tbuckley/cabot-search huggingface dataset:
PB1937 CHROMOSOMAL ABERRATIONS IN CHRONIC MYELOID LEUKEMIA AND THEIR IMPACT ON RESPONSE TO CONVENTIONAL TYROSINE KINASE INHIBITORS AND RISK OF BLASTIC TRANSFORMATION.
Authors: S. Maqsood, F. Ali, N. Siddiqui, A. Hameed
Journal: HemaSphere (2019)

Background: Chronic Myeloid Leukemia(CML) is a common hematological malignancy with tyrosine kinase inhibitors(TKI) forming the main stay of treatment. Aims: The purpose of this project was to study the clinical presentation of patients with CML harboring additional chromosomal abnormalities at diagnosis and disease outcomes. Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at our institution. Results: Response to initial TKI A total of 283 patients were diagnosed with CML from January 2010 to January 2015. Thirty one patients were found to have ACAs at the time of diagnosis in addition to BCR‐ABL fusion gene. 23 patients (74.2%) were males whereas 8(25.8%) were females. 13(41.9%) were in the age group of 31 to 50 years. 30 patients were started on Imatinib and one on Nilotinib. 16 patients (51.6%) achieved complete hematological response within 3 months. However a complete molecular and cytogenetic response was never achieved in 17 (54.8%) and 18 (58.1%) patients respectively. Cytogenetics Analysis and ACAs Conventional cytogenetic analysis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. Risk of blastic transformation Eight patients (25.8%) transformed to acute myeloid leukemia(AML) whereas 3 (9.7%) patients had a transformation to acute lymphoblastic leukemia(ALL). Therapy and response in transformed patients Out of the 11 patients who transformed to AML and ALL, 6 patients underwent induction chemotherapy while 5 were not considered fit for it on account of poor performance score and lack of resources. Out of these 6 patients, none responded to induction chemo. Summary/Conclusion: In summary, this study aimed to look at the clinical presentation of patients with CML harboring additional chromosomal abnormalities at diagnosis, cytogenetic analysis, risk of blastic transformation and response to treatment in transformed patients. Despite an early hematological response, more than half of the patients failed to achieve complete molecular and cytogenetic response which clearly shows suboptimal response to the tyrosine kinase inhibitors in this particular set of CML patients. There was transformation to acute leukemia in 35.5% of patients. We were able to give induction chemotherapy to only 6 out of 11 patients and none of them responded to it. This study showed that presence of ACA at the time of diagnosis is a high risk feature for patients with CML and confers poor prognosis when treated with conventional TKI. Further studies are required in our population regarding alternative therapy for such patient population.
Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data
Authors: Juan Fernández-Tajes, Kyle J. Gaulton, Martijn van de Bunt, Jason Torres, Matthias Thurner, Anubha Mahajan, Anna L. Gloyn, Kasper Lage, Mark I. McCarthy
Journal: Genome Medicine (2019)

Genome-wide association studies (GWAS) have identified several hundred susceptibility loci for type 2 diabetes (T2D). One critical, but unresolved, issue concerns the extent to which the mechanisms through which these diverse signals influencing T2D predisposition converge on a limited set of biological processes. However, the causal variants identified by GWAS mostly fall into a non-coding sequence, complicating the task of defining the effector transcripts through which they operate. Here, we describe implementation of an analytical pipeline to address this question. First, we integrate multiple sources of genetic, genomic and biological data to assign positional candidacy scores to the genes that map to T2D GWAS signals. Second, we introduce genes with high scores as seeds within a network optimization algorithm (the asymmetric prize-collecting Steiner tree approach) which uses external, experimentally confirmed protein-protein interaction (PPI) data to generate high-confidence sub-networks. Third, we use GWAS data to test the T2D association enrichment of the "non-seed" proteins introduced into the network, as a measure of the overall functional connectivity of the network. We find (a) non-seed proteins in the T2D protein-interaction network so generated (comprising 705 nodes) are enriched for association to T2D (p = 0.0014) but not control traits, (b) stronger T2D-enrichment for islets than other tissues when we use RNA expression data to generate tissue-specific PPI networks and (c) enhanced enrichment (p = 3.9 × 10− 5) when we combine the analysis of the islet-specific PPI network with a focus on the subset of T2D GWAS loci which act through defective insulin secretion. These analyses reveal a pattern of non-random functional connectivity between candidate causal genes at T2D GWAS loci and highlight the products of genes including YWHAG, SMAD4 or CDK2 as potential contributors to T2D-relevant islet dysfunction. The approach we describe can be applied to other complex genetic and genomic datasets, facilitating integration of diverse data types into disease-associated networks.
Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
Authors: Georgia Gunner, Lucas Cheadle, Kasey M. Johnson, Pinar Ayata, Ana Badimon, Erica Mondo, M. Aurel Nagy, Liwang Liu, Shane M. Bemiller, Ki-Wook Kim, Sergio A. Lira, Bruce T. Lamb, Andrew R. Tapper, Richard M. Ransohoff, Michael E. Greenberg, Anne Schaefer, Dorothy P. Schafer
Journal: Nature Neuroscience (2019)
Common and Dissociable Contributions of Alexithymia and Autism to Domain-Specific Interoceptive Dysregulations: A Dimensional Neuroimaging Approach
Authors: Jialin Li, Lei Xu, Xiaoxiao Zheng, Meina Fu, Feng Zhou, Xiaolei Xu, Xiaole Ma, Keshuang Li, Keith M. Kendrick, Benjamin Becker
Journal: Psychotherapy and Psychosomatics (2018)

Alexithymia represents a transdiagnostic marker across psychiatric entities associated with emotional impairments, including autism spectrum disorders (ASD). Accumulating evidence suggests that interoceptive dysfunctions that underpin the core symptomatic emotion recognition and empathy deficits in ASD may be contributed to by high levels of alexithymia rather than autistic symptoms per se. However, previous findings are hampered by generally elevated alexithymia in ASD patients, and thus were not able to differentiate common and distinct contributions across the entire spectrum of variations of autism and alexithymia. Moreover, the multi-factorial nature of the domains affected, such as distinct neural reactivity towards perceiving physical and affective pain, has not been accounted for. Against this background the present fMRI study employed a dimensional trait approach in n = 242 healthy subjects to determine common and distinct associations between both traits and pain empathic responses towards physical and affective pain. Higher levels of alexithymia associated with increased left anterior insula pain empathic reactivity. Disentangling these effects revealed a positive association during perceived physical pain, but a negative one during affective pain. No significant associations with trait autism were found, but an interaction effect between the trait dimensions was observed in the mid-cingulate cortex. Moderation analysis demonstrated that trait autism only impacted mid-cingulate reactivity towards physical pain in high alexithymia subjects, whereas reactivity towards affective pain was specifically associated with trait autism in low alexithymia subjects. Findings confirm previous patient studies suggesting that alexithymia rather than autism per se may drive altered insula pain empathic reactivity. Importantly, the present approach allowed for the first time to demonstrate that the impact of alexithymia on insula reactivity varies as a function of the pain empathic domain and that effects on other core empathy nodes evolve in interaction with trait autism.
Abstract 14911: Dipeptidyl Peptidase-4 Deteriorates Cardiac Function During Autoimmune Myocarditis by Facilitating Cathepsin-G Activity
Authors: Yasuhiro Maejima, Yusuke Ito, Natsuko Tamura, Ryo Watanabe, Mitsuaki Isobe
Journal: Circulation (2015)

Post-myocarditis dilated cardiomyopathy is the most common cause of non-hereditary heart failure developing at a young age. Our colleagues have shown previously that dipeptidyl peptidase-4 (DPP-4) worsens the development of experimental autoimmune myocarditis (EAM) by promoting expression of inflammatory cytokines and cardiac fibrosis in mice. In order to clarify how DPP-4 mediates this detrimental effect in the EAM heart, mouse EAM model generated by immunizing with α-MHC peptide in BALB/c mice were given a diet mixed with linagliptin, a selective DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA group, N = 6), or normal diet (CONT group, N = 6). After 21 days of EAM induction, lung weight / body weight were significantly smaller in LINA group than in CONT group (7.7 ± 0.1 mg/g* vs. 8.3 ± 0.1 mg/g, *P &lt; 0.05). Left ventricular ejection fraction after induction of EAM was significantly higher in LINA group than in CONT group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, *P &lt; 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells infiltrated to inflamed myocardium was significantly smaller in LINA group than in CONT group. Consistent with this result and the previous finding that Th17 cells express high level of enzymatically active DPP-4, the DPP-4 activity in inflamed myocardium was significantly lower in LINA group than in CONT group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, *P &lt; 0.05). Mass spectrometry analysis using lysates from inflamed myocardium co-immunoprecipitated with Flag-DPP-4 recombinant protein revealed that DPP-4 bound to cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM heart. Co-immunoprecipitation - western blot analysis verified the physical interaction between DPP-4 and CTSG. The activity of CTSG in inflamed myocardium was significantly higher in EAM mice compared to those in untreated mice, and CTSG activity in the EAM heart was significantly lower in LINA group than in CONT group. The amount of angiotensin II, a major product catalyzed by CTSG, in the EAM heart was also significantly lower in LINA group than in CONT group. Collectively, these results suggest that DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM, possibly through enhancing CTSG activity in the heart.
Abstract 11365: The Interaction Between Mitochondrial Stress and the Innate Immune System Receptor NLRP3
Authors: Trine Ranheim, May-Kristin Torp, Pål Aukrust, Arne Yndestad, Kåre-Olav Stensløkken
Journal: Circulation (2018)

Introduction: The heart is a ”mitochondrion-dense” organ, and as much as 30% of the volume of the cardiomyocyte is occupied by mitochondria. Mitochondria are both the target and origin of many of t...
PB2412 ADULT THALASSEMIA PATIENTS OF PEDIATRIC HEMATOLOGY CLINIC: A SINGLE CENTER EXPERENCE IN TURKEY
Authors: Z. Karakas, S. Ocak, M. Bilici, Y. Yılmaz, R. Tuna, S. Karaman, D. Tugcu, A. Unuvar
Journal: HemaSphere (2019)

Background: Advances in understanding and treatments in transfusion dependent thalassemia (TDT) improved the clinical outcomes. Disease‐related complications seem to be the challenging problem in aging patients with thalassemia who now survive longer than in the past. Aims: Here we aimed to describe clinical features of adult thalassemia patients followed on the pediatric hematology clinic. Methods: All the patients with TDT and older than 25‐years were reviewed retrospectively. Demogrophical, cilinical features, status of iron overload and treatment and disease related complications were recorded. Results: A total of 69 patients were evaluated. Thirty three were female and 36 were male. Mean age was 32.9 years (range 25‐53 years). Mean duration of follow‐up and iron chelation therapy were 31,2 years (range 14‐50 years), and 25 years (range 7‐ 31 years), respectively.Fortyfour patients had splenectomy. Mean ferritin levels was found to be 1645 ng/ml (range between 361‐8600 ng/ml). Cardiac iron status were evaluated in 44 patients and cardiac T2∗was normal (&gt;20 msec) in 40 patients, moderate and severe iron overload was shown in 1 and 3 patients, respectively. 1 patients had moderate. Liver iron status was normal (&lt;2 mg) in 16 out of 53 patients with liver T2∗ MRI. Liver iron overload was found to be mild (2‐5 mg) in 11 patients, moderate (5‐10 mg) in 10 patients and severe (&gt;10 mg) in 16 patients. A strong positive correleation was found between serum ferritin levels and liver iron overload (p &lt; 0.001). There was no significant association between cardiac iron overload and serum ferritin levels. Also a slight association was shown cardiac and liver iron overload (p = 0.03). Summary/Conclusion: In our country the adult TDT patients are still on follow‐up in pediatric hematology clinics based on the experience of the pediatric hematologists on those patients. Although these older patients were constituted a new cohort, in this study the clinical features and status of iron overload in older TDT patients were found to be acceptable and similar to younger TDT's regarding despite long period of regular transfusion and histroical features of the treatment.
Optical and physical mapping with local finishing enables megabase-scale resolution of agronomically important regions in the wheat genome
Authors: Gabriel Keeble-Gagnère, Philippe Rigault, Josquin Tibbits, Raj Pasam, Matthew Hayden, Kerrie Forrest, Zeev Frenkel, Abraham Korol, B. Emma Huang, Colin Cavanagh, Jen Taylor, Michael Abrouk, Andrew Sharpe, David Konkin, Pierre Sourdille, Benoît Darrier, Frédéric Choulet, Aurélien Bernard, Simone Rochfort, Adam Dimech, Nathan Watson-Haigh, Ute Baumann, Paul Eckermann, Delphine Fleury, Angela Juhasz, Sébastien Boisvert, Marc-Alexandre Nolin, Jaroslav Doležel, Hana Šimková, Helena Toegelová, Jan Šafář, Ming-Cheng Luo, Francisco Câmara, Matthias Pfeifer, Don Isdale, Johan Nyström-Persson, None IWGSC, Dal-Hoe Koo, Matthew Tinning, Dangqun Cui, Zhengang Ru, Rudi Appels
Journal: Genome biology (2018)

Numerous scaffold-level sequences for wheat are now being released and, in this context, we report on a strategy for improving the overall assembly to a level comparable to that of the human genome. Using chromosome 7A of wheat as a model, sequence-finished megabase-scale sections of this chromosome were established by combining a new independent assembly using a bacterial artificial chromosome (BAC)-based physical map, BAC pool paired-end sequencing, chromosome-arm-specific mate-pair sequencing and Bionano optical mapping with the International Wheat Genome Sequencing Consortium RefSeq v1.0 sequence and its underlying raw data. The combined assembly results in 18 super-scaffolds across the chromosome. The value of finished genome regions is demonstrated for two approximately 2.5 Mb regions associated with yield and the grain quality phenotype of fructan carbohydrate grain levels. In addition, the 50 Mb centromere region analysis incorporates cytological data highlighting the importance of non-sequence data in the assembly of this complex genome region. Sufficient genome sequence information is shown to now be available for the wheat community to produce sequence-finished releases of each chromosome of the reference genome. The high-level completion identified that an array of seven fructosyl transferase genes underpins grain quality and that yield attributes are affected by five F-box-only-protein-ubiquitin ligase domain and four root-specific lipid transfer domain genes. The completed sequence also includes the centromere.
GITAR: An Open Source Tool for Analysis and Visualization of Hi-C Data
Authors: Riccardo Calandrelli, Qiuyang Wu, Jihong Guan, Sheng Zhong
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Interactions between chromatin segments play a large role in functional genomic assays and developments in genomic interaction detection methods have shown interacting topological domains within the genome. Among these methods, Hi-C plays a key role. Here, we present the Genome Interaction Tools and Resources (GITAR), a software to perform a comprehensive Hi-C data analysis, including data preprocessing, normalization, and visualization, as well as analysis of topologically-associated domains (TADs). GITAR is composed of two main modules: (1) HiCtool, a Python library to process and visualize Hi-C data, including TAD analysis; and (2) processed data library, a large collection of human and mouse datasets processed using HiCtool. HiCtool leads the user step-by-step through a pipeline, which goes from the raw Hi-C data to the computation, visualization, and optimized storage of intra-chromosomal contact matrices and TAD coordinates. A large collection of standardized processed data allows the users to compare different datasets in a consistent way, while saving time to obtain data for visualization or additional analyses. More importantly, GITAR enables users without any programming or bioinformatic expertise to work with Hi-C data. GITAR is publicly available at http://genomegitar.org as an open-source software.
PB1878 β‐CATENIN IS AN EFFECTOR OF THE CROSS‐TALK BETWEEN CLL B‐CELLS AND THE MICROENVIRONMENT
Authors: S. Ouriemmi, N. Varin‐Blank, D. Ledoux, L. Gardano
Journal: HemaSphere (2019)

Background: CLL is a lymphoproliferative disorder characterized by the accumulation of CD5+ B cells in the blood and lymphoid organs (bone marrow, lymph nodes and spleen). This accumulation is mainly due to an increased survival and proliferation of tumor B cells within the lymphoid organs through interaction with the microenvironment as isolated B‐CLL cells rapidly undergo apoptosis in vitro . In the quest for the molecular basis of the communication between B‐CLL cells and the microenvironment, we focused our attention on β‐catenin that participates to the stabilization of cell‐cell contacts and signal transduction. Cytosolic β‐catenin level is maintained low following its phosphorylation that triggers the degradation by the proteasome. Several molecules, such as Wnt ligands inhibit β‐catenin phosphorylation and induce its stabilization. Aims: The aim of our study is to evalute the role of β‐catenin in the cross talk between CLL B cells and the microenvironnement. Methods: Co‐cultures of primary B‐CLL cells and human bone marrow stromal cells line (HS‐5). Results: Using a model of co‐culture of primary B‐CLL cells and human marrow stromal cells we observed that the co‐culture rapidly stabilizes β‐catenin in B‐CLL cells. Since in B‐CLL cells the pathway linked to antigen stimulation is essential for survival, we explored whether β‐catenin stabilization involve BCR pathway effectors. Interestingly, we observed that the inhibition of the kinase BTK hampers β‐catenin stabilization in presence of stromal cells. Concomitant with the participation of BTK, a phosphatase activity is involved in β‐catenin stabilization. We are currently addressing whether and how the stabilization of β‐catenin regulates cell survival and the interactions between B‐CLL and stromal cells. Summary/Conclusion: Our results will convey new elements to describe the cross‐talk between tumor cells and the microenvironment to define new targets that interfere with this dialogue as alternative therapeutic strategies.
Abstract 17768: Reduced Number of Platelets in Cardiac Critical Patients Requiring Mechanical Circulatory Support Associates Increased Risk of Cardiovascular Mortality After Device Removal
Authors: Asuka Takano, Hiroshi Iwata, Kyoko Kubota, Atsushi Kimura, Shinya Okazaki, Satoru Suwa, Masataka Sumiyoshi, Atsushi Amano, Hiroyuki Daida
Journal: Circulation (2017)

Introduction: Prognostic implication of reduced number of platelets, thrombocytopenia, in critical patients with cardiovascular (CV) disease has not been fully addressed. This study primarily aimed...
FRI0603 SARCOIDOSIS IN A TERTIARY HOSPITAL
Authors: Isabel Madroñal García, Clara Aguilera Cros, Maria Dolores Arcila Duran, Lara Mendez, Marina Gomez Vargas, Alberto Ruiz Roman, Ricardo Juan Gil Velez, Jose Antonio Rodriguez Portal, Noemi Patricia Garrido Puñal, Esteban Rubio Romero
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Sarcoidosis (S) is a systemic granulomatous disease of unknown etiology. The most frequent affectation is pulmonary, ocular and cutaneous, although sarcoidosis can damage other organs, such as the musculoskeletal system. <h3>Objectives</h3> To describe the clinical characteristics and the radiological pattern, in a cohort with predominant pulmonary S, as well as to establish the relationship between the angiotensin converting enzyme (ACE) levels and the S course (chronification or remission). <h3>Methods</h3> This is a retrospective descriptive study of patients treated in our hospital, since 2008 to 2018, with diagnosis of S. The data was obtained through the review of medical records. The delay in the diagnosis of S was defined as the difference in months between the initial diagnostic suspicion and the final diagnosis of S. We use Chi-square tests to study the association between ACE levels and the course of the disease. <h3>Results</h3> Fifty-five patients (31 women) were included, with a mean age of 52 ± 12 years. The first diagnosis was: 85% S, 10% lymphoma and 4% tuberculosis. The median of months for the definitive diagnosis of S was 5.5 months. Extrapulmonary clinical manifestations in table 1. The ACE is increased in 38 patients (70%). Simple x-ray and high resolution tomography of chest were done in all patients. Pulmonary stage 2 was the most frequent (51%), followed by stage 3 (16%), stage 0 (14%) and stage 4 (9%). In 90% of the patients, histological confirmation was obtained by transbronchial (47%), cutaneous (11%) or lymph node biopsy (29%). 94% of the patients have been treated with oral glucocorticoids, 52% associate immunosuppressive therapy (Methotrexate 27% and Azathioprine 14%) or biological treatment (1 patient with Adalimumab and another with Infliximab). In 54% of the patients the S had a chronic course and in 43% S remitted. Increased levels of ACE were associated with clinical remission of the disease and normal levels with chronicity (p: 0.013). <h3>Conclusion</h3> The results of our study resembles, in general, what has been published in the literature. In our study, elevated ACE is associated with remission of the disease, contrary to the published, in which increased levels of ACE in symptomatic patients may reflect disease activity. <h3>Disclosure of Interests</h3> None declared