tbuckley/cabot-search huggingface dataset:
Abstract 9929: Inhibition of Receptor for Advanced Glycation End Products (RAGE) Reduces E-Cigarette-Induced Increase in Endothelial Permeability
Authors: Daniel D Han, Fengyun Xu, Ronak Derakhshandeh, Abel Huang, Adam Whitlatch, Rachel J Keith, Naomi Hamburg, Peter Ganz, Judith Hellman, Suzaynn Schick, Matthew L Springer, Leila Mohammadi
Journal: Circulation (2021)

Introduction: A growing body of research has linked e-cigarette (e-cig) use and vascular dysfunction. However, the molecular mechanism of endothelial function impairment from e-cig use is relatively unknown. We investigated how e-cig use affects endothelial permeability and its regulation by the receptor for advanced glycation end products (RAGE) pathway. Hypothesis: E-cig use increases endothelial permeability compared to both cigarette users and non-users via increasing ligands of RAGE. Methods: We recruited 120 healthy participants who either chronically use e-cigs (n=42), cigarettes (n=28), or no products (n=50), with no dual users. Serum levels of the RAGE ligand subunit S100A8 and the complete RAGE ligand calprotectin were quantified by Luminex and ELISA. Endothelial permeability was measured in cultured human lung microvascular endothelial cells (HMVEC-Ls) that were incubated in all participants’ sera individually by using electric cell-substrate impedance sensing (ECIS). 1 ug/mL of FPS-ZM1 (RAGE inhibitor) and TAK-242 (TLR4 inhibitor) diluted in DMSO were administered to HMVEC-Ls with individual sera. 200 pg/mL of calprotectin and DMSO were administered as positive and negative controls. Results: Incubation of HMVEC-Ls with e-cig users’ sera significantly increased endothelial permeability compared to sera from cigarette smokers and non-users. There was no significant difference in calprotectin serum levels, but S100A8 level was significantly and substantially higher in e-cig users’ sera than in smokers’ and non-user’s sera. Inhibition of RAGE, but not of TLR4, significantly reduced permeability only in e-cig users’ sera compared to vehicle. Conclusions: Endothelial permeability resulting from e-cig use relies on activation of the RAGE pathway and can be partially prevented by inhibition of RAGE.
NCMP-18. FIXED PTOSIS AS A SYMPTOM OF MYOSITIS SECONDARY TO CHECKPOINT INHIBITION
Authors: Ashley Aaroe, Sudhakar Tummala
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND A growing number of patients with cancer receive checkpoint inhibitor (CPI) based immunotherapy. Peripheral nervous system toxicities including myositis, myasthenia gravis and inflammatory neuropathy are distinct from their non immunotherapy-related equivalents, with unique clinical presentations and therapeutic considerations. METHODS Patients with CPI myositis and non-fatigable ptosis were identified, and clinical data was retrospectively extracted from the electronic medical record in compliance with MD Anderson Cancer Center Institutional Review Board guidelines. RESULTS 14 patients were identified. Average maximum creatine kinase (CK) was 3571 U/L (range 20-19,794). 9 patients had electromyography and nerve conduction studies documented in our system; all had electrodiagnostic evidence of myopathy and two had evidence of concomitant myasthenia gravis by electrodecrement. Two muscle biopsies revealed myositis with inflammatory T-cell infiltrate. 6 had positive anti-striated muscle antibody titers, 9/14 had concomitant myocarditis, 2 had hepatitis, 2 had pneumonitis and 1 had thyroiditis. All received high dose steroids, 11 received plasma exchange, 4 received rituximab, 4 received tacrolimus and 2 received tocilizumab. 7/14 patients died (50%). Mean time from initial neurology consultation for symptoms to death was 6.46 months (range .3-24). 5 patients had documented clinical stabilization or mild improvement on post-discharge follow-up. CONCLUSIONS While ptosis in patients receiving CPI can initially suggest myasthenia gravis, in patients with rapid onset and ultimately fixed deficits there should be a high index of suspicion for immunotherapy related restricted localized myositis. Myositis may coincide with other toxicities, such as myocarditis and pneumonitis, and can be fatal despite aggressive treatment. Deficits persist on post-discharge follow-up, suggesting protracted recovery for patients who survive.
Abstract 14018: lncRNA HAS2-AS1 Regulates Sunitinib-Induced Endothelial Dysfunction by Preserving the Endothelial Glycocalyx
Authors: Sarath Babu Nukala, Youjeong Kwon, Jordan Jousma, Gege Yan, Zhenbo Han, Yoonje Cho, Ning-Yi Shao, Won Hee Lee, Sang-Ging Ong
Journal: Circulation (2021)

Introduction: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiotoxicities. Sunitinib, a multi receptor tyrosine kinase inhibitor, has been reported to cause vascular toxicity. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their role in cardio-oncology remains poorly understood. Hypothesis: We hypothesize that lncRNAs may be involved in sunitinib-induced endothelial dysfunction and may represent a target class amenable for therapeutic action. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNA candidates that are dysregulated in human induced pluripotent stem cells-derived ECs (hiPSC-ECs) treated with sunitinib. We discovered sunitinib epigenetically repressed the expression of lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1). Downstream mechanistic studies revealed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced production of hyaluronic acid (HA) and aggrecan, two major constituents of the endothelial glycocalyx (EG), resulting in decreased viability, impaired angiogenesis, and increased vascular permeability. Supplementation of sunitinib-treated hiPSC-ECs with HA or overexpression of HAS2 restored the integrity of the glycocalyx and prevented sunitinib-induced endothelial dysfunction. These results were further validated in an in vivo mouse model of sunitinib-induced dysfunction as shown by reduced coronary flow reserve (CFR), degraded EG within the aorta, and increased vascular permeability. Conclusions: Our study established that deficiency of HAS2-AS1, coupled with reduced production of HA that is essential for proper glycocalyx formation, may be responsible for sunitinib-induced endothelial damage. Therapeutic strategies targeting the extracellular matrix components of the glycocalyx may represent a broad strategy to prevent sunitinib-induced endothelial dysfunction.
Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States
Authors: Pankit Vachhani, Jonathan A. Abbas, Evelyn M. Flahavan, Esprit Ma, Tao Xu, Huan Jin, Melissa Montez, Weize Huang, Anda Gershon, Grace Ku, Brannon Flores, Maika Onishi, Cat N. Bui, William Donnellan
Journal: Blood (2021)
Abstract 10966: Characterization of the Novel Cardiac Splicing Factor Slm2 in Heart Failure, Which Regulates Splicing of Titin
Authors: Jes-Niels Boeckel, Maximilian Nicolas Moebius-Winkler, Marion Müller, Sabine Rebs, Nicole Eger, Laura Schoppe, Rewatti Tappu, Karoline Elizabeth Kokot, Jasmin M Kneuer, Susanne Gaul, diana martins bordalo, alain lai, Jan Haas, Mahsa Ghanbari, Philipp Drewe-Boss, Martin Liss, Hugo A Katus, Uwe Ohler, Michael gotthardt, Ulrich Laufs, Katrin Streckfuß-Bömeke, Benjamin Meder
Journal: Circulation (2021)

Introduction: The versatility of the human genome is increased by the process of alternative mRNA splicing. Impaired splicing of the cardiac transcriptome is involved in the pathophysiology of heart failure. Especially, mutations in cardiac-specific splicing factors such as RBM20 cause severe forms of cardiomyopathy. Aim: We aimed to identify novel cardiomyopathy-associated splicing factors in the human heart using a score of myocardial tissue specificity including 53 human tissues and disease-associated expression changes in hearts of dilated cardiomyopathy (DCM) patients and controls. Methods &amp; Results: We found the splicing factor Slm2 to be significantly upregulated on the mRNA and protein level in the human myocardium of patients diagnosed with DCM (1.88 and 5.3-fold, both P&lt;0.05). Reduction of Slm2 in vivo resulted in DCM in zebrafish and sarcomere irregularity and altered calcium cycling in human cardiomyocytes. Sequencing of RNAs bound to Slm2 isolated from diseased human hearts, revealed the interaction of Slm2 with important mRNA transcripts encoding for sarcomere constituents, such as troponin I, troponin T, tropomyosin and titin. In the failing human myocardium, Slm2 bound to an alternative titin mRNA variant including retained introns. In detail, Slm2 interacted with exons of the titin mRNA encoding for the PEVK region, which mediates flexibility and contractile properties of the heart muscle. Using a splice reporter assay, which contains parts of titin’s PEVK region, we found Slm2 mediating the splicing process of intron retention. Conclusion: Slm2 is a novel splicing factor in the diseased human myocardium, maintaining cardiomyocyte integrity and function by binding and splicing essential sarcomere constituents including titin.
CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS
Authors: Anna Laemmerer, Dominik Kirchhofer, Sibylle Madlener, Daniela Loetsch-Gojo, Carola Jaunecker, Anna Schrempf, Johannes Reisecker, Petra Vician, Lisa Gabler, Lisa Mayr, Joanna Loizou, Irene Slavc, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.
Abstract 14327: Intramyocardial Delivery of an Imageable Theranostic Hydrogel Post Myocardial Infarction Alters Regional Strain and Reduces Remodeling in Chronic Porcine Model
Authors: Inga H Melvinsdottir, Dan Midgett, Shin-rong Lee, Selen Uman, John Kim, Ricardo Avendano, Stephanie Thorn, Taras Lysyy, Kristjan Arnarsson, Jay D Humphrey, James S Duncan, Jason A Burdick, Albert Sinusas
Journal: Circulation (2021)

Introduction: Myocardial infarction (MI) causes acute regional changes in stiffness and strain, resulting in pathological remodeling in the left ventricle (LV). Intramyocardial injection of hydrogel (HG) into the MI region may alter deformation and improve LV remodeling. Using high resolution cineCT (CCT) we evaluated changes in regional strain, global function, and geometry in chronic porcine MI model. Methods: Yorkshire pigs (n=12) subjected to 90 min balloon occlusion and reperfusion were randomized 5 days post MI to intramyocardial delivery of MI+HG (n=6) or MI only (n=6). Imageable HG was delivered in a 3x3 grid after assessing MI region with hybrid 201 Tl SPECT/CT. Contrast CCT was performed at baseline, day 5 (post MI before HG delivery), and day 12 (7 days post HG delivery) to assess end diastolic volume (EDV) and ejection fraction (EF). Custom software was used to calculate 3D myocardial Lagrangian strains on 6 HG animals and 3 MI only animals in remote, border (&gt;50% normal) and MI regions (&lt;50% normal). Results: At day 5 in both groups, EDV increased by 13.2% (p=0.016), LVEF decreased by 15.7% (p=0.008), and radial strain (E rr ) decreased in MI region by -0.11 (p=0.007). On day 12, EDV decreased by 8.3% in the MI+HG group but increased by 10.4% in the MI only group (p=0.003). LVEF increased significantly in the MI+HG group by 8.96% and was significantly greater than in MI only group (p=0.027) which had no significant changes. Average change in E rr between baseline and day 12 was not different between groups within the MI (p=0.13) or border region (p=0.67). However, average E rr did not decline in the MI+HG group (+0.029) but significantly declined in MI only group (-0.14, p=0.017) (MI+HG vs MI only; p=0.003), mirroring EDV changes. Conclusions: Intramyocardial delivery of HG 5 days post-MI resulted in greater improvement in E rr in remote region and global LVEF and a decrease in EDV suggesting reduced LV remodeling compared to MI only controls.
Modeling the Cellular Origin of EVI1 + MLL-AF9-Driven Acute Myeloid Leukemia (AML)
Authors: Hugues-Etienne Chatel-Soulet, Sabine Juge, Frederik Otzen Bagger, Alexandar Tzankov, Mineo Kurokawa, Jonathan Séguin, Juerg Schwaller
Journal: Blood (2021)
Abstract 11990: Insulin-Like Growth Factor Binding Protein 2 is a Novel Marker of Early Smooth Muscle Cell Phenotype Modulation in Thoracic Aortic Aneurysm
Authors: Albert J Pedroza, Alex R Dalal, Rohan Shad, Paul Cheng, Nobu Yokoyama, Ken Nakamura, William Hiesinger, Thomas Quertermous, Michael P Fischbein
Journal: Circulation (2021)

Introduction: Single cell RNA sequencing (scRNAseq) enables high resolution analysis of vascular smooth muscle cell (SMC) phenotype modulation in thoracic aortic aneurysm. Insulin-like growth factor binding protein-2 ( Igfbp2 ) expression by SMCs is activated early in a murine Marfan syndrome (MFS) aortic aneurysm model. IGFBP2 modulates IGF1 bioavailability and interacts directly with SMCs via integrins. We hypothesize that IGFBP2 is a marker of early SMC modulation in human aortopathy. Methods: Surgically resected aortic aneurysm tissue was collected from patients spanning the clinical spectrum of monogenic aortopathies ( ACTA2, FBN1, TGFBR1 (n=2), TGFB2, or SMAD3 variants). Tissues were digested and processed for scRNAseq. SMC clusters from all patients were jointly analyzed with pseudotemporal trajectory analysis to reconstruct the SMC phenotypic continuum. Primary MFS human (n=5) aortic root SMCs underwent IGFBP2 silencing via siRNA followed by bulk RNAseq. Results: scRNAseq identified two main SMC clusters, comprising 39% of all cells in the dataset, including a quiescent contractile SMCs and a modulated, synthetic subset. Pseudotemporal ordering generated a continuous ‘pseudotime’ scale inversely correlated with contractile gene (e.g., CNN1, MYH11) expression, modeling gradual de-differentiation in vivo . We identified similar markers of late SMC modulation (e.g., TNFRSF11B , MMP2, CYTL1, COL1A1 ) in patients of all genotypes. IGFBP2 expression showed comparatively earlier activation and peak with reduced expression late in pseudotime. Silencing IGFBP2 in human MFS SMCs in vitro significantly depressed contractile gene expression. Conclusions: SMC modulation occurs in consistent pattern across hereditary aortopathy subtypes. IGFBP2 activation occurs early in this trajectory, marking cells in phenotypic transition. IGFBP2 may promote contractile phenotype maintenance, presenting a novel pathway for potential therapies.
Association between BCL2, BCL2 E17, MCL1 and BAX Protein Expression, Bone Marrow Microenvironment Histological Features, Clinical Presentation, Therapeutic Outcome, and the Overall Survival in Newly Diagnosed Multiple Myeloma
Authors: Anita Skrtic, Ozren Jaksic, Slobodanka Ostojic, Mariastefania Antica, Petra Crnkovic, Josipa Skelin, Silvana Jurenec, Borna Habijanec, Delfa Radic Kristo
Journal: Blood (2021)
Abstract 12418: History of Physical or Sexual Abuse in Early Life and Risk of Preeclampsia
Authors: Jennifer J Stuart, Susan M Mason, Iris A Becene, Karestan C Koenen, Kathryn M Rexrode, Janet W Rich-edwards
Journal: Circulation (2021)

Introduction: Women with a history of abuse are more likely to develop chronic hypertension later in life. However, it is unknown whether early life abuse is associated with the risk of developing preeclampsia, a hypertensive disorder that complicates 5-7% of pregnancies. Hypothesis: We hypothesized that women with a history of physical or sexual abuse during early life would have a higher risk of developing preeclampsia during their first pregnancy. Methods: Nurses’ Health Study II participants reported on their histories of physical and sexual abuse in early life (childhood [0-10 years] or adolescence [11-17 years]) in 2001 and pregnancy complications (including preeclampsia) in 2009. Parous women with available information on early life abuse and pregnancy history comprised the study sample (n=46,212). Modified Poisson regression models were used to estimate risk ratios (RR) and 95% confidence intervals (CI) for the associations between physical and sexual abuse in early life and preeclampsia. Models were adjusted for maternal age at pregnancy, year of birth, race/ethnicity, body size (somatogram) at age five, and childhood socioeconomic status. Results: More than half of women (53%; n=24,212) reported a history of physical abuse in early life, with 9% reporting severe abuse. A history of sexual abuse in early life was reported among 33% of women (n=15,389); 22% reported touch only sexual abuse while 11% reported a history of forced sexual activity. History of severe physical abuse in early life was associated with a 37% increased risk of preeclampsia in first pregnancy (CI: 1.19-1.57) compared to no early life physical abuse. History of forced sexual activity in early life was associated with a 33% increased risk of preeclampsia in first pregnancy (CI: 1.19-1.48) compared to no early life sexual abuse. Histories of less severe physical abuse or touch only sexual abuse were not associated with preeclampsia risk. Conclusion: Women with a history of severe physical or sexual abuse in childhood or adolescence appear to have an increased risk of developing preeclampsia during pregnancy.
Biomarker‐based assessment of collagen cross‐linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the <scp>HOMAGE</scp> clinical trial
Authors: Susana Ravassa, Begoña López, João Pedro Ferreira, Nicolas Girerd, Erwan Bozec, Pierpaolo Pellicori, Beatrice Mariottoni, Franco Cosmi, Mark Hazebroek, Job A.J. Verdonschot, Joe Cuthbert, Johannes Petutschnigg, María U. Moreno, Stephane Heymans, Jan A. Staessen, Burkert Pieske, Frank Edelmann, Andrew L. Clark, John G.F. Cleland, Faiez Zannad, Javier Díez, Arantxa González
Journal: European Journal of Heart Failure (2021)

The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial.Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differencesspiro/control : -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m2 ; interaction pacross-tertiles = 0.005; interaction pthird tertile = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differencesspiro/control : -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction pacross-tertiles = 0.09; interaction pthird tertile < 0.001].These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).
Abstract 10061: Association of Frailty with In-Hospital and Long-Term Outcomes Among St-Elevation Myocardial Infarction Patients Receiving Primary PCI
Authors: Farshad Hosseini, Ian Pitcher, Mehima Kang, Martha MacKay, Joel Singer, Terry Lee, Kenneth Madden, John A CAIRNS, Graham C Wong, Christopher Fordyce
Journal: Circulation (2021)

Introduction: The impact of frailty on outcomes in a contemporary ST-segment-elevation myocardial infarction (STEMI) population is unclear. This study hypothesized that frail STEMI patients undergoing primary percutaneous coronary intervention (pPCI) have worse in-hospital and 1-year outcomes compared to non-frail STEMI patients. Methods: We retrospectively identified 600 STEMI patients who had received pPCI (2013 - 2016). A frailty index (FI) was determined using the health deficit accumulation model (Table 1). Frail patients were defined as those with a FI &gt; 0.25. The composite outcome comprised in-hospital heart failure, cardiogenic shock, re-infarction, major bleeding, stroke and all-cause mortality. A multivariable model adjusting for age and sex was performed. Results: Among 600 STEMI patients receiving pPCI, 67 (11.2%) were classified as frail. Compared to non-frail patients, frail patients were older (mean 80.3 vs. 75.8 years, p &lt; 0.001) and had a higher comorbidity burden. After adjustment, baseline frailty was independently associated with delayed reperfusion time, in-hospital all-cause mortality, and higher incidence of the composite outcome (Figure 1). Frailty was also associated with increased 1-year all-cause mortality and cardiovascular rehospitalization. Conclusions: Among STEMI patients receiving pPCI, 1 in 10 were frail. Frailty was associated with increased rate of the primary in-hospital composite adverse outcome, delayed reperfusion time and worse long-term outcomes. Efforts to routinely identify frail STEMI patients and to implement best practices to reduce the risk of adverse events in this vulnerable population are warranted.