tbuckley/cabot-search huggingface dataset:
BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia
Authors: Haley E. Ramsey, Dalton Greenwood, Susu Zhang, Merrida Childress, Maria P. Arrate, Agnieszka E. Gorska, Londa Fuller, Yue Zhao, Kristy Stengel, Melissa A. Fischer, Matthew C. Stubbs, Phillip C.C. Liu, Kelli Boyd, Jeffrey C. Rathmell, Scott W. Hiebert, Michael R. Savona
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity. Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models. Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity
Authors: Lu Liu, Ayaka Inoki, Kelly Fan, Fengbiao Mao, Guojun Shi, Xi Jin, Meiling Zhao, Gina Ney, Morgan Jones, Shengyi Sun, Yali Dou, Ken Inoki, Ling Qi, Qing Li
Journal: Blood (2020)
AB0960 RELATIONSHIP BETWEEN THE CAREGIVER BURDEN AND UPPER LIMB-NECK DISABILITY AND PAIN IN BABY CAREGIVERS
Authors: G. Aydin, A. Demirel, N. Bulut, A. A. Karaduman, S. Serel Arslan, Ö. Yilmaz, İ. Gürbüz
Journal: Annals of the Rheumatic Diseases (2020)

Background: Although caregiving is a normal part of being a parent of a young child, it is still unclear whether caregiving causes upper limb or neck disability in the caregiver. Objectives: The aim of this study was to investigate the relationship between caregiver burden and upper limb-neck disabilities and pain in baby caregivers. Methods: Sixty caregivers who are responsible for the caregiving of a 0-2 year old healthy baby, were included in this study. Physical characteristics and the gender of the caregivers were recorded. Caregiver burden was assessed by the Zarit Burden Interview; upper limb problems by DASH and neck problems by the Neck Disability Index and Neck Bournemouth Questionnaire. In addition, pain severity related to neck and upper limb was evaluated by using Visual Analog Scale over a 10 level scale. Results: The mean age of the caregivers was 30.96 ± 6.43 year. The mean body mass index of the caregivers was 23.34 ± 3.29 indicating normal body composition. Height and weight were 163.75 ± 6.01 and 62.55 ± 8.98, respectively. Ninety-five percent of the caregivers were mother and the others were the babysitter. A weak relationship was determined between the Zarit Burden Interview and DASH (p=0.02, r=0.2), while no relationship was found between caregiver burden and other assessments. Caregivers were found to have very low pain severity in the upper limb and neck. Conclusion: It has been previously reported that caregiving for a disabled child or adult causes care burden and various musculoskeletal disorders 1-4 . Current study demonstrated that giving care for a healthy child did not create care burden, and caused lower levels of pain in the upper limb and neck. References: [1]Santos, M. T. B. R., Biancardi, M., Guare, R. O., &amp; Jardim, J. R. (2010). Caries prevalence in patients with cerebral palsy and the burden of caring for them. Special Care in Dentistry , 30 (5), 206-210. [2]Sharan, D., Ajeesh, P. S., Rameshkumar, R., &amp; Manjula, M. (2012). Musculoskeletal disorders in caregivers of children with cerebral palsy following a multilevel surgery. Work , 41 (Supplement 1), 1891-1895. [3]Akosile, C. O., Okoye, E. C., Adegoke, B. O. A., Mbada, C. E., Maruf, F. A., &amp; Okeke, I. A. (2013). Burden, health and quality of life of Nigerian stroke caregivers. Health Care Current Reviews , 1 (1), 105. [4]Darragh, A. R., Sommerich, C. M., Lavender, S. A., Tanner, K. J., Vogel, K., &amp; Campo, M. (2015). Musculoskeletal discomfort, physical demand, and caregiving activities in informal caregivers. Journal of Applied Gerontology , 34 (6), 734-760. Disclosure of Interests: None declared
ALK-transformed mature T lymphocytes restore early thymus progenitor features
Authors: Annabelle Congras, Coralie Hoareau-Aveilla, Nina Caillet, Marie Tosolini, Patrick Villarese, Agata Cieslak, Laura Rodriguez, Vahid Asnafi, Elisabeth Macintyre, Gerda Egger, Pierre Brousset, Laurence Lamant, Fabienne Meggetto
Journal: Journal of Clinical Investigation (2020)

Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient–derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK–transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients' anaplastic large cell lymphomas. Integration of "Omic" data revealed that NPM-ALK–transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern.
Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study
Authors: Sung-Eun Lee, Joon Seong Park, Young Rok Do, Sung-Hyun Kim, Dae Young Zang, Sukjoong Oh, Jae-Yong Kwak, Jeong-A Kim, Yeung-Chul Mun, Won Sik Lee, Dong-Wook Kim
Journal: Blood (2020)
Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans
Authors: Lilia Espada, Alexander Dakhovnik, Prerana Chaudhari, Asya Martirosyan, Laura Miek, Tetiana Poliezhaieva, Yvonne Schaub, Ashish Nair, Nadia Döring, Norman Rahnis, Oliver Werz, Andreas Koeberle, Joanna Kirkpatrick, Alessandro Ori, Maria A. Ermolaeva
Journal: Nature Metabolism (2020)
In‐hospital care in acute heart failure during the <scp>COVID</scp> ‐19 pandemic: insights from the <scp>German‐wide Helios</scp> hospital network
Authors: Sebastian König, Sven Hohenstein, Andreas Meier‐Hellmann, Ralf Kuhlen, Gerhard Hindricks, Andreas Bollmann
Journal: European Journal of Heart Failure (2020)

Abstract Aims The coronavirus disease 2019 (COVID‐19) pandemic has led to changes in health care utilization for different acute cardiovascular diseases. Whether hospitalization rates and in‐hospital mortality were affected by the pandemic in patients with acute symptomatic heart failure (HF) was investigated in this study. Methods and results Administrative data provided by 67 German Helios hospitals were examined for patients with a main discharge diagnosis of HF using ICD codes. Urgent hospital admissions per day were compared for a study period (13 March–21 May 2020) with control intervals in 2020 (1 January–12 March) and 2019 (13 March–21 May), resulting in a total of 13 484 patients excluding all patients with laboratory‐proven COVID‐19 infection. Incidence rate ratios (IRR) were calculated using Poisson regression. Generalized linear mixed models were used for univariable and multivariable analysis to identify predictors of in‐hospital mortality. The number of admissions per day was lower in the study period compared to the same year [IRR 0.69, 95% confidence interval (CI) 0.67–0.73, P &lt; 0.01] and the previous year control group (IRR 0.73, 95% CI 0.70–0.76, P &lt; 0.01). Age was similar throughout the intervals, but case severity increased in terms of distribution within New York Heart Association (NYHA) classes and comorbidities. Within the study period, 30‐day rates for urgent hospital readmissions were higher compared to the same year but not the previous year control group. In‐hospital mortality was 7.3% in the study period, 6.1% in the same year ( P = 0.03) and 6.0% in the previous year control group ( P = 0.02). In multivariable analysis, age, NYHA class and other predictors of fatal outcome were identified but hospitalization during the study period was not independently associated with mortality. Conclusion Our data showed a significant reduction of urgent hospital admissions for HF with increased case severity and concomitant in‐hospital mortality during the COVID‐19 pandemic in Germany. Identifying causes of reduced inpatient treatment rates is essential for the understanding and valuation with regard to future optimal management of patients with HF.
Review of &lt;I&gt;Our Posthuman Future&lt;/I&gt;, &lt;I&gt;The Future Is Now: America Confronts the New Genetics&lt;/I&gt;, and &lt;I&gt;Redesigning Humans: Our Inevitable Genetic Future&lt;/I&gt;
Authors: Arthur L. Caplan
Journal: The American Journal of Bioethics (2002)
Abstract 271: Mitochondrial DNA Copy Number in Peripheral Blood Cells is Associated With All -Cause Mortality in Older Cardiovascular Patients
Authors: Oxana Galenko, James Juan, Benjamin D Horne, Stacey Knight, John F Carlquist
Journal: Circulation Research (2020)

Background: Mitochondrial DNA copy number (Mt CN) is a surrogate marker of mitochondrial function. Variations in Mt CN have been associated with several age-related diseases. Lower Mt CN may indicate impaired cellular energy production whereas higher Mt CN may compensate for energy disbalance but also may lead to cellular damage through oxidative stress. This study evaluated the association of Mt CN and all-cause mortality in older cardiovascular patients (Pt). Methods: The study was approved by the Intermountain Healthcare Institutional Review Board. Consenting subjects (n=2,253) were participants in the INSPIRE registry undergoing cardiac catheterization at the Intermountain Heart Institute. Total DNA was extracted from EDTA stabilized blood with either Puregene (Qiagen) or Reliaprep (Promega) reagents. Relative Mt CN measurements were performed with multiplexed real-time polymerase chain reaction coamplifying a stable site of Mt D- Loop and a region of a single copy nuclear β-2-microglobulin gene(β2M) and calculated as a ratio of Mt to β2M DNA. Cox regression was used to evaluate the association of Mt CN with all-cause mortality, with adjustment considering 32 covariables. Further adjustment entered the Intermountain Risk Score (IMRS), a validated mortality risk predictor. Results: Mean Pt age was age 62.3±13.8 yrs.; 65.2% were male; 1,122 (50%) died during 25.4 years of follow-up. Mt CN was lower for males (539±449 vs 654 ± 1053 for females; p=0.004). Mt CN was 616±917 in decedents and 542±438 in survivors (p=0.014). In univariable Cox regression, Quartile 1 versus Quartile 4 of Mt CN was associated with the highest mortality risk (hazard ratio [HR]=1.45, CI=1.22, 1.71, p&lt;0.001). This association remained significant after multivariable adjustment (HR=1.30, CI=1.10, 1.54, p=0.003). There was minimal correlation between IMRS and Mt CN continuous values (r= -0.09 for males, r= -0.13 for females). In Cox regression, adjustment for IMRS and covariables showed Mt CN remained associated with mortality (HR=1.30, CI=1.08, 1.57, p=0.006). Conclusions: Low Mt CN is independently associated with higher risk of all-cause mortality. Further studies validating this finding and examining potential underlying physiologic protective mechanisms may prove to be of therapeutic and prognostic value.
Ixazomib Based Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials
Authors: Anum Javaid, Faryal Razzaq, Muhammad Ashar Ali, Muhammad Abu Zar, Atif Sohail, Ahmad Iftikhar, Rana Usman, Muhammad Yasir Anwar, Hamza Hassan, Faiz Anwer
Journal: Blood (2020)
Cytokine Rescue and Targeting of Inflammation-Sensitive RUNX1 Deficient Human CD34+ Hematopoietic Stem and Progenitor Cells
Authors: Amy Fan, Armon Azizi, Kevin Nuno, Yusuke Nakauchi, Feifei Zhao, Andreas Reinisch, David Cruz Hernandez, Ravindra Majeti
Journal: Blood (2020)
Safety and Preliminary Efficacy Results from a Phase Ib/II Study of Cobimetinib As a Single Agent and in Combination with Venetoclax with or without Atezolizumab in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Fredrik Schjesvold, Vincent Ribrag, Paula Rodriguez-Otero, Pawel J. Robak, Markus Hansson, Roman Hajek, Adrián Alegre Amor, Joaquin Martinez-López, Maika Onishi, Jorge D. Gallo, Aparna Raval, Sameer Deshpande, Vikram Malhi, Wan-Jen Hong, Marc S. Raab
Journal: Blood (2020)
Mosaic Mutagenesis <i>In Vivo</i> Reveals Mutant Blood Stem Cells Intrinsically Resistant to Inflammatory Mediators in Clonal Hematopoiesis
Authors: Serine Avagyan, Jonathan E Henninger, William P. Mannherz, Meeta Mistry, Song P. Yang, Margaret Weber, Jessica Moore, Leonard I. Zon
Journal: Blood (2020)
Abstract 375: Insights Into Molecular Mechanism of Cardiovascular Disorder in HIV+ Patients
Authors: Manish Gupta, Kaylyn Scanlon, Avni Mukker, Deepti Gupta, Jay Rappaport, Manish K Gupta
Journal: Circulation Research (2020)

Background: Antiretroviral therapy (ART) improves the survival of people living with HIV (PLHIV); however, the rate of cardiovascular disorder and heart failure is significantly increased among the PLHIV. Molecular basis of heart failure in the PLHIV undergoing antiretroviral drug treatment is not clear. The aim of this study is to explore the role of antiretroviral drugs in post translational modification of histones and its epigenetic regulation of gene expression in cardiomyocytes. Methods and Results: Primary rat ventricular cardiomyocytes were treated with a combination of antiretroviral drugs (5 μM of Atazanavir, Abacavir, Ritonavir and Lamivudine) for 4, 12 and 24 hours, and expression of major histone marks playing a role in gene activation (H3K9ac and H3K27ac) and repression (H3K27me3, H3K9me3) were evaluated by western blotting. Our data suggest that treatment with antiretroviral drugs leads to de-acetylation at H3K9ac and H3K27ac, and promotes methylation at H3K27me3 and H3k9me3. Additionally, the expression of epigenetic modifying enzymes was examined by PCR array in cardiomyocytes treated with antiretroviral drugs. PCR array data show that histone deacetylase enzyme Sirt1/2, and methyltransferase enzyme Suv39h1 and Ezh12 were upregulated in drug treated cardiomyocytes. Further, western blot data show that Sirt1, Suv39h1 and Ezh2 protein expression was significantly upregulated in drugs treated cardiomyocytes. Moreover, expression analysis of human cardiac tissue further shows that expression of Sirt1, Suv39h1 and Ezh2 was significantly upregulated in HIV+ patients heart compares to healthy donor. Mechanistically, our data show that expression of epigenetic modifying enzymes was differentially regulated in drug treated cardiomyocytes which may lead to epigenetic modifications of histone proteins. Conclusion: Antiretroviral drug treatment promotes epigenetic alteration in the chromatin which may lead to a change in gene expression of cardiomyocytes. This study may lead to novel therapeutic strategies for the treatment of heart failure in PLWHA.
Effect of Pegcetacoplan on Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Pegasus Phase 3 Trial Comparing Pegcetacoplan to Eculizumab
Authors: Alexander Röth, Britta Hoechsmann, Morag Griffin, Carlos M. de Castro, Jeffrey Szer, Kensuke Usuki, Juliette Soret, Mohamed Hamdani, Temitayo Ajayi, Sujata P. Sarda, Jens Panse
Journal: Blood (2020)
Clinical course of COVID-19 in a cohort of 342 familial Mediterranean fever patients with a long-term treatment by colchicine in a French endemic area
Authors: Rim Bourguiba, Marion Delplanque, Caroline Vinit, Felix Ackermann, Léa Savey, Gilles Grateau, Veronique Hentgen, Sophie Georgin-lavialle
Journal: Annals of the Rheumatic Diseases (2020)

Table 1 Clinical course of 27 patients displaying COVID-19 in a cohort of 342 familial Mediterranean fever patients with a long-term treatment by colchicine in a French endemic area Sex ratio 1 Age years, median 33 (17-87)
Co-Targeting BET Bromodomain Proteins and Aberrant Signaling in AML
Authors: Benjamin J. Huang, Xinyue Wang, Max Harris, Anica Wandler, Eugene Hwang, Michael R. Burgess, Qing Li, Paul Severson, Ben Powell, Edward A. Kolb, Soheil Meshinchi, Barry S Taylor, Gideon Bollag, Kevin M. Shannon
Journal: Blood (2020)
Phase I/II Clinical Trial of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas
Authors: Ajay Major, Justin Kline, Theodore G. Karrison, Paul A S Fishkin, Amy S Kimball, Adam M Petrich, Sreenivasa Nattam, Bethany G Sleckman, Kenneth Cohen, Koen van Besien, Aaron P. Rapoport, Sonali M. Smith
Journal: Blood (2020)
Reconstruction of Sickle Cell Disease with Circulating Sickling Red Blood Cells in Novel Humanized Cytokines and Liver Mistrg Mice
Authors: Yuanbin Song, Rana Gbyli, Liang Shan, Wei Liu, Yimeng Gao, Amisha Patel, Xiaoying Fu, Xiaman Wang, Mina L. Xu, Ashley Qin, Emanuela Bruscia, Toma Tebaldi, Giulia Biancon, Padmavathi Mamillapalli, David Urbonas, David Gonzales, Diane S. Krause, Jonathan Alderman, Richard Flavell, Stephanie Halene
Journal: Blood (2020)
A Novel Therapeutic Strategy for Preferential Elimination of Multiple Myeloma Cells By Targeting Protein Disulfide Isomerase
Authors: Metis Hasipek, Dale Grabowski, Yihong Guan, Anand D. Tiwari, Xiaorong Gu, Jason Valent, Jaroslaw Maciejewski, Frederic Joel Reu, James G Phillips, Babal K. Jha
Journal: Blood (2020)
Clinical Experience of Tabelecleucel in Patients with Life-Threatening Complications of Epstein-Barr Virus Viremia
Authors: L Torno, A Dahlberg, Armin Ghobadi, P Stiff, R Reshef, W-K Weng, W Navarro, L Gamelin, R Dinavahi, Y Sun, N Guzman-Becerra, S Prockop
Journal: Blood (2020)
Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study
Authors: Alfredo Rivas-Delgado, Ferran Nadeu, Anna Enjuanes, Sebastián Casanueva-Eliceiry, Pablo Mozas, Laura Magnano, Natalia Castrejón de Anta, Jordina Rovira, Ivan Dlouhy, Silvia Martín, Miguel Osuna, Sonia Rodríguez, Marc Simó, Magda Pinyol, Tycho Baumann, Silvia Beà, Olga Balagué, Julio Delgado, Neus Villamor, Xavier Setoain, Elías Campo, Eva Giné, Armando López-Guillermo
Journal: Clinical Cancer Research (2020)

Abstract Purpose: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL). Experimental Design: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available. Results: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2–78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (&amp;gt;2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P &amp;lt; 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses. Conclusions: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.
<i>GATA3</i> Gene - a Potential New Biomarker Associated with Adverse Outcomes in ALK1-Negative Anaplastic Large Cell Lymphoma: Preliminary Results from a Retrospective Cohort of 80 South American Cases of Nodal Peripheral T Lymphoma
Authors: Luis Alberto de Padua Covas Lage, Claudio Vinicius Brito, Debora Levy, Hebert Fabricio Culler, Samuel Campanelli Freitas Couto, Lucas BO Alves, Maria C Zerbini, Vanderson Rocha, Juliana Pereira
Journal: Blood (2020)