tbuckley/cabot-search huggingface dataset:
Abstract 248: Microfibrillar-Associated Protein 4 Regulates Maladaptive Cardiac Remodeling
Authors: Lisa E Dorn, William Lawrence, Jennifer M Petrosino, Xianyao Xu, Thomas J Hund, Anders Schlosser, Grith L Sorensen, Federica Accornero
Journal: Circulation Research (2019)

Cardiac hypertrophy is a well-known risk factor for heart failure. Cardiomyocytes are often considered the ultimate culprit of cardiac remodeling following stress, despite comprising less than half of the heart’s total cells. Recent work has begun to recognize the importance of non-myocyte populations in the heart, yet how signaling between these and cardiomyocytes can dictate cardiac remodeling is still largely unknown. We have found that Microfibrillar-associated protein 4 (MFAP4) is a novel mediator of intercellular communication in the heart, and is specifically required for cardiac adaptation to stress. MFAP4 is an extracellular matrix protein that has been previously shown as a necessary component of arterial remodeling following injury, but its role in cardiac hypertrophy has not been explored. Our data revealed that, in the heart, MFAP4 is selectively secreted by vascular smooth muscle cells and endothelial cells in response to transforming growth factor β (TGFβ) activation. To determine the role of MFAP4 in cardiac hypertrophy, we subjected MFAP4-deficient mice to two forms of stress: chronic pressure overload or 1 week administration of the pro-fibrotic agent Angiotensin II (AngII). MFAP4-deficient mice developed accelerated cardiac hypertrophy, fibrotic remodeling, and marked cardiac functional defects with pressure overload when compared to wild-type animals. Also, AngII administration was sufficient to exacerbate cardiac hypertrophy prior to marked cardiac functional decline in MFAP4-deficient mice, suggesting a primary role for MFAP4 in regulating cardiomyocyte growth. Furthermore, aging-induced cardiac stress led to left ventricular dilation and spontaneous development of functional defects in otherwise unstressed MFAP4-deficient mice. Mechanistically, MFAP4 possess an integrin-binding domain and can affect cardiac homeostasis downstream of cardiomyocyte integrins via altered signaling through the FAK-ERK cascade, well-known to dictate cardiomyocyte geometric remodeling. Overall, our study demonstrates a critical role for MFAP4 on cardiac hypertrophy and function post-injury, underscoring the importance of non-myocyte-derived factors on cardiomyocyte pathophysiology.
Vaccination with DC/Multiple Myeloma Fusions in Conjunction with Stem Cell Transplantation.
Authors: David Avigan, Jacalyn Rosenblatt, Baldev Vasir, Zekui Wu, Adam Bissonnette, Claire MacNamara, Lynne Uhl, Corrine Lenahan, Kenneth Miller, James D. Levine, Robin Joyce, Karen Lowe, Dilani Dombagoda, Paul Richardson, Kenneth Anderson, Nikhil Munshi, Donald Kuffe
Journal: Blood (2007)
A Regulatory Promoter Polymorphism and Hypermethylation of Intron 1 Are Associated with Reduced Expression of KLF5 and Inferior Survival in AML
Authors: Anna L Brown, Sonya M Diakiw, Michelle Perugini, Nik Cummings, Andrew H Wei, L. Bik To, Ian D Lewis, Richard J D'Andrea
Journal: Blood (2012)
Bone Turnover In Multiple Myeloma: Impact Of Bortezomib-Based Induction Therapy, High-Dose Melphalan, and Lenalidomide Consolidation On Osteoblast and Osteoclast Function Within The GMMG-MM5 Trial
Authors: Anja Seckinger, Tobias Meißner, Uta Bertsch, Hans Salwender, Jan Dürig, Mathias Hänel, Igor W. Blau, Christof Scheid, Katja Weisel, Bernard Klein, Hartmut Goldschmidt, Dirk Hose
Journal: Blood (2013)
Abstract 149: Endothelial-specific Overexpression of Metallothionein Prevents Diabetes Mellitus-induced Impairment in Ischemia Angiogenesis via Preservation of Hif-1á/sdf-1 in Endothelial Progenitor Cells
Authors: Kai Wang, Xiaozhen Dai, Junhong He, Chengkui Yang, Kupper Wintergerst, Paul Epstein, Lu Cai, Yi Tan
Journal: Circulation Research (2019)

Diabetes mellitus associated dysfunction of endothelial progenitor cells (EPCs) may contribute to dysregulation of endothelial regeneration. Whether oxidative protection of EPCs by an antioxidant, such as the protein metallothionein (MT) can have positive angiogenic effects and by what mechanisms remain unclear. Endothelial-specific MT overexpression (JTMT) mice were made diabetic by high fat diet followed by streptozocin administration (HFD/STZ). Diabetic hind limb ischemia (HLI) was established by femoral artery ligation. Bone marrow mononuclear cells (MNCs) collected from JTMT mice were transplanted into db/db mice with HLI. Blood reperfusion was monitored. High glucose and hypoxia conditions in culture were adopted to mimic diabetic ischemia. Compared with wild-type (WT) littermates, JTMT mice were resistant to diabetes-induced impairment in ischemia angiogenesis and blood reperfusion in HFD/STZ diabetes. Similarly, transplantation of MT overexpressing MNCs showed better therapeutic effect on db/db mice with HLI than transplantation of WT MNCs. These changes were accompanied by increased mobilization and infiltration of EPCs in JTMT mice, and enhanced incorporation of EPCs into capillaries in JTMT MNCs transplanted db/db mice. Furthermore, EPCs from JTMT mice exhibited augmented cell survival, tube formation, and migration capacities under diabetic ischemia-like conditions. Mechanistically, the expression of hypoxia-inducible factor 1α (HIF-1α) and the secretion of stromal cell-derived factor (SDF-1) in blood and expression in ischemic tissues were upregulated in JTMT and JTMT-MNC transplanted db/db mice, and in cultured JTMT EPCs, which were accompanied by marked amelioration of oxidative stress. However, MT-mediated elevation of SDF-1 and improvements of function in EPCs were all abrogated by siRNA knockdown of HIF-1α expression without effect on the anti-oxidative capacity of MT. Endothelial-specific MT elevation is sufficient to protect against diabetes mellitus-induced impairment of ischemia angiogenesis by promoting EPC function. The benefits of MT are predominantly mediated by upregulation of the HIF-1α/SDF-1 pathway.
The role of facility variation on racial disparities in use of hypofractionated whole breast radiotherapy.
Authors: Anna Mary Brown Laucis, Reshma Jagsi, Kent A. Griffith, Michael M. Dominello, Eleanor M. Walker, Eyad I. Abu-Isa, Joshua T. Dilworth, Frank Vicini, Paul George Kocheril, Cynthia Holland Browne, Melissa A. Mietzel, Jean M Moran, James Hayman, Lori J. Pierce
Journal: Journal of Clinical Oncology (2019)

141 Background: Concerns about racial disparities in the adoption of medical advances motivate investigation of the use of hypofractionated radiotherapy, a less burdensome and less costly approach that is efficacious for most patients with early-stage breast cancer. Methods: A prospectively collected statewide quality consortium database from 25 institutions was queried for breast cancer patients who completed hypofractionated (HF) or conventionally fractionated whole breast radiotherapy (RT) from 1/2012-12/2018. We used patient-level multivariable modeling to evaluate associations between HF use and race, controlling for patient and facility factors, and multilevel modeling to account for patient clustering within facilities. Results: Of 10,318 patients analyzed, 80% self-reported their race as White, 18% as Black, and 2% as Asian, similar to statewide and national distributions. 31% of Whites were treated at academic centers compared to 65% of Blacks and 65% of Asians. In 2018, HF was utilized in 75% of Whites versus 60% of Blacks and 68% of Asians. On patient-level multivariable analysis (see Table), Black and Asian race were significantly associated with a lower likelihood of HF receipt, despite accounting for treatment year, age, laterality, BMI, breast volume, comorbidities, stage, triple-negative status, IMRT use, academic center treatment, and 2011 ASTRO Hypofractionation Guideline eligibility. On multilevel analysis, race was no longer significantly associated with HF receipt. Conclusions: We observed thatBlack and Asian patients receive hypofractionated RT less often, despite more frequent treatment at academic centers. Multilevel modeling eliminated this disparity, suggesting that differences in facility-specific HF use may contribute. Further inquiry is needed to determine if reduction of facility-level variation may reduce disparities in accessing HF treatment.[Table: see text]
Complete Sequencing and Comparison of 12 Normal Karyotype M1 AML Genomes with 12 t(15;17) Positive M3-APL Genomes
Authors: John S. Welch, David Larson, Li Ding, Michael D. McLellan, Tamara Lamprecht, Cyriac Kandoth, Jacqueline E. Payton, Jack Baty, Christopher C. Harris, Cheryl F. Lichti, Robert S. Fulton, David J. Dooling, Daniel C Koboldt, Heather Schmidt, Qunyuan Zhang, John R. Osborne, Ling Lin, Michelle O'Laughlin, Joshua F. McMichael, Kim D. Delehaunty, Sean D. McGrath, Lucinda A. Fulton, Vincent J Magrini, Tammi L. Vickery, Todd Wylie, Jason Walker, Peter Westervelt, Michael H. Tomasson, Mark A. Watson, Sharon Heath, William D. Shannon, Rakesh Nagarajan, Daniel C. Link, Timothy Graubert, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson, Timothy J Ley
Journal: Blood (2011)
Phase 2 Trial of Single Agent Gedatolisib (PF-05212384), a Dual PI3K/mTOR Inhibitor, for Adverse Prognosis and Relapse/Refractory AML: Clinical and Transcriptomic Results
Authors: Jacques Vargaftig, Hassan Farhat, Lionel Ades, Adrien Briaux, Camille Benoist, Isabelle Turbiez, Norbert Vey, Sylvie Glaisner, Céline Callens
Journal: Blood (2018)
The Impact of Continuity of Care On Survival Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation; Improved Overall Survival in the Absence of Severe Graft Vs. Host Disease
Authors: Yasser Khaled, Melhem M. Solh, Robert B. Reynolds, Carlos Alemany, Raul Castillo, Sarah George, Linda Lukman, Ahmed Zakari, Lee Zehngebot
Journal: Blood (2012)
PD-1-Mediated T Cell Exhaustion Is Prevalent Among Patients with MPN-Associated Myelofibrosis Independent of JAK1/2 Inhibition
Authors: Ivo Veletic, Taghi Manshouri, Graciela M. Nogueras González, Sanja Prijic, Joseph E. Bove, Ying Zhang, Srdan Verstovsek, Zeev E. Estrov
Journal: Blood (2018)
Abstract 224: Sub-cytotoxic Levels of Heavy Metals Induce Pro-inflammatory Signaling in the Aortic Endothelium without Impairing Flow-Mediated Dilation in Rats
Authors: Pooneh Nabavizadeh, Sharina Ibrahim, Adam Fries, Jiangtao Liu, Ronak Derakhshandeh, Matthew L Springer
Journal: Circulation Research (2019)

Introduction: Acute exposure to tobacco or marijuana secondhand smoke (SHS) causes endothelial dysfunction. The identity of specific SHS constituents that cause vascular toxicity is unclear. Heavy metals are present in SHS and at elevated levels in the blood of smokers, and may mediate acute endothelial dysfunction through reactive oxygen species formation and decreasing NO bioavailability. We assessed the effects of exposure to cadmium, lead, mercury, and arsenic at levels present in the blood of human smokers on flow-mediated dilation (FMD) as a measure of endothelial function in rats. We also evaluated the effects of heavy metal exposure on intimal structure, protein localization pattern, and inflammatory gene expression in the aortic endothelium. Hypothesis: Sub-cytotoxic levels of heavy metals impair FMD, alter intimal structure, and induce pro-inflammatory signaling in endothelium. Methods: We injected rats (n=8/group) with heavy metal cocktail or vehicle intravenously and quantitated pre- and post-exposure FMDs measures defined as percent vasodilation of femoral artery after transient ischemia. We performed en face aorta immunostaining and assessed endothelial cell axis alignment, cell length ratio, and localization pattern of PECAM-1, VE-cadherin, and vimentin. We also quantified gene expression of key endothelial proteins in aorta homogenates. Results: FMD was not impaired in the heavy metal group (8.8±3.6(SD)% vs. 12.9±8.0%, p=.31 or controls (7.5±2.7% vs. 8.8±5.8%, p=.63). No significant difference in cell length ratio and endothelial x and y axes of alignment were detected between groups (p&gt;.8) and localization of PECAM-1, VE-cadherin, and vimentin in the aorta endothelium remained unaltered following heavy metal injection. However, expression of PECAM-1 and VE-cadherin was significantly lower in the heavy metal-treated rats, while VCAM-1 gene expression was significantly higher (p&lt;.05). Conclusion: Acute exposure to sub-cytotoxic levels of heavy metals can induce pro-inflammatory signaling in endothelium, which could potentially lead to vascular injury. However, FMD and endothelial structure remain unchanged by heavy metal exposure.
Abstract 787: Rose - A Novel Vascular Anti-inflammatory Agent
Authors: Mark C Arokiaraj, Eric Menesson
Journal: Circulation Research (2019)

Introduction: Inflammation is common in clinical practice and often results in significant complications. The study was performed in search of a novel anti-inflammatory agent for inflammation modulation which would be useful for cardiovascular disorders and various clinical scenarios. Methods: A crushed red rose extract was prepared from the petals, and it was processed for analysis. The extract was tested on HUVEC cells at various concentrations. By microscopic analysis of cells, a safe concentration was identified, and the levels below the safe limit were tested at 72 hours and seven days for selected cytokines secretion. Results: Majority of the tested Inflammatory cytokine secretion was reduced by the treatment of red rose extract on the cells. VEGF and angiogenic cytokine levels were reduced, but VEGF-R levels were maintained after the cell treatment. Below the safe concentration limit of the extract there were only minimal changes in the cytokines levels tested at various dilutions of the extract.The study results show a significant reduction in the secretion of anti-inflammatory cytokines by red rose extract. The effects of rose extract inhibited major inflammatory cytokines like IL-1, IL-2, RANTES, IGF-1, IL-8 etc. MCP 3 (CCL7) and PDGF BB levels were less than 10% of the baseline values. There was also a tendency in fall at 72 hours, and thereafter a rise at 7 day levels observed in the values of some cytokines. Conclusion: There is potential for a red rose extract treatment in the regulation of inflammatory cytokines secretion. Further studies need to be performed to identify the benefits and side effects profile.
Abstract 262: Gene Expression Profiling of Hypertrophic and Failing Cardiomyocytes Identifies New Players Involved in Heart Failure
Authors: Marta Vigil-Garcia, Charlotte J Demkes, Joep E Eding, Danielle Versteeg, Hesther de Ruiter, Monika M Gladka, Magdalena Harakalova, Alex Bossu, Aryan Vink, Folkert W Asselbergs, Toon van Veen, Eva van Rooij
Journal: Circulation Research (2019)

Pathological remodeling during cardiac disease is a detrimental response characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to heart failure. Genome wide expression analysis on full heart tissue have been instrumental for the identification of molecular mechanisms at play. However, these data so far were based on signals derived from all cardiac cell types and a more specific view on molecular changes driving cardiomyocyte hypertrophy and failure could aid in the development of therapies aimed at improving maladaptive remodeling. Here, we generated a cardiomyocyte-specific reporter mouse (Myh6-Cre-tdTomato) that we exposed to pressure overload by transverse aortic banding (TAB). Using Fluorescence-activated Cell Sorting (FACS) we collected both hypertrophic (one week after TAB) and failing (eight weeks after TAB) cardiomyocytes. Using these cells, we performed RNA-seq and obtained subsets of genes and pathways differentially regulated and specific for either the hypertrophic or failing stages. Among these upregulated genes we identified known marker genes for cardiomyocyte failure, such as Nppb and Myh7, but also identified genes that so far have not been linked to a failing state. RNA-seq on failing and healthy human heart samples confirmed the increased expression for several of these genes regulated during cardiomyocyte failure and allowed us to show an expressional correlation to NPPB/MYH7. Moreover, we could recapitulate the upregulation of these novel genes in stressed human induced-pluripotent stem cell (iPSC)-derived cardiomyocytes. We discovered that phosphofructokinase-platelet (PFKP) protein, a glycolytic enzyme, is strongly induced in human failing cardiomyocytes. Currently, ongoing studies are focused on defining the functional relevance of the novel failure related genes in stressed iPS-derived cardiomyocytes. Our findings suggest that cardiomyocyte-specific transcriptomic analysis allows for the identification of hypertrophic and failing gene expression profiles and helps to unveil novel genes relevant for heart disease.
Improved Relapse Rate, T Cell Recovery and Engraftment in High Risk Hematological Malignancies with Enhanced Lympho-Depletion Prior to T-Cell Replete Peripheral Blood Haploidentical (HID) Hematopoietic Stem Cell Transplantation (HCT)
Authors: Yasser Khaled, Joshua Boss, Joel Gradowski, Robert Bradley, Jason C. Chandler
Journal: Blood (2018)
Level of scientific evidence supporting NCCN guidelines: Is there evidence of progress?
Authors: Aakash Desai, Ronald S. Go, Thejaswi Poonacha
Journal: Journal of Clinical Oncology (2019)

14 Background: National Comprehensive Cancer Network (NCCN) guidelines are the most comprehensive and widely used standard for clinical care in oncology by clinicians and payors in the US. The level of scientific evidence in NCCN guidelines has not been studied since it’s last review in 2010. We describe the categories of evidence and consensus (EC) among the 10 most common cancers in the US as of 2019 and compare them with 2010 guidelines. Methods: We obtained the 2019 version of NCCN guidelines. The definitions for various categories of EC used were: Category 1 (high level evidence such as randomized controlled trials with uniform consensus), 2A (lower level of evidence with uniform consensus), 2B (lower level of evidence without a uniform consensus but with no major disagreement) and 3 (any level of evidence but with major disagreement). We compared our results with previously published results from 2010 guidelines. Results: Total recommendations increased by 77% from 1023 (2010) to 1818 (2019). Of the 1818 recommendations, Category 1, 2A, 2B and 3 EC were 7%, 87%, 6% and 0% while in 2010 they were 5%, 85%, 9% and 1% respectively. Recommendations with category 1 EC were found in lung (13%), prostate (11%), melanoma (8%), breast (7%), NHL (5%), kidney (2%), bladder (2%) and colorectal (2%) guidelines. Pancreatic and uterine cancer guidelines had no recommendations with category 1 EC. 19% of therapeutic recommendations were category 1 EC with the majority (65%) pertaining to initial therapy. Guidelines with highest proportions of therapeutic recommendations with category 1 EC were breast (30%), lung (10%), and kidney (10%) cancers. No category 1 EC recommendations existed in screening or surveillance. Although we found an increase in the total number of recommendations, the distribution of different types of categories of EC are largely similar to 2010. Conclusions: Recommendations in 2019 NCCN guidelines are largely derived from lower levels of evidence with uniform expert opinion. Despite the major advances in oncology in the past decade, this is largely unchanged. Our study underscores the urgent need and available opportunities to expand the current evidence base in oncology which forms the platform for clinical practice guidelines.
Abstract 771: Identification of Pathological Pathways in Hypertrophic Cardiomyopathy via Single Nuclei RNA-Sequencing
Authors: Amy Larson, Heather K Bowditch, Hassan Rastegar, Frederick Chen, Ethan Rowin, Marty Maron, Gordon Huggins, Michael T Chin
Journal: Circulation Research (2019)

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease, is characterized by left ventricular hypertrophy, is often asymmetric, and is unexplained by secondary causes. The molecular and cellular basis of this asymmetric hypertrophy is unknown. HCM has been thought of as a disease of the sarcomere, with mutations in more than a dozen sarcomere-associated proteins correlated with HCM. These mutations, however, exhibit large phenotypic heterogeneity with little correlation between mutation and severity. Treatment of HCM is limited and thus, understanding what drives the disease at the molecular and cellular level could lead to novel treatment strategies. Obstructive HCM is a severe form of the disease where the left ventricular outflow tract is obstructed. Patients with obstructive HCM often undergo septal myectomy surgery to remove the obstructive lesion. To understand the underlying mechanisms of obstructive HCM, we performed single nuclei RNA-sequencing on thousands of nuclei from 11 patients’ myectomy samples to determine the gene expression patterns in individual cells and identify the cell populations in those lesions. We used rejected donor hearts that do not exhibit any LV hypertrophy or have any major cardiovascular defects as control samples to compare the gene expression patterns in those cardiomyocytes to those in obstructive HCM lesions. We performed principal component analysis and hierarchical clustering on the RNA expression counts to identify the different cell populations in each dataset, and looked for cell populations that were present across all HCM datasets. This analysis revealed distinct cardiomyocyte populations in obstructive lesions. Differential gene expression analysis among these clusters revealed a minority cardiomyocyte population in the obstructive lesions that exhibited a relatively normal gene expression pattern, while the majority cardiomyocyte cluster exhibited a shift in gene expression to genes involved in growth pathways. This abnormal cardiomyocyte population was absent in the control datasets. These findings imply that obstructive lesions seen in HCM may arise from abnormal growth of a subset of cardiomyocytes that could possibly be targeted by novel therapeutics.