qing Liu, Shifeng Wang, Roy Curtiss, Qingke Kong
Journal: Theranostics (2019)

Shigella flexneri (S. flexneri), a leading cause of bacillary dysentery, is a major public health concern particularly affecting children in developing nations. We have constructed a novel attenuated Salmonella vaccine system based on the regulated delayed antigen synthesis (RDAS) and regulated delayed expression of attenuating phenotype (RDEAP) systems for delivering the S. flexneri 2a (Sf2a) O-antigen. Methods: The new Salmonella vaccine platform was constructed through chromosomal integration of the araC PBADlacI and araC PBADwbaP cassettes, resulting in a gradual depletion of WbaP enzyme. An expression vector, encoding Sf2a O-antigen biosynthesis under the control of the LacI-repressible Ptrc promoter, was maintained in the Salmonella vaccine strain through antibiotic-independent selection. Mice immunized with the vaccine candidates were evaluated for cell-mediate and humoral immune responses. Results: In the presence of exogenous arabinose, the Salmonella vaccine strain synthesized native Salmonella LPS as a consequence of WbaP expression. Moreover, arabinose supported LacI expression, thereby repressing Sf2a O-antigen production. In the absence of arabinose in vivo, native Salmonella LPS synthesis is repressed whilst the synthesis of the Sf2a O-antigen is induced. Murine immunization with the Salmonella vaccine strain elicited robust Sf2a-specific protective immune responses together with long term immunity. Conclusion: These findings demonstrate the protective efficacy of recombinant Sf2a O-antigen delivered by a Salmonella vaccine platform.
NBLAST: Rapid, Sensitive Comparison of Neuronal Structure and Construction of Neuron Family Databases
Authors: Marta Costa, James D. Manton, Aaron D. Ostrovsky, Steffen Prohaska, Gregory S.X.E. Jefferis
Journal: Neuron (2016)

Neural circuit mapping is generating datasets of tens of thousands of labeled neurons. New computational tools are needed to search and organize these data. We present NBLAST, a sensitive and rapid algorithm, for measuring pairwise neuronal similarity. NBLAST considers both position and local geometry, decomposing neurons into short segments; matched segments are scored using a probabilistic scoring matrix defined by statistics of matches and non-matches. We validated NBLAST on a published dataset of 16,129 single Drosophila neurons. NBLAST can distinguish neuronal types down to the finest level (single identified neurons) without a priori information. Cluster analysis of extensively studied neuronal classes identified new types and unreported topographical features. Fully automated clustering organized the validation dataset into 1,052 clusters, many of which map onto previously described neuronal types. NBLAST supports additional query types, including searching neurons against transgene expression patterns. Finally, we show that NBLAST is effective with data from other invertebrates and zebrafish.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJhY2I5ZGYyYjM4NDU3YmM1YTUzYzdkYjNmNjEwZTQ4ZiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4MTcxMDE4fQ.esxS0ekj1Y2KrsvFNwLvBdO2uH7jTmSFdQuhvlKJHyudrp2pKJEX-13uDWQ0Vb-JtD0U9SwqzpnV2DKOlPJvu29jUXE06S3vSh1rpOHE7yqVyktsslvNDCTAC9dV_z1qUYL5DGzpgAxr_zWEnxssrGPSboU8WmBMtoEOD5p6_YUaw9I62XinRlM7U8lo0lTExmdwYGzd5e9RzdbxAl5X6uTJOqnjVEFEfw9qJnokYGLy9vHYQEzzmtU6zKKKq4FSXrZE-iprVz0KxAHTxxYlvTNb_xsfwA4twiDr5oq6vAmeX6SWLOruwCJx91IIIeKvrS8GHJZSnb9ca5CAPHmtng(mp4, (15.82 MB) Download video
Abstract 16578: Two Cysteine S-nitrosylation Sites on the Cardiac Sodium Channel Are Responsible for Increased Late Sodium Current in Long QT Syndromes Type 9 & Type 12 but Not Type 3
Authors: Xuhua Chen, Jianding Cheng, John W Kyle, Brandi A Wiedmeyer, Graham S Adsit, Carmen R Valdivia, Alyson K Fisher, Jonathan C Makielski
Journal: Circulation (2017)

Introduction: Direct S-nitrosylation (SNO) of cysteine in the cardiac sodium channel (NaV1.5) has been implicated in enhanced late sodium current (INaL) in Long QT syndromes type 9 (LQT9) and 12 (L...
Variation in Recombination Rate Is Shaped by Domestication and Environmental Conditions in Barley
Authors: Steven Dreissig, Martin Mascher, Stefan Heckmann
Journal: Molecular Biology and Evolution (2019)

Abstract Meiotic recombination generates genetic diversity upon which selection can act. Recombination rates are highly variable between species, populations, individuals, sexes, chromosomes, and chromosomal regions. The underlying mechanisms are controlled at the genetic and epigenetic level and show plasticity toward the environment. Environmental plasticity may be divided into short- and long-term responses. We estimated recombination rates in natural populations of wild barley and domesticated landraces using a population genetics approach. We analyzed recombination landscapes in wild barley and domesticated landraces at high resolution. In wild barley, high recombination rates are found in more interstitial chromosome regions in contrast to distal chromosome regions in domesticated barley. Among subpopulations of wild barley, natural variation in effective recombination rate is correlated with temperature, isothermality, and solar radiation in a nonlinear manner. A positive linear correlation was found between effective recombination rate and annual precipitation. We discuss our findings with respect to how the environment might shape effective recombination rates in natural populations. Higher recombination rates in wild barley populations subjected to specific environmental conditions could be a means to maintain fitness in a strictly inbreeding species.
PB1998 PROGNOSTIC VALUE OF PRETRANSPLANT PET/CT IN HODGKIN LYMPHOMA
Authors: Z. Dr Miltényi, E. Punk, L.I. Dr Pinczés, Á. Illés
Journal: HemaSphere (2019)

Background: Autologous stem cell transplant (ASCT) is the standard of treatment in patients with refractory/relapsed Hodgkin lymphoma (HL). Several adverse prognostic factors at relapse are known (stage, anaemia, B signs, Karnofsky score, early relapse etc.) to predict the outcome after ASCT. Aims: We analyzed the prognostic value of pre‐ transplant PET/CT and number of salvage therapy retrospectively. Methods: Between January 1, 2007 and December 31, 2018 pre‐transplantation 18 FDG‐PET/CT scans of Hodgkin‐lymphoma patients were performed. Deauville criteria were used for evaluation of PET/CT scans. Positive PET scans were defined, if Deauville score was 4 or 5. We analyzed the effect of PET/CT results for survival (overall‐, relapse‐ and event free), and investigated differences between PET positive and PET negative groups. Statistical analysis was performed using IBM SPSS 25 programme. Results: Sixty‐two Hodgkin‐lymphoma patients (33 men and 29 women) had PET/CT scan before AHSCT. Median age at the time of AHSCT was 35 (19‐65) years. Median follow up time was 55.4 (0‐175) months. There were 49 (79%) PET negative and 13 (21%) PET positive patients. Five‐year overall survival rate was 80% in PET‐ group, and 46.2 % in PET+ group (p &lt; 0.042). Five‐year relapse‐free and event‐free survival rate for negative and positive groups were 85.5% and 43.5% (p &lt; 0.012), and 70.3% and 30.8% (p &lt; 0.006). There were 6 relapse and 9 deaths (3 due to HL) in PET‐ group, and 5 relapse and 6 deaths (due to HL) in PET+ group. Twenty‐five of 49 patients in the PET‐ group got only one type of salvage treatment (DHAP) before AHSCT, against 2 of 13 patients in PET+ group (p = 0.046). Patients who acquired PET negative status after DHAP therapy only, had no relapse. Patients who were treated with 2 or more lines of salvage therapy and acquired PET negative status after these treatments, has no significantly better relapse‐free survival, than patients who remained PET positive. Summary/Conclusion: C linical routine use of PET/CT before AHSCT is highly suggested based on our investigation. PET‐ patients have significantly better OS, PFS and EFS. PET negative status attends better prognosis, if it is reached with first salvage treatment.
Epigenetic activation and memory at a <i>TGFB2</i> enhancer in systemic sclerosis
Authors: Joseph Yusup Shin, James Daniel Beckett, Rustam Bagirzadeh, Tyler J. Creamer, Ami A. Shah, Zsuzsanna McMahan, Julie J. Paik, Margaret M. Sampedro, Elena G. MacFarlane, Michael A. Beer, Daniel Warren, Fredrick M. Wigley, Harry C. Dietz
Journal: Science Translational Medicine (2019)

NF-κB and BRD4 epigenetically activate a TGFB2 enhancer to lock sclerotic patient fibroblasts into a profibrotic synthetic state.
Up-regulation of PCOLCE by TWIST1 promotes metastasis in Osteosarcoma
Authors: Shang Wang, Li Zhong, Yin Li, Desheng Xiao, Ruhua Zhang, Dan Liao, Dongming Lv, Xin Wang, Juanfei Wang, Xianbiao Xie, Jing Chen, Yuanzhong Wu, Tiebang Kang
Journal: Theranostics (2019)

Procollagen C-proteinase enhancer protein (PCOLCE) was originally identified as an enhancer to facilitate the catalysis of procollagens by BMP1. PCOLCE participates in the reconstitution of extracellular and corneal repair. The elevation of PCOLCE in blood indicates that breast cancer has metastasized into the bones. However, direct research on PCOLCE has not been reported. Methods: ECM candidates were identified by RNA-seq analysis from 4 normal and 16 osteosarcoma tissues. The in vitro migration and invasion abilities of osteosarcoma cells were determined by a Transwell assay. A spontaneous metastatic osteosarcoma model was established to assess osteosarcoma metastasis in vivo. The N-linked glycosylated amino acids were identified by PNGase F treatment combined with Western blotting. The mechanism of TWIST1 regulating PCOLCE transcription was elucidated by luciferase, qPCR and ChIP assays. Results: PCOLCE was markedly up-regulated in human osteosarcoma tissues compared to its expression in noncancerous adjacent tissues; high PCOLCE expression in tissues correlated with a poor patient prognosis, and the knockdown of PCOLCE by shRNAs impaired the migration, invasion and lung metastasis of osteosarcoma cells. The overexpression of wild-type PCOLCE, but not its N29Q mutant, promoted migration, invasion and metastasis, indicating that the glycosylation of PCOLCE at Asn29 is necessary for its functions in osteosarcoma. TWIST1, a key transcription factor in metastasis, was also overexpressed in osteosarcoma tissues and positively correlated with either PCOLCE or its potential procollagen substrates, such as COL1A1, COL1A2, COL5A1, COL8A2 and COL10A1. Conclusion: Our findings are the first to provide evidence that PCOLCE plays a critical role in promoting the lung metastasis of osteosarcoma, and this up-regulation of PCOLCE by TWIST1 may lead to a new therapeutic strategy to treat patients with metastatic osteosarcoma.
Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data
Authors: Xiaoran Lai, Oliver M. Geier, Thomas Fleischer, Øystein Garred, Elin Borgen, Simon W. Funke, Surendra Kumar, Marie E. Rognes, Therese Seierstad, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Olav Engebraaten, Alvaro Köhn-Luque, Arnoldo Frigessi
Journal: Cancer Research (2019)

Abstract The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes. Significance: Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome.
FRI0680 THE ASSOCIATION BETWEEN ANKYLOSING SPONDYLITIS AND UNEMPLOYMENT
Authors: Sinead Maguire, Gillian Fitzgerald, Claire Sheehy, Finbar Barry O’shea
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Previous registry studies have noted increased rates of unemployment in patients with ankylosing spondylitis (AS)(1-2). With improved treatment options and earlier detection of AS, its was anticipated that this would no longer be true. <h3>Objectives</h3> The Ankylosing Spondylitis Registry of Ireland(ASRI) is a source of epidemiological data on AS patient in Ireland. The aim of this study was to examine unemployment rates in this population and possible links with disease activity, function and quality of life. <h3>Methods</h3> An analysis of the patient population of the ASRI with data collected from 2013 to 2017 was performed using IBM SPSS Statistics version 25. Comparison of the mean ASQoL, HAQ, BASDAI, BASFI, and BASMI score were carried out between those employed versus those unemployed. An independent two tailed t test and a Mann Whitney U test was then carried out to determine significance. Further analysis was then performed using patient age and disease duration. <h3>Results</h3> At the time of analysis 734 patient were enrolled in the registry. The mean age was 45 years, with 77% male and 23% female, mean duration of disease was 18 years (means: ASQoL 6.6, HAQ 0.5, BASDAI 4.0, BASFI 3.6, BASMI 3.6). Unemployment rate in the ASRI population was 23%. National unemployment during the same time period was noticeably lower with a range of 6.2% to 13.1% (3). Those patients were also noted to have higher ASQoL (9.7 versus 5.6), HAQ (0.85 versus 0.45), BASDAI (5.3 versus 3.7), and BASFI scores (5.2 versus 3.2). The difference between the means was statistically significant (p&lt;0.05) across all 4 measures. However, BASMI scores were significantly lower in the unemployed (3.8 versus 3.0). No statistically significant difference was detected between genders. The distribution of age and disease duration was determined to be equal between the groups. <h3>Conclusion</h3> There is a higher prevalence of unemployment in the AS population as compared to the general population. Unemployed AS patients tend to have decreased quality of life, poorer levels of function, and higher levels of disease activity. Further research is needed to determine a causation between level of disease activity and employment. <h3>References</h3> [1. ] Webers C, Vanhoof L, Genderen SV, et al; Employment perspectives of patients with ankylosing spondylitis in the biologics era; Annals of the Rheumatic Diseases 2017;76:157. [2] Webers C, et al; Employment and the role of personal factors amoung patients with ankylosing spondylitis: a Dutch cross-sectional case-control study; RMD Open 2018. Jun27;4(1) [3] Central Statistics Office Ireland <h3>Disclosure of Interests</h3> Sinead Maguire: None declared, Gillian Fitzgerald Grant/research support from: Recipient of the Bresnihan-Molloy Scholarship funded by AbbVie, Claire Sheehy: None declared, Finbar Barry O'Shea: None declared