tbuckley/cabot-search huggingface dataset:
Abstract 368: Disease and Phenotype-relevant Genetic Variants Identified From Histone Acetylomes in Human Hearts
Authors: Chukwuemeka George Anene Nzelu, Wilson Tan, Eleanor Wong, Mick Lee, Matias Ilmari Autio, Susan Tan, Pan Bangfen, Michael Morley, Kenneth Margulies, Thomas Cappola, Marie Loh, John Chambers, Shyam Prabhakar, Roger Foo
Journal: Circulation Research (2019)

Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to meet genome-wide statistical significance. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising sub-threshold variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR 5%) pointed to pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test to call out 1,680 haQTLs (FDR 10%). RNA-seq performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression QTLs), either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. We validated 2 of the haQTLs through base editing to show that the presence of those SNPs indeed affects gene expression in human embryonic stem cells-derived cardiomyocytes. Furthermore, a concordant relationship between the gain or disruption of transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalisation of haQTLs with heart-related GWAS datasets. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.
Novel Rare Genetic Variants Associated with Airflow Obstruction in the General Population
Authors: Maaike de Vries, Diana A. van der Plaat, Ivana Nedeljkovic, K. Joeri van der Velde, Najaf Amin, Cornelia M. van Duijn, Judith M. Vonk, H. Marike Boezen, Cleo C. van Diemen
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Total Body Irradiation (TBI) or Busulfan (Bu) Plus High Dose Melphalan After Bortezomib (Bz) Containing Regimen As Front Line Treatment of High Risk Multiple Myeloma (MM) Patients with 17p Deletion and/or t(4;14) Translocation
Authors: Bertrand Arnulf, Raphael Szalat, Lionel Karlin, Stephanie Harel, Bouchra Asli, Marion Malphettes, Jean Soulier, Jean Paul Fermand
Journal: Blood (2011)
"Function First" Screen of Primary AML Cells Identifies Common and Personalised Therapeutic Targets
Authors: Jamshid S Khorashad, Carme Ripoll Fiol, Eva Yebra-Fernandez, Elisabet Nadal-Melsio, Mahroo Karimpoor, Simone Claudiani, Alistair Reid, Steven Knapper, Kikkeri Naresh, Jane Apperley, Clinton C. Mason
Journal: Blood (2018)
Abstract 588: Beta-blockers Reverse Beta Adrenergic Receptors Desensitization Under Hypoxia
Authors: Yu Sun, Manveen Gupta, Kate Stenson, Sathyamangla Prasad
Journal: Circulation Research (2019)

Hypoxia to heart or brain is a primary cause of heart failure or stroke. Studies have shown hypoxia increases the beta-adrenergic receptors (βARs) phosphorylation and dysfunction (Cheong et. al., 2016). These observations provide evidence that βARs can directly be regulated by hypoxia but less is known about the underlying mechanisms. We postulated that hypoxia shifts the homeostasis between kinase and phosphatase driven mechanisms may underlie βAR dysfunction. β2AR HEK 293 cells were exposed to hypoxia (2% O 2 ) and assessed the mechanisms underlying desensitization (G-protein coupled receptor kinases, GRKs) and resensitization (Protein phosphatase 2A, PP2A). Six hours of hypoxia treatment resulted in increase of βAR phosphorylation and GRK2 expression. Assessment of βAR phosphorylation in the plasma membrane and endosomal fractions surprisingly, showed marked increase in β2AR phosphorylation in the endosomal fraction. Furthermore, we also observed that receptor associated PP2A activity was inhibited in the endosomes following hypoxia with minimal changes of activity at the plasma membranes. Similarly subjecting normal mice to 20 hours of hypoxia resulted in significant cardiac dysfunction (% FS: Normoxia 38.83% vs. Hypoxia 32.38%, P=0.0055; % EF: Normoxia 69.71% vs. Hypoxia 60.76%,P=0.0105) and was associated with significant increase in β2AR phosphorylation associated with significant loss in βAR function as measured by G-protein coupling adenylyl cyclase activity. Given that β-blockers confer beneficial effects, we tested whether β-blocker (propranolol) would prevent βARs phosphorylation under hypoxia or normoxia. Consistently, β-blocker treatment in normoxia results in increased β2AR phosphorylation however, remarkably β-blocker treatment in hypoxia results in loss of β2AR phosphorylation, reduction in GRK2 expression and increase in βAR-associated PP2A. These studies show that agonist-independent hypoxia-driven β2AR dysfunction can be ameliorated by β-blockers and the underlying mechanisms for this expected findings will be discussed in the presentation. These findings have significant clinical implications as understanding these mechanisms could provide novel insights into the benefits provided by β-blockers.
Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma
Authors: Ying-Chun Shen, Chia-Lang Hsu, Yung-Ming Jeng, Ming-Chih Ho, Cheng-Maw Ho, Ching-Ping Yeh, Chia-Yu Yeh, Meng-Chi Hsu, Ray-Heng Hu, Ann-Lii Cheng
Journal: Journal of Hepatology (2019)
Rituximab (R)-CHOP Therapy Has Progressed Arteriosclerosis with an Elevation of Von Willebrand Factor (vWF) in Patients with Malignant Lymphoma
Authors: Naomi Shimizu, Shouko Nakamura, Naoyuki Kawagoe, Rena Oka, Yasuhiro Watanabe, Sho Tanaka, Yuta Sato, Takashi Yamaguchi, Masahiro Ohira, Atsuhito Saiki, Chiaki Nakaseko, Emiko Sakaida, Hideaki Bujo, Kohji Shirai, Ichiro Tatsuno
Journal: Blood (2018)
Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response
Authors: Bridget P. Keenan, Lawrence Fong, Robin K. Kelley
Journal: Journal for ImmunoTherapy of Cancer (2019)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy.
Neurodegenerative Disease Mortality among Former Professional Soccer Players
Authors: Daniel F. Mackay, Emma R. Russell, Katy Stewart, John A. MacLean, Jill P. Pell, William Stewart
Journal: New England Journal of Medicine (2019)

Neurodegenerative disorders have been reported in elite athletes who participated in contact sports. The incidence of neurodegenerative disease among former professional soccer players has not been well characterized.
The Germline JAK2 GGCC (46/1) Haplotype and Survival Among 414 Molecularly-Annotated Patients with Primary Myelofibrosis
Authors: Ayalew Tefferi, Terra L. Lasho, Christy Finke, Mythri Mudireddy, Natasha Szuber, Rangit Reddy Vallapureddy, Domenico Penna, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Animesh Pardanani
Journal: Blood (2018)
Abstract 467: Identification of Novel Pathogenic Mutations in Non-Canonical RNA Splice Sites in Congenital Heart Disease
Authors: Min Young Jang, Angela C Tai, Parth N Patel, Kaoru Ito, Joshua Gorham, Alexandre C Pereira, David M McKean, Christine E Seidman, J G Seidman
Journal: Circulation Research (2019)

Rationale: Congenital heart disease (CHD) occurs in about 1 in 100 live births, yet known genetic causes explain less than 20% of CHD cases. While variants that cause frameshift, nonsense, start/stop site gain or loss, and canonical splice site alterations are readily categorized as being pathogenic or loss-of-function (LOF), interpreting the clinical significance of variants without obvious functional consequences remains challenging. Here, we aim to improve classification of variants of unknown significance (VUS) in non-canonical RNA splice sites that may be pathogenic for CHD. Methods: We tested candidate LOF de novo (DNV) and rare (p &lt; 2E-5) inherited variants from whole exome sequencing of 4474 CHD probands and their parents in the NHLBI Pediatric Cardiac Genetics Consortium. Briefly, variants underwent computational selection to prioritize VUS in splice regions that are likely to alter splicing (“high-likelihood VUS”). These variants then underwent in vitro analysis including Minigene construction, transfection, RNA isolation, and sequencing to confirm splicing outcomes. Results: Preliminary results limited to DNV variants showed that 163 of 2678 (6.08%) were high-likelihood VUS. Subsequent analysis in vitro assay of high-likelihood VUS yielded 53 as splice-altering (p &lt; 0.05) and thus LOF. Combined with previously identified 366 DNV LOF variants, the addition of these splice-altering variants represents a 15.3% increase in total LOF DNV variant calls. This includes new pathogenic mutations in known CHD genes such as KMT2D . In one case, a CHD proband with features of Kabuki Syndrome without a definitive diagnosis was found to have a splice-altering variant in KMT2D . We have extended this assay to 34518 rare, inherited variants in the same cohort, of which 868 (2.54%) are in genes previously associated with CHD. Conclusion: Consideration of non-canonical RNA splice sites in this assay increased the yield of LOF mutations from traditional sequencing methods by 15.3% in the CHD cohort. Further analysis of splice-altering variants in both known and unknown pathogenic genes will improve diagnostic classification of VUS and gene-based diagnosis of CHD.
BCL-2 Inhibitor Venetoclax (ABT-199) and MEK Inhibitor GDC-0973 Synergise to Target AML Progenitors and Overcome Drug Resistance with the Use of PET Scanning in a Mouse Model of HR-MDS to Monitor Response to Treatment
Authors: Rose Ann Padua, Laure Sarda-Mantel, Mathieu Chiquet, Claire Kappel, Patricia Krief, Niclas Setterblad, Fortune Hontonnou, Benoit Hosten, Nicolas Vignal, Fabien Zassadowski, Bruno Cassinat, Panhong Gou, Stephane Giraudier, Marina Y. Konopleva, Michael Andreeff, Marika PLA, Lionel Ades, Pierre Fenaux, Christine Chomienne
Journal: Blood (2018)
Interventional Strategies to Contain Colonization and Infections Caused By Carbapenemase Producing Klebsiella Pneumonia in Haematological Malignancies
Authors: Alessandra Malato, Francesco Acquaviva, Rosaria Felice, Silvana Magrin, Maria Grazia Donà, Rosanna Scimè, Stefania Tringali, Baldi maria Teresa, Francesco Fabbiano
Journal: Blood (2014)
HLA Class II Upregulation During An Ongoing Viral Infection Can Lead to HLA-DP Directed Graft-Versus-Host Disease After HLA-DPB1 Mismatched CD4+ Donor Lymphocyte Infusion
Authors: Sanja Stevanovic, Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Jessica C. Harskamp, C.J.M. Halkes, Marieke Griffioen, J.H. Frederik Falkenburg
Journal: Blood (2011)
Pre-Transplant Monocytic Myeloid-Derived Suppressor Cell Frequency Has No Prognostic Role for Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Remission
Authors: Colin Godwin, Jonathan R. Fromm, Brenda M. Sandmaier, Marco Mielcarek, Brent Wood, Frederick R. Appelbaum, Rainer F. Storb, Roland B. Walter
Journal: Blood (2018)
A population-based study of medical cannabis utilization in patients with cancer.
Authors: Safiya Karim, Jingyu Bu, Ed Jess, Winson Y. Cheung, Marc Kerba
Journal: Journal of Clinical Oncology (2019)

124 Background: Between 2014 and 2018, access to cannabis for medical purposes was regulated by Health Canada. Surveys have demonstrated that cancer patients use cannabis to manage symptoms and side effects. Medical cannabis utilization patterns in cancer patients under Canada’s regulatory framework have not been well-described. We aimed to determine the proportion of cancer patients who used medical cannabis, timing of use in relation to cancer treatment and sociodemographic factors predicting use. Methods: The Alberta Cancer Registry was used to identify all patients age ≥ 18 diagnosed with invasive cancer in the province from April 01, 2014 to December 31, 2016. These cases were linked to records from the College of Physicians and Surgeons of Alberta database which collects data on patients who received an authorization for medical cannabis. Authorization was used as a surrogate for medical cannabis utilization. Univariate and multivariate logistic regression models were constructed to determine factors associated with medical cannabis utilization. Results: We identified 41,889 patients between April 1, 2014 and December 31, 2016. Median age at cancer diagnosis was 65 and 50% were female. Among these patients, 1,070 (2.5%) used medical cannabis. Of these patients, 541 (51%) used medical cannabis within 1 year of diagnosis, 248 (52%) within one year of the start of systemic therapy and 128 (41%) within one year of the start of radiation therapy. On multivariate analysis, patients aged 18-29 (OR 12.4, 95% CI 7.8-19.7) and those receiving systemic therapy (OR 2.0, 95% CI 1.7-2.4) were more likely to use medical cannabis (p &lt; 0.001). There were 171 unique physicians who authorized medical cannabis of which only 3.5% (6/171) were oncologists. Conclusions: A small proportion of cancer patients used medical cannabis under Health Canada’s regulatory framework. Utilization was associated with a cancer diagnosis and receiving treatment. Younger patients and those undergoing systemic treatment were predictors of medical cannabis use. Further study is required to understand utilization patterns after cannabis legalization and how to incorporate these findings into patient-centered cancer care.
The ‘Finnish new variant of Chlamydia trachomatis’ escaping detection in the Aptima Combo 2 assay is widespread across Norway, June to August 2019
Authors: Tone Bjordal Johansen, Hilde Kløvstad, Rikard Rykkvin, Einar Bredo Herrfurth-Erichsen, Joakim Sorthe, Gro Njølstad, Marit Helen Ebbesen, Randi Monsen Nygaard, Ellen Kristin Sandmoen, Carina Thilesen, Annette Onken, Inger Liljedal, Ronza Hadad, Magnus Unemo
Journal: Eurosurveillance (2019)

The 'Finnish new variant of Chlamydia trachomatis' (FI-nvCT), escaping detection in the Aptima Combo 2 assay (AC2), is widespread across Norway. From June to August 2019, 84% (81/97) of available AC2/Aptima CT discordant samples from five laboratories were confirmed as FI-nvCT. Two additional CT variants (CT 23S rRNA C1514T and G1523A) also escaped AC2 detection. The high FI-nvCT proportion might indicate a long-term national spread and it cannot be excluded that FI-nvCT emerged in Norway.
A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis.
Authors: Srdan Verstovsek, Animesh D. Pardanani, Neil P. Shah, Lubomir Sokol, Martha Wadleigh, D. Gary Gilliland, Alan F. List, Ayalew Tefferi, Hagop M. Kantarjian, Lynne A. Bui, Douglas O. Clary
Journal: Blood (2007)
Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic Testing in Rare Diseases: Where Are We?
Authors: Zhichao Liu, Liyuan Zhu, Ruth Roberts, Weida Tong
Journal: Trends in Genetics (2019)

Next-generation sequencing (NGS) technologies have changed the landscape of genetic testing in rare diseases. However, the rapid evolution of NGS technologies has outpaced its clinical adoption. Here, we re-evaluate the critical steps in the clinical application of NGS-based genetic testing from an informatics perspective. We suggest a 'fit-for-purpose' triage of current NGS technologies. We also point out potential shortcomings in the clinical management of genetic variants and offer ideas for potential improvement. We specifically emphasize the importance of ensuring the accuracy and reproducibility of NGS-based genetic testing in the context of rare disease diagnosis. We highlight the role of artificial intelligence (AI) in enhancing understanding and prioritization of variance in the clinical setting and propose deep learning frameworks for further investigation.
FPN1, Targeted By Mir-17-5p, Regulates Cellular Iron Homeostasis Via activating Nrf2/Mir-17-5p/FPN1 Axis in Preclinical Model of Multiple Myeloma
Authors: Yuanyuan Kong, Shuaikang Chang, Liangning Hu, Gege Chen, Yi Tao, Yingcong Wang, Dandan Yu, Kang Lu, Yongsheng Xie, Wenxuan Bu, Jumei Shi
Journal: Blood (2018)
Monitoring of Minimal Residual Disease Using Next-Generation Deep-Sequencing in 460 Acute Myeloid Leukemia Cases identifies RUNX1 Mutated Patients with Resistant Disease
Authors: Alexander Kohlmann, Vera Grossmann, Stefan Harbich, Frank Dicker, Tamara Alpermann, Niroshan Nadarajah, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, Susanne Schnittger
Journal: Blood (2011)
The Role of NRAS G12D Mutations in the Response to Conventional Chemotherapy and 5-Azacitidine in Secondary AML
Authors: Andoni Garitano-Trojaola, Eva Teufel, Matteo Claudio Da Via', Ana Sancho, Nadine Rodhes, Thorsten Stuehmer, Santiago Barrio Garcia, Jürgen Groll, Torsten Haferlach, Raoul Tibes, Andreas Rosenwald, Hermann Einsele, Martin Kortüm
Journal: Blood (2018)
Effect of high patient out-of-pocket (OOP) cost for oral tyrosine kinase inhibitors (TKIs) on survival in EGFR and ALK positive stage IV non-small cell lung cancer (NSCLC).
Authors: Bernardo H. L. Goulart, Joseph M. Unger, Shasank Chennupati, Kathryn Egan, Catherine R. Fedorenko, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

3 Background: Patients with EGFR+ or ALK+ NSCLC benefit from oral TKIs, but high patient OOP TKI costs could negatively impact survival by reducing likelihood of continuing TKI therapy. We assessed the association of high OOP TKI costs with overall survival (OS), medication possession ratio (MPR) and duration of TKI therapy (DOT) in patients with metastatic EGFR+ and ALK+ NSCLC. Methods: We identified patients with EGFR+ and ALK+ NSCLC diagnosed between 01/01/2010 and 12/31/2016 in the Washington State SEER registry using natural language processing, followed by manual confirmation of molecular tests. We linked registry records to commercial and Medicare (including part D) claims. Eligible patients had stage IV NSCLC, sensitizing EGFR mutations or ALK+ by FISH, ≥1 pharmacy claims for EGFR or ALK TKIs, ≥3 months survival from TKI start, and ≥12 months of insurance enrollment post diagnosis. We estimated OOP TKI costs by subtracting the amount paid from the amount allowed in pharmacy claims. We categorized patients by quartiles of monthly OOP costs calculated for the first 3 months of TKI therapy (Q1 &lt; Q2 &lt; Q3 &lt; Q4). We used landmark survival analysis with multivariate Cox regression to test the association of monthly OOP costs in the first 3 months of TKIs and OS starting at 3 months of TKI therapy between Q1-Q3 vs Q4. We used t-tests to compare MPR and DOT for the 1st TKI between Q1-3 and Q4. Results: For 106 eligible patients (median age 69; 67% female; 73% White; 35% Medicare, 85% EGFR+), the median monthly OOP TKI costs at 3 months were $0 (Q1); $1,432 (Q2); $1,798 (Q3); $2,888 (Q4). Mean MPR was 1.20 vs. 1.06 (P = 0.02), and median DOT was 8 vs. 4 months (P &lt; 0.01) for Q1-3 vs. Q4. Median OS was 22 vs. 9 months for Q1-3 vs 4. Compared with Q1-3, Q4 patients had a hazard ratio for death of 1.76 (95% CI = 1.05; 2.94; P = 0.03), adjusted for age, sex, insurance, mutation, income, chemotherapy use, and time to TKI start. There were no statistically significant associations comparing Q1 to Q2-4, or Q1-2 to Q3-4. Conclusions: Higher patient OOP TKI costs are associated with lower number of TKI prescriptions, shorter duration of TKI therapy and inferior survival in advanced EGFR+ and ALK+ NSCLC.
Abstract 171: The Effects of Adolescent Binge Alcohol Exposure to Cardiovascular Structure and Function
Authors: Lizhuo Ai, Edith Perez, Maxime Heroux, Andrei Zlobin, AnnaDorothea Asimes, Quan Cao, Charles S Chung, Toni R Pak, Jonathan A Kirk
Journal: Circulation Research (2019)

While the effects of alcohol consumption on the adult heart have been well studied, the impact to the adolescent heart is almost entirely unknown. Adolescents primarily consume alcohol in a binge pattern, which elevates blood alcohol content (BAC) to 0.08 g/dL within 2 hours. During adolescence the body grows rapidly, and the heart must also grow (through cellular hypertrophy) to meet this increasing demand. Our goal was to determine the impact of adolescent binge alcohol exposure on the heart, using an outbred rat model. On postnatal day (PND) 37 (adolescence), rats were gavaged 3 g/kg EtOH for 3 days, H2O for 2 days, and EtOH for 3 more days, then sacrificed following the last dose (Binge). The control group received only H2O (Water). Both groups had normal food and water intake and weight gain. BAC was 0.08 g/dL in the Binge group and 0 in the Water group. Water rats experienced a ~40% increase in LV end-diastolic volume (LVEDV) due to normal growth along with a parallel increase in end-systolic volume such that ejection fraction (EF) was preserved. Conversely, Binge rats only had half that increase in LVEDV, and a decrease in systolic diameter resulting in increased EF. We hypothesize alcohol impaired normal cardiac growth, and systolic function increased to maintain cardiac output. Increased systolic function suggested beta-adrenergic activation, which was supported by increased troponin I phosphorylation at the PKA sites in the Binge group. Doppler indicated the E/A ratio increased with age in the Water group, but in the Binge group the E/A ratio did not change with age. Further, the Binge group displayed increased single cell passive stiffness level (sarcomere length: 1.7-2.4 μm) compared to Water, likely due to altered titin phosphorylation. Lastly, we performed RNA-seq and identified 58 down-regulated and 10 up-regulated genes in the Binge group. Many of these genes suggest a switch in substrate utilization from fatty acid to glucose metabolism in the Binge rats. These data reveal a previously unappreciated pathological impact of adolescent binge alcohol exposure. The young heart can compensate for these consequences at first and appear healthy. However, the long term impact of these effects may be significant and whose underlying cause was previously unknown.
Prognostic Impact of Deletion 17p Clone Size on Outcome in Chronic Lymphocytic Leukemia Patients (A Real Life Routine Practice Perspective in Brazil)
Authors: Ricardo Bigni, Teresa de Souza Fernandez, Mayara Rego, Ingrid Luise, Eliana Abdelhay, Cecilia Fernandez, Keyla Araujo
Journal: Blood (2018)