tbuckley/cabot-search huggingface dataset:
Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
Authors: Nicolas Ricard, Rizaldy P. Scott, Carmen J. Booth, Heino Velazquez, Nicholas A. Cilfone, Javier L. Baylon, Jeffrey R. Gulcher, Susan E. Quaggin, Thomas W. Chittenden, Michael Simons
Journal: The Journal of Experimental Medicine (2019)

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.
Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular Nucleus
Authors: Gil Mandelbaum, Julian Taranda, Trevor M. Haynes, Daniel R. Hochbaum, Kee Wui Huang, Minsuk Hyun, Kannan Umadevi Venkataraju, Christoph Straub, Wengang Wang, Keiramarie Robertson, Pavel Osten, Bernardo L. Sabatini
Journal: Neuron (2019)
Recombination-Aware Phylogenomics Reveals the Structured Genomic Landscape of Hybridizing Cat Species
Authors: Gang Li, Henrique V Figueiró, Eduardo Eizirik, William J Murphy
Journal: Molecular Biology and Evolution (2019)

Current phylogenomic approaches implicitly assume that the predominant phylogenetic signal within a genome reflects the true evolutionary history of organisms, without assessing the confounding effects of postspeciation gene flow that can produce a mosaic of phylogenetic signals that interact with recombinational variation. Here, we tested the validity of this assumption with a phylogenomic analysis of 27 species of the cat family, assessing local effects of recombination rate on species tree inference and divergence time estimation across their genomes. We found that the prevailing phylogenetic signal within the autosomes is not always representative of the most probable speciation history, due to ancient hybridization throughout felid evolution. Instead, phylogenetic signal was concentrated within regions of low recombination, and notably enriched within large X chromosome recombination cold spots that exhibited recurrent patterns of strong genetic differentiation and selective sweeps across mammalian orders. By contrast, regions of high recombination were enriched for signatures of ancient gene flow, and these sequences inflated crown-lineage divergence times by ∼40%. We conclude that existing phylogenomic approaches to infer the Tree of Life may be highly misleading without considering the genomic architecture of phylogenetic signal relative to recombination rate and its interplay with historical hybridization.
Population Genetics Based Phylogenetics Under Stabilizing Selection for an Optimal Amino Acid Sequence: A Nested Modeling Approach
Authors: Jeremy M Beaulieu, Brian C O’Meara, Russell Zaretzki, Cedric Landerer, Juanjuan Chai, Michael A Gilchrist
Journal: Molecular Biology and Evolution (2018)

We present a new phylogenetic approach, selection on amino acids and codons (SelAC), whose substitution rates are based on a nested model linking protein expression to population genetics. Unlike simpler codon models that assume a single substitution matrix for all sites, our model more realistically represents the evolution of protein-coding DNA under the assumption of consistent, stabilizing selection using a cost-benefit approach. This cost-benefit approach allows us to generate a set of 20 optimal amino acid-specific matrix families using just a handful of parameters and naturally links the strength of stabilizing selection to protein synthesis levels, which we can estimate. Using a yeast data set of 100 orthologs for 6 taxa, we find SelAC fits the data much better than popular models by 104-105 Akike information criterion units adjusted for small sample bias. Our results also indicated that nested, mechanistic models better predict observed data patterns highlighting the improvement in biological realism in amino acid sequence evolution that our model provides. Additional parameters estimated by SelAC indicate that a large amount of nonphylogenetic, but biologically meaningful, information can be inferred from existing data. For example, SelAC prediction of gene-specific protein synthesis rates correlates well with both empirical (r=0.33-0.48) and other theoretical predictions (r=0.45-0.64) for multiple yeast species. SelAC also provides estimates of the optimal amino acid at each site. Finally, because SelAC is a nested approach based on clearly stated biological assumptions, future modifications, such as including shifts in the optimal amino acid sequence within or across lineages, are possible.
Clinical pathologic status and expression of tumor markers in 5,000 Chinese breast cancers
Authors: J. Zhang, R. Hui, P. Liu, Y. Yu, Y. Liu, X. Hao
Journal: Journal of Clinical Oncology (2006)

10644 Background: To evaluate the correlations of clinical pathologic status, expression of tumor markers and prognosis in 5000 Chinese breast cancer. Methods: A series primary operable breast cancers from 2002 to 2005 were studied in Tianjin Cancer Hospital. 55% of them are premenopausal and median age is 45 years old; 45% of them are postmenopausal and median age is 58 years old. All of the cases were reviewed by pathologist. ER, PgR, HER-2, p53, PCNA were measured by imunohistochemistry (IHC). Recurrence or metastasis were seen in 126 cases (median follow-up 30 months). Results: Negative axillary lymph nodes in 49.8%,and nodes positive in 50.2% (1 to 3 nodes positive in 28.3%, 4 to 9 nodes positive in 12.1% and over 10 nodes positive in 9.8%). Hermone receptor were observed in 51.7% ER+, 44.7% PgR+, 36.2% ER+/PgR+, 15.5% ER+/PgR−, 8.5% ER−/PgR+, 39.8% ER−/PgR−. HER-2 were observed in 56.8% her-2(-) ,21.7% her-2(+), 10.4% her-2(++) and 11.1% her-2(+++). p53 were observed in 34.4% (+) and PCNA were observed in 85.9% (+). Conclusions: First, Her-2 expression is shown positive correlation with positive axillary lymph nodes, especially remarkable correlated in the number of positive nodes in premenopausal patients. Second, Her-2 expression is shown negative correlation with ER and PgR. Third, Her-2 expression has no correlation with histologic grades of tumors and in some conditions has positive correlation with p53 and PCNA. Fifth, Her-2 expression has no correlation with recurrence, but positive correlation with distant metastasis. In general, Her-2 expression in breast cancer could be taken as the independent index for predicting prognosis. Status of axillary lymph nodes, expression of ER, PgR are the independent factor for expression of her-2. Expression of p53 and PCNA couldn’t be taken as the independent index for predict prognosis. No significant financial relationships to disclose.
FRI0229 SOLUBLE CD163 IS A BIOMARKER FOR ACCELERATED ATHEROSCLEROSIS IN SLE PATIENTS AT APPARENT LOW RISK FOR CARDIOVASCULAR DISEASE
Authors: Clemence David, Rachid Abbas, Brigitte Escoubet, Benedicte Giroux Leprieur, Anne Boutten, Thomas Papo, Monique Dehoux, Karim Sacre
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Cardiovascular disease (CVD) due to accelerated atherosclerosis is the leading cause of death in SLE. Probably because they do not incorporate important risk factors such as overweight, chronic kidney disease or systemic inflammation, models for predicting CVD established in the general population (such as Framingham model) underestimate the cardiovascular risk in SLE. Identification of biological markers for CVD may help to classify high-risk subjects and set up targeted prevention in SLE. <h3>Objectives</h3> Our study aimed to determine whether sCD163, a soluble macrophage marker upregulated in numerous inflammatory disorders, might be predictive of accelerated atherosclerosis associated with SLE <h3>Methods</h3> Carotid ultrasound was prospectively performed in 63 consecutive SLE patients asymptomatic for cardiovascular disease (CVD) and 18 volunteer health-workers. Ultrasound was performed at baseline and during follow up. Serum level of sCD163 was determined at baseline using ELISA. The primary outcome was the presence of a carotid plaque. Factors associated with carotid plaques were identified through multivariate analysis. <h3>Results</h3> Despite a low risk for cardiovascular events according to Framingham score in both groups (2.1% ± 3.8 in SLE vs 2.1% ± 2.9 in controls; p=0.416), ultrasound study at baseline showed a carotid plaque in 23 (36.5%) SLE patients versus 2 (11.1%) controls (p=0.039). Multivariate analysis showed that SLE status increased the risk for carotid plaque by a factor of 9 (p=0.017). In SLE patients, sCD163 level was high (483.7ng/ml ± 260.8 versus 282.1ng/ml ± 97.5 in controls; p&lt;0.001) and independently associated with carotid plaques as assessed by stratification based on sCD163 quartile values (p=0.009), receiver operating characteristic (ROC) (p=0.001) and multivariate analysis (p=0.015). Eventually, sCD163 at baseline was associated with the onset of carotid plaque during follow up (3±1.4 years) in SLE patients who had no carotid plaque at first evaluation (p=0.041) Conclusion: sCD163 is associated with progressing carotid plaque in SLE and may be a useful biomarker for accelerated atherosclerosis in SLE patients at apparent low risk for CVD <h3> Disclosure of Interests: </h3> Clemence David: None declared, Rachid Abbas: None declared, Brigitte Escoubet: None declared, Benedicte Giroux Leprieur: None declared, Anne Boutten: None declared, Thomas Papo: None declared, Monique Dehoux: None declared, karim sacre Grant/research support from: GSK
AB0960 THE HELIOS (HACETTEPE UNIVERSITY ELECTRONIC RESEARCH FORMS) REGISTRY: USE OF BIOLOGIC DRUGS IN AUTOINFLAMMATORY DISEASES
Authors: Selcan Demir, Ezgi Deniz Batu, Fuat Akal, Erdal Sag, Ummusen Kaya Akca, Elif Arslanoğlu, Emil Aliyev, Kübra Yüksel, Armağan Keskin, Yelda Bilginer, Seza özen
Journal: Annals of the Rheumatic Diseases (2019)

Results: The study group consisted of 12 juvenile BD patients with CVST.At the time of CVST diagnosis, the most common symptom was headache (%100), followed by vomiting (25%), blurred vision (16.6-7%), and disturbances in eye movements (16.7%).Six (50%) patients presented with sinus venous thrombosis as an initial symptom.Transverse sinus was the most frequently affected sinus (9/12, 75%) followed by superior sagittal sinus (8/12, 66.6%) and sigmoid sinus (1/12, 8.3%).The median (minimum-maximum) BDCAF was 6 (5-8).Four children (33.3%) had another venous thrombosis apart from CVST.All patients received pulse methylprednisolone for three consecutive days continued with oral prednisolone.Steroid treatment was tapered and discontinued minimum in six months.Eleven patients received azathioprine concomitant to steroid treatment at the time of CVST.All the patients received anticoagulant therapy concomitantly.Only one patient had relapse.Median (min-max) follow-up period was 4 years (1-10).In the literature review, we identified nine articles, describing 35 pediatric CVST patients associated with BD.Thirty patients achieved remission, while five patients had residual neurologic deficit.Conclusion: Further multicenter studies with more patients and prospective follow-up may help us to understand the whole spectrum in these patients.
SP0006 CASE 2 DISCUSSANT: LONG TERM EFFICACY OF REMISSION-MAINTENANCE REGIMENS FOR GPA
Authors: Peter Villiger
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> A case of Giant Cell Arteritis with different visual symptoms and delayed diagnosis will be presented. This 74 year-old patient was pulsed with Glucocorticoids (GC) and thereafter treated with Tocilizumab (TCZ). She rapidly achieved full and lasting remission. After 12 months of treatment with TCZ, infusions were stopped. The patient suffered minor relapse 4 months after treatment discontinuation and again responded to TCZ. The case raises several questions such as: How to dose and how long to treat with TCZ? How to reduce dose and when to stop GC? Are there variables to quantify subclinical diseases activity as CRP and ESR are unreliable under TCZ treatment? Are there predictive factors for relapse after treatment discontinuation? How to control development of disease damage over time? <h3>Disclosure of Interests:</h3> None declared
S116 A BUSULFAN FOLLOWING CYCLOPHOSPHAMIDE, PROTOCOL IMPROVED RESULTS IN ALTERNATIVE DONOR TRANSPLANT FOR PATIENTS WITH THALASSEMIA MAJOR: A RESULT FROM LONG-TERM LARGE-SIZE MULTI-CENTER STUDY IN CHINA
Authors: C. Li, Y. He, H. Jiang, C. Li, Y. Zhu, X. Wu, S. Liu, J. Liao, X. Feng, H. Liu, Z. Peng, X. Yang
Journal: HemaSphere (2019)

Background: HLA matched sibling donor HSCT (SDT) had been proved as first selection for thalassemia major (TM) and results of alternative donor (AD) HSCT (ADT) including unrelated donor HSCT (UDT), cord blood transplantation (CBT) and parent donor HSCT (PDT) continuously improved in practice of leukemia HSCT in the last decade, but outcome of ADT in TM were not both the idea or in small-size study. Aims: to fine out a protocol to improve outcomes of ADT for TM patients. Methods: Total 586 consecutive (2008-12-1 to 2016-6-30)TM patients from four pediatric HSCT centers in China were analyzed with median follow-up of 57 (21–116) months. Ratio of male to female was 378 to 208, Median age was 6 (range, 1–23) years old. 10/10 and 9/10 HLA mismatch were defined as full-match (FM) and well-match (WM), respectively. 224 patients underwent SDT (221 FM, 3 WM), 47 FM-CBT, 315 ADT including 275 UDTs (214 FM, 61 WM) and 40 PDTs (21 FM, 19 WM). G-CSF mobilized peripheral blood stem cells was adopted as stem cell source in almost HSCTs but CBTs. All patients received a uniform conditioning with Cyclophosphamide (Cy), Fludarabine, Thiotepa and intravenous Busulfan (Bu). Prophylaxis of GVHD included ATG and Sirolimus or Tacrolimus or Cyclosporine A. Particularity of the protocol was Bu following Cy, a constant target dose (8.0 x108/kg) and multi-drugs combining. Results: 9-year OS, TFS, GR and TRM were 94.4%, 91.6%, 3.9% and 5.6%, respectively, in total 586 HSCTs (Fig.1); 95.9%, 95.5%, 1.4% and 4.1%, respectively, in 224 SDTs, 92.7%, 88.9%, 5.3% and 7.3%, respectively, in 315 ADTs; 92.4%, 88.1%, 6% and 7.6%, respectively, in 275 UDTs (Fig.2); 97.9%, 95.4%, 2.6% and 2.1%, respectively, in 47 sibling CBTs; and 95%, 95%, 0 % and 5%,respectively, in 40 PDTs. ADT had more III-IV aGVHD than MST (7% vs. 1.5%). Likewise, To compare matched HSCT, well-matched HSCT had more ≥ II cGVHD (5.1% vs. 0.8%). Incidence of VOD and cytopenia after engraftment were 2.7%. was 14.5 in total, respectively.Summary/Conclusion: A Bu following Cy, constant target dose and multi-drug combining protocol improved markedly the results in ADT although ADT had more III-IV aGVHD than SDT. When compared with FM-ADT, WM-ADT had more ≥II cGVHD in spite of similar OS, TFS, TRM and GR. We don’t suggest, therefor, to use well matched ADT in TM HSCT.
Lack of training in eating disorders is contributing to avoidable deaths, MPs conclude
Authors: Jacqui Thornton
Journal: BMJ (2019)

A serious lack of training about eating disorders among doctors is contributing to too many avoidable deaths in the NHS, a parliamentary report says.

Training on the subject at medical school is limited to “just a few hours” and was a “consistent theme” in its investigation, said the House of Commons Public Administration and Constitutional Affairs Committee in its report.1

It calls for the General Medical Council to “use its influence to ensure medical schools improve outcomes.” It also calls for better postgraduate training. GPs, who are often the first port of call, need adequate training in recognising eating disorders and in communicating with these patients.

MPs on the committee heard that one GP was concerned that a patient would die but wrongly believed the patient could not be …
PS1297 EFFICACY AND SAFETY OF INTRAVENOUS IRON THERAPY IN CHILDREN: A KOREAN SINGLE CENTER STUDY
Authors: N. Jung, Y.J. Shim, H.S. Kim
Journal: HemaSphere (2019)

Background: Although Intravenous (IV) iron is widely and safely administrated to adults for various indications including severe anemia, chronic blood loss and postoperative anemia, Administration of IV iron is rarely used in children due to lack of pediatric data. Aims: The aim of this study was to determine the indications for IV iron and to evaluate the efficacy and safety of IV iron infusions to children who were visited a single Korean center. Methods: This retrospective study collected data from ≤18 year‐old children who were received IV iron at the Keimyung University Dongsan Medical Center between July 2003 to December 2018. Exclusion criteria included: (1) receiving a packed red blood cell transfusion or erythropoietin, (2) surgery or massive bleeding before obtaining the laboratory results of post IV iron infusion. We compared laboratory results including hemoglobin (Hb) concentrate, mean corpuscular volume (MCV), serum ferritin level between pre and post‐IV iron infusion. Also, the medical records were reviewed for adverse effects. All statistical analyses were performed using IBM SPSS software (version 23.0; IBM Corp., Armonk, NY), and P‐values of &lt;0.05 were considered statistically significant. Results: Total 31 children (male:female = 18:13; median age 4.5 years, range 0.3–17.9) received total 80 infusions of IV iron therapy. The most common etiology of anemia was gastrointestinal cause. Oral iron intolerance (32%) and refractoriness (26%) were common indications for IV iron infusion. Seventeen patients received a total 43 infusions of iron sucrose (median dose, 3.9 mg/kg, range 1.0 to 20.4), fifteen patients received a total 37 infusions of ferric carboxymaltose (median dose, 5 mg/kg, range 3.3 to 18.8). All Patients had follow up laboratory test at 1–120 days (median 15 days) after their infusions. Except 2 patients, all patients showed good hematologic response. The median pre‐infusion Hb, MCV and ferritin values were 9.0 g/dL (range 6.1–13.6), 75.9 fL (55.9–94.3) and 12.2 ng/mL (1.7–284.9), respectively. The median post‐infusion Hb, MCV and ferritin values were 10.7 g/dL (6.3–14.7), 79.6 fL (64.9–103.5) and 54.0 ng/mL (3.9–842.8), respectively. There were statistically significant improvements in these values (p‐value &lt;0.001). No patients experienced severe adverse effects such as anaphylaxis. Summary/Conclusion: The most common indication for IV iron among Korean children was oral iron intolerance. The use of IV iron is effective and safe treatment in children. image
PB2299 AN INVESTIGATION INTO THE PRESENCE OF COMPLEMENT PROTEINS ON ERYTHROCYTE VESICLES IN SICKLE CELL DISEASE
Authors: C. Obieze
Journal: HemaSphere (2019)

Background: A single amino acid substitution in the globin gene segment is the underlying genetic defect in sickle cell disease (SCD) creating a haemoglobin molecule which polymerizes on deoxygenation. Recent insights into the pathophysiology of the disease have pointed to the roles inflammation and hypercoagulability play in disease manifestation and severity caused, in part, by increased phosphatidylserine exposure and extracellular vesiculation by sickle red cells. Current works have identified some of these vesicles as those released from reticulocytes in the process of maturation to the red blood cell. These vesicles are termed ‘inside‐out’ autophagic vesicles as they are the result of the fusion of endocytosed parts of the cell membrane with autophagic endosomes and are positive for intracellular glycophorin A (GPA) epitope using BRIC163 antibody. Further analysis has shown that some of these vesicles are also positive for extracellular GPA epitope using BRIC256 antibody raising the possibility that the vesicle membrane may have become permeabilized. One possible permeabilizing mechanism is the membrane attack complex of the complement system. Aims: The aim of this project was to investigate the presence of complement proteins on vesicles isolated from plasma or attached to erythrocytes using flow cytometry and confocal microscopy Methods: Vesicles were isolated from SCD plasma (n = 2) and healthy control (n = 1) using 2 different techniques: membrane‐based isolation technique and fluorescent‐activated cell sorter (FACS) and studied with flow cytometry using BRIC163, BRIC256, C3, C4, C3c and C3d antibodies. Cultured reticulocyte (n = 2), sickle red cells (n = 3) and healthy control red cells (n = 2) were analyzed with confocal microscopy using Annexin‐V, BRIC163, C3, C4, C3c and C3d antibodies. Results: Results show the presence of complement proteins on vesicles in both SCD plasma and healthy control in levels as high as 100% for BRIC163 vesicles in healthy control. Confocal analyses reveal this deposition is also present on vesicles prior to release and is associated with PS exposure. Summary/Conclusion: Complement proteins are present on vesicles in plasma and erythrocytes and may suggest activation and formation of the MAC complex. Further work is required to determine the involvement of these proteins in vesicle formation and release.
PB2058 THE PROGNOSTIC ROLE OF MYOCYTE‐SPECIFIC ENHANCER FACTOR 2 C (MEF2 C) IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMAS (DLBCL)
Authors: M. Anastasiou, Z. Tsakiraki, A. Spathis, A. Bouchla, S. Papageorgiou, I. Panayiotides, V. Pappa, P. Foukas
Journal: HemaSphere (2019)

Background: DLBCL is the most common subtype of non‐Hodgkin's lymphomas. However, the pathogenesis of DLBCL is not fully understood. Transcription factors or signaling pathways involved in normal B cell development and function might represent future therapeutic targets. Such a transcription factor is MEF2 C contributing to B cell activation and germinal center formation. Aims: This study aims at investigating the role of MEF2 C as prognostic biomarker in DLBCL. Methods 82 patients with DLBCL were enrolled in our study. We assessed the expression of MEF2 C by performing immunohistochemistry (IHC) on paraffin slides of 62 tissue blocks and results were evaluated by using the H‐score semiquantitative approach, with a range from 0 to 300. Additionally, we analyzed clinical [sex, age, stage of DLBCL, performance status, extranodal sites, B symptoms, International Prognostic Index (IPI), age‐adjusted IPI, revised‐IPI, National Comprehensive Cancer Network (NCCN)‐IPI], laboratory [lactate dehydrogenase (LDH), hemoglobin (Hb), white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelets and beta‐2‐microglobulin] and pathologic characteristics (CD10, BCL6, MUM‐1, Ki‐67) of patients in relation to overall (OS) and disease free survival (DFS). Results: Mean and median value of MEF2 C H‐score was 120 ± 58. We observed a statistical significant correlation with age (p= 0.021) and a tendency to correlate with LDH (p = 0.18). The expression of MEF2 C was not associated with other clinical or laboratory values. MEF2 C positivity &gt;80% was correlated with borderline inferior OS (p = 0.083). Among patients, who survived more than 12 months after initial diagnosis, those with MEF2 C H score &lt;120 had a significant better OS comparing with those with MEF2 C H score &gt;120 (p = 0.009). Summary/Conclusion: High IHC expression of MEF2 C showed a negative prognostic influence in patients with OS more than 12 months after initial diagnosis. However, these results should be confirmed in larger groups of DLBCL patients and the underlying oncogenic mechanism of MEF2 C in DLBCL should be further explored.